Skip to main content

Advertisement

Micronutrients and many important factors that affect the physiological functions of toll-like receptors

Article metrics

  • 477 Accesses

Abstract

Background

Toll-like receptors (TLRs) are type I integral transmembrane receptors involved in recognition and conveying of pathogens to the immune system. These receptors are located either on cell surfaces or within endosomes. They are activated by specific ligand leading to the release of cytokines via signal transduction pathway. The excess production of these cytokines leads to disrupt the immune homeostasis. There are several factors regulating TLR expression and consequently affecting their functions. Among these are inflammation, cytokines, some cellular process, air pollution, depression, stress, some drugs, genetic polymorphism, nutrition, and micronutrients. Some micronutrients (vitamins and trace elements) may be considered as important TLR regulators, as they have immunomodulatory functions. Vitamins D, B12, and A; zinc; copper; and iron have important role on innate immune responses.

Aim of work

This review gives a brief idea on TLR family and attempts to cover the factors affecting the physiological functions of them.

Conclusion

Of many factors affecting TLRs functions are micronutrients. There is a shortage of researches concerning the effect of micronutrients deficiency on the function of TLRs, all of which focused on vitamin D but other vitamins have not got the same importance that they deserve. This orients our efforts to work at this point in the future.

Background

Toll-like receptors (TLRs) is a family of pattern recognition receptors (PRRs) and the main components of innate immunity (Kawai and Akira 2010). They can protect the host against a vast array of microbial infections (Zhang and Liang 2016). TLR activation stimulates signaling cascades by the host as a defense mechanism against invaders and to repair the damaged tissue (Wang et al. 2015). The binding of ligand to TLR resulted in the recruitment of several adaptor proteins and led to activation of many transcriptional factors which drive the expression of cytokine genes (Kawasaki and Kawai 2014). The released cytokines promote inflammatory responses, affect the physiological processes of the host body, and represent as the master contributors of many diseases (Bresnahan and Tanumihardjo 2014). There are many factors regulating TLR function; some of these factors include inflammation (Schroeder 2009), cytokine (Miettinen et al. 2001), cellular processes such as cell migration and apoptosis (Herrera et al. 2011), air pollution (Zhang and Gallo 2016), neuropsychiatric disorders (García Bueno et al. 2016), drugs (Bode et al. 2014a), genetic polymorphism (Tsujimoto et al. 2008), physical exercise (Cavalcante et al. 2018), aging (Shaw et al. 2011a), and nutritional status (Vidya et al. 2017). Good nutrition is required for the immune system to function properly (Mora et al. 2010). Micronutrients are needed in small amounts, but are essential for good health (Fuhrman 2014). Their deficiencies could impair innate immunity and increase susceptibility to infections (Chandra 2002). Vitamin D, B12, and A were evaluated for their importance as they are modulators of the immune system (Todorova et al. 2017) as well as some minerals such as zinc, copper, and iron that are essential for efficient immune function (Djoko et al. 2015). This review gives an overview of the TLR family and discusses the different factors affecting the physiological functions of TLRs.

Overview of Toll-like receptors

TLRs belong to type I transmembrane glycoproteins with 20-27 leucine-rich repeat motifs for ligand recognition at N-terminus, a single transmembrane helix and a conserved cytoplasmic Toll/Interleukin-1 (IL-1) receptor (TIR) domain at C-terminus for intracellular signaling transduction (Bryant et al. 2015). They can functionally recognize external pathogen-associated molecular patterns (PAMPs) and internal damage-associated molecular patterns (DAMPs) (Yu and Feng 2018). While external ligands include lipopeptides, lipopolysccharides (LPS), and bacterial flagellin (Ayres and Schneider 2012), internal ligands include hyaluronan, fibrinogen, heat shock proteins, and elements of damaged/fragmented DNA and RNA (Fig. 1) (Murad 2014). Currently, a total of 13 TLRs have been identified; TLRs 1–10 are expressed in humans despite the function of TLR10 being still unclear, in addition to TLR11 and 12 that are expressed in mouse (Moresco et al. 2011). TLRs are expressed in a variety of immune cells including dendritic cells, monocytes, macrophages, and B lymphocytes and non-immune cells such as epithelial cells, endothelial cells, and fibroblasts (Delneste et al. 2007). TLR1, 2, 4, 5, 6, and 10 are expressed largely on the cell surface while TLR3, 7, 8, and 9 are primarily expressed in the endosomes (Fig. 2) (Gay et al. 2014). The main characteristics that distinguish different TLRs are ligand specificity, signal transduction pathways, and subcellular localization (Singh et al. 2014). The molecular pathways of TLR signal transduction require two main adaptor proteins: myeloid differentiation factor 88 (MyD88) that is utilized by all TLRs except TLR3 and TIR-domain-containing adaptor-inducing interferon-β (TRIF) that is utilized by TLR3 and 4 (Kawasaki and Kawai 2014), resulting in the generation of pro-inflammatory and type 1 interferon through the activation of nuclear factor kappa-B (NF-κB) and interferon regulatory factors (IRFs) (Zhang and Liang 2016).

Fig. 1
figure1

Exogenous and endogenous ligand of TLRs

Fig. 2
figure2

Members and location of TLRs

Factors affecting the physiological functions of TLRs

Expression of TLRs by the host immune system is a crucial step in detection of infection (Hug et al. 2018). However, various factors control the extent of their expression according to the prevalence and regulation of these factors (Vidya et al. 2017; Singh et al. 2014), of these factors are inflammation, cytokines, some cellular processes, air pollution, depression, stress, glucocorticoids and other drugs, genetic polymorphism, physical exercise, aging, and nutritional status.

Inflammation

Inflammation is the biological response to harmful stimuli that can be a double-edged sword, although it plays a protective role in eliminating pathogenic factors, but uncontrolled inflammation is associated with several chronic diseases (Dong et al. 2016). It is an integral part of immune response (Schroeder 2009). Whatever the stimulus is, TLRs play a main role in the initiation and propagation of inflammation through the production of the pro-inflammatory cytokines (Zhang and Gallo 2016).

Cytokines

Cytokines have been shown to modulate the expression and activation of TLRs (Noppert et al. 2007). While TNF-α induces pro-inflammatory activity in TLR signaling, mainly in TLR2, and is involved in many illness (Gambhir et al. 2012; Schnetzke et al. 2015), IFN-α and IFN-β have immunomodulatory anti-inflammatory activities that are involved in some disease treatment (Rathinam et al. 2012). Viral infection of human macrophages induces TLR1, 2, 3, and 7 mRNA expression in type 1 interferon-dependent process (Miettinen et al. 2001).

Cellular processes

Some cellular processes have been found drastically to alter the gene expression of the cell thus affecting TLRs expression (Vidya et al. 2017). These processes include epithelial-mesenchymal transition (EMT) process, where the epithelial cells loss their cell polarity and cell-cell adhesion and the damaged cells alter their physical and chemical properties during tissue repair and wound healing (Polyak and Weinberg 2009); migration process, where the cells that do not undergo EMT migrate to the injury site (Lauffenburger et al. 1996); apoptosis that is induced by cellular or environmental stimuli where every apoptotic pathway involves the transcription of various genes (Brachat et al. 2000); and cell cycle where it regulates the gene associated with the shutdown of cell division (Herrera et al. 2011).

Air pollution

Exposure to air pollutants is found to modify innate TLR signalling (Bauer and Diaz-SD 2012). Air pollutants include particulate matter (PM)-associated biological components (bacteria, fungal spores, viruses, pollen and endotoxin), cigarette smoke (CS), and ozone (Fig. 3), which can work to stimulate a pro-inflammatory response in the respiratory air way mediated by TLR activation through either direct interaction with the receptor (Plummer et al. 2012) or via production of DAMPs (Lafferty et al. 2010). In respiratory tract infection, TLR2 and TLR4 signaling is upregulated in neutrophils of the air way (Bauer and Diaz-SD 2012) and alveolar macrophage (Cottey et al. 2010) with altered cytokine profile (TNF-α, IL-6) and type 1 interferon (IFN-α,β).

Fig. 3
figure3

Effect of air pollutants on TLRs signalling

Depression

Several studies revealed the effect of neuropsychiatric diseases in the expression/activity of TLRs (García Bueno et al. 2016). TLR3 and 4 expression was significantly increased in the brain of depressed subjects, and their overexpression caused the abnormalities in cytokine levels in the brain and peripheral samples of suicidal victims (Pandey et al. 2014). Furthermore, TLR4 was highly expressed in PBMC of patients with major depressive disorder (MDD), and this heightened expression was reduced following treatment and paralleled amelioration in depressive symptoms (Kéri et al. 2014). The responsiveness toward depressive status indicates that TLR4 activity could directly be involved in the pathophysiology of MDD (Liu et al. 2014). It was also revealed that the expression of TLR3, 4, 5, and 7 was high in animal model with MDD (Hung et al. 2014). TLR2 and 4 activation was associated with IL-1, IL-6, and TNF-α production in irritable bowel syndrome patients with depression (Jizhong et al. 2016). Enhanced peripheral TLR4 expression/activity has been described in subjects with neuropsychiatric diseases and in autistic children (García Bueno et al. 2016).

Glucocorticoids (GC) and other drugs

Natural and synthetic GC have immunosuppressive and anti-inflammatory activity for the majority of autoimmune and inflammatory diseases, despite dangerous side effects associated with GC therapy (Flammer and Rogatsky 2011). TLR expression is influenced by GC (Imasato et al. 2002). The activation of NF-κB is also inhibited by GC (Lancaster et al. 2005). TLR signaling is modulated by GC in liver cell line resulting in downregulation of TLR1 and 9 expression, suppression of pro-inflammatory cytokines, and upregulation of anti-inflammatory cytokines (Broering et al. 2011). Other drugs include antibiotics found to regulate the immune response in different degrees by modulating TLR1, 2, 4, and 6, and cytokine expression (IL-1β and IL-6) such as in sepsis inflammatory condition (Bode et al. 2014b). Antidepressants normalize the increased TLR3, 5, 7, 8, and 9 profile in MDD patients (Hung et al. 2016). Semapimod, an anti-inflammatory drug, is found to inhibit TLR4 and 9 signaling in an experimental model (Wang et al. 2016). Estradiol and progesterone is found to modulate TLR1, 2, 3, 4, 5, and 6 gene expression in human fallopian tube cell line (Zandieh et al. 2016).

Stress

TLR4 mRNA in the rat brain has been shown to upregulate in response to different protocols of stress exposure such as repeated social defeat, restraint stress, and chronic mild stress. NF-kB activation and cellular oxidative/nitrosative damage are reduced when TLR4 pathway was disturbed (Gárate et al. 2013; Gárate et al. 2014). TLR4 is involved in immune changes as a result of endogenous stress signals (Liu et al. 2014). Activation of peripheral and brain TLR4 triggers sickness behavior, and its expression is a risk factor of depression (Hines et al. 2013). Stress exposure elicits a NF-kB pro-inflammatory response in brain driven by a prior activation of TLR4 (Trotta et al. 2014).

Genetic polymorphisms

Genetic polymorphisms in TLR4 gene affect sensitivity to allergens (Zhang et al. 2011). The reduced asthma risk may be correlated with TLR4 gene as indicated by the association between TLR4 polymorphisms and the development of asthma (Tizaoui et al. 2015). The polymorphisms of both TLR4 and TNF-α may increase the risk of developing tuberculosis after exposure to mycobacterium (Jafari et al. 2018). In addition to TLR4, variants of TLR2 gene affect lung function in children with asthma (Klaassen et al. 2013). Polymorphisms of TLR2 and 4 affect the risk of infectious complications in patients with acute myeloid leukemia subjected to chemotherapy (Schnetzke et al. 2015).

Physical exercise

The effects of physical exercise on TLR expression and on inflammatory cytokines production have been demonstrated in few studies, till now it is still an area of controversy. Furthermore, the effect of acute exercise on TLR expression has received even less attention (Cavalcante et al. 2018). Early studies state that prolonged strenuous exercise causes suppression of both TLR expression and function. Individuals who participated in intensive exercise training have an increased susceptibility to upper respiratory tract infections (Peters et al. 1993). It is possible that the exercise-induced suppression in TLR expression and function was involved in TLR signaling (Lancaster et al. 2005). Both acute aerobic and chronic resistance exercise have been reported to decrease monocyte cell surface expression of TLR4 (Stewart et al. 2005), while (McFarlin et al. 2004) found no effect of an acute resistance exercise on monocyte cell surface TLR4 expression. The difference in these findings might be related to the age of the subject and severity/duration of the exercise stimulus (Gleeson et al. 2006). Exercise may act as an anti-inflammatory modulator through different processes including cytokines and TLR signaling (Mikkelsen et al. 2017). While animal studies globally showed a marked downregulation of TLR2 and 4 after endurance exercise accompanied with a reduction in the activation of NF-κB signaling and cytokine production, evidences in human were not strong enough to conclude the same effect (Rada et al. 2018).

Aging and immunosenescence

Aging is a complex phenomenon that leads to many changes in the physiological systems of the body. Immunosenescence is one of the most important changes that occur in all elements of the immune system (Montgomery 2016). It is associated with a low-grade inflammation, inflammaging (Fulop et al. 2017). Aging is also associated with the emergence of many diseases via inflammaging, for example, innate immune response in elderly people is impaired and the susceptibility to infection increased as in pulmonary infection (Boe et al. n.d.). The function of human TLRs is impaired with aging. Age-associated alteration in innate cells appeared to have reduced TLR signaling through NF-κB resulting in decreased production of inflammatory cytokine and altered chemotaxis responses as well as decreased phagocytosis and antigen presentation capacity (Shaw et al. 2011b).

Nutrition

Nutrition, (Fig. 4) (https://foodandhealth.com/make-a-nutrition-poster/) is one of the various factors that govern TLR expression (Vidya et al. 2017). Some diets were found to be important sources of increased TLRs inflammatory stimulants (So and Ouchi 2010).

Fig. 4
figure4

Nutrition; an important factor affecting TLRs

Processed food containing microbial stimulants

Food containing inflammatory stimuli was the main interest of scientist Clett Erridge. He assessed the presence of TLR2 and 4 microbial stimulants bacterial lipopeptides and LPS, respectively, in a variety of common foodstuffs. He detected the highest levels of TLR-stimulants in processed foods, minimally processed vegetables (MPV), and dairy products while fresh fruits and vegetables contained minimal or undetectable amounts (Erridge 2010). The amount of TLR2 and 4 stimulants in food extracts is found to promote insulin resistance and atherosclerosis in an animal model and correlated with their capacity to induce TNF-α (Erridge 2011). In a more recent study, he demonstrated that the pro-inflammatory stimulants of TLR2 and 4 in some processed foods were associated with the risk of cardiometabolic diseases (Erridge et al. 2016). In addition, bacterial polysaccharides identified in eatable plants such as apple or ginseng were found to interact also with TLR4 (Zhang et al. 2016).

High-fat diet

TLR2 and TLR4 have been involved in inflammatory responses to high-fat diet (HFD)-induced obesity in rats (Wan et al. 2014; Lee et al. 2015). HFD resulted in decreased TLR2 and 4 expression on CD14 monocytes and impaired their function which was detected by the increased secretion of IL-1β, IL-6, and TNF-α from PBMCs in human (Wan et al. 2014). HFD induced TLR4-dependent macrophage cell activation with significant increase in NF-κB and IL-6 (Lee et al. 2015). The expression of TLR2 and 4 were upregulated, and the translocation of NFκB into the nucleus was activated in high cholesterol/HFD fed mice lung. In vitro, oxidized low-density lipoprotein (oxLDL) could directly upregulate the expression of TLR2 and 4 in lung epithelial cell lines (Fang et al. 2017).

Non-microbial stimulants

Plant polyphenols from cranberries, tea, and grapes are non-microbial activators that inhibit LPS-induced NF-kB activation in TLR4 signaling (Delehanty et al. 2007). W-3 polyunsaturated fatty acids (PUFA) were found to suppress the excessive inflammatory response by decreasing the expression of TLR2 and 4 and some related inflammatory factors in PBMCs of patients with severe multiple trauma (Yi et al. 2011). Saturated fatty acids (SFAs) are also non-microbial activators of the TLR-signalling pathways (Lee et al. 2015; Erridge and Samani 2009). Lauric acid of coconut oil activates the TLR4 and regulates the expression of several pro-inflammatory genes (Wong et al. 2009; Calder 2013; Rocha et al. 2016). A similar effect was also described for the palmitic and stearic acids of palm oil and Shea butter, respectively, whose regulation of pro-inflammatory genes occurs primarily via the TLR4/NF-κB signalling pathway (Choi et al. 2012; Eguchi et al. 2013). Non-bacterial polysaccharides have also been discovered in fungi and algae, including glucans isolated from oat, barley, and wheat which were found to stimulate TLR4 to prevent diseases (Ina et al. 2013; Zhang et al. 2014). As glucans, Β-fructans were also found to activate TLR2/NF-κB in human immune cells (Ende 2013; Vogt et al. 2013). In a cell culture, β-fructans protected the integrity of intestinal epithelial monolayers (Vogt et al. 2014). Pectins, such as lemon pectin, activate TLR2 and TLR4 and increase intestinal epithelial function in cellular cultures via activation of MyD88/NF-κB pathway (Vogt et al. 2016).

Selected micronutrients

Some micronutrients (vitamins and trace elements) can influence several components of innate immunity in addition to their various physiological roles (Chandra 2002), “they may be considered as important TLRs regulators,” as they have immunomodulatory functions (Erickson et al. 2000). Of micronutrients; vitamins D, B12, and A; zinc; copper;and iron (Mora et al. 2010; Vázquez et al. 2014; Kogan et al. 2017) have important role on innate immune responses (Fig. 5) (https://www.thaqafnafsak.com/2015/10/htmI/).

Fig. 5
figure5

Selected micronutrient that influence TLRs

Vitamins

Vitamin D

Vitamin D is found to influence both innate and adaptive immunity (Wei and Christakos 2015). The discovery of vitamin D receptors (VDR) (Kamen and Tangpricha 2010) and its activating enzyme 1-α-hydroxylase (Prietl et al. 2013) attracted researchers’ attention to focus on its importance. VDR are expressed in many cells of immune system including macrophage, dendritic cells, T cells, and B cell (Korf et al. 2014). Vitamin D received its importance as it is well involved in promoting innate immune response, stimulating cell proliferation and differentiation (Myszka and Klinger 2014) and downregulating dendritic cell responses (Chen et al. 2007; Jeffery et al. 2009). The immunomodulation of vitamin D includes attenuation and stimulation of Th1 and Th2 cell proliferation (Battault et al. 2013). Vitamin D was reported to suppress the Th1 cells by inhibition of pro-inflammatory (IL-1, TNF-α, IFN-γ) secretion (Pettengill et al. 2014). Regarding Th2, vitamin D enhances the synthesis, secretion, and release of anti-inflammatory cytokines (IL-4 and IL-10) (Bivona et al. 2017). Deficiency in vitamin D causes pro-inflammatory stress (Barker et al. 2013), which increased risk of infections, chronic inflammation, and autoimmune diseases (Slusher et al. 2015; Vanherwegen et al. 2017).

  • The source of vitamin D

The source of vitamin D can be either synthesized in the human skin after exposure to ultraviolet sunlight (Bendik et al. 2014) or obtained from very few foods such as fatty fish, cod liver oils, beef liver, and eggs (Smith et al. 2017).

  • Regulatory role of vitamin D on TLRs

The link between TLRs and vitamin D-mediated innate immunity has been reported (Fig. 6) (Arababadi et al. 2018). In an early study, the accurate signal system by which TLR activation induces expression of VDR and 1-α-hydroxylase remains obscure (Liu et al. 2006). Recently, it was revealed that vitamin D effects on innate immunity were predominantly linked to Toll-like receptors (Sadeghi et al. 2016). The innate immune response includes an obvious inflammatory component, and vitamin D opposed these events by promoting over response to PAMPs through downregulation of TLRs on monocytes. CD14, a co-receptor of TLR4 that recognizes LPS, is vigorously stimulated by vitamin D (Wang 2004). The upregulation of VDR by LPS may further enhance vitamin D (Tang et al. 2012). It was proved that vitamin D influence on TLR4 in response to ligand leads to antigen presenting cell activation (Gambhir et al. 2012), and it was observed that vitamin D enhances innate antiviral immune response by upregulating IFN-β expression in human hepatocytes with hepatitis C virus (HCV) (Gal-Tanamy et al. 2011). The activation of vitamin D decreased the inflammatory status in innate immune response (Calton et al. 2015). Vitamin D has been found to regulate IL-10 secretion from Tregs where TLR9 was highly expressed. In vitro study has shown that vitamin D was found to downregulate INF-γ gene expression through the adjustment of gene activity (Urry et al. 2009), leading to the decrease of pro-inflammatory INF-γ release (Ragab et al. 2016). Regarding bacteria fighting, activation of TLRs triggers antimicrobial activity against intercellular bacteria, by upregulating VDR expression and the 1-α-hydroxylase genes, leading to the induction of antimicrobial peptide cathelicidin that is responsible for killing bacteria, while deficiency of vitamin D negatively impacts that mechanism (Liu et al. 2006), besides it induces autophagy and phagocytosis in human monocytes/macrophages (Yuk et al. 2011). Vitamin D can inhibit the NF-κB signaling pathway after TLR2 and TLR4 stimulation in patients with tuberculosis and HIV co-infection (Coussens et al. 2014). In autoimmune diseases, monocyte exposure to vitamin D causes downregulation of TLR2, 4, and 9 expression and reduces IL-6 secretion (Sadeghi et al. 2016). The expressions of TLR2 and 4 on monocytes of active Behcet’s disease and type 1 diabetes patients were negatively associated with their vitamin D levels, and TNF-α synthesis was also decreased upon TLR stimulation in vitamin D-treated monocytes (Do et al. 2008; Devaraj et al. 2011).

Fig. 6
figure6

The relation between vitamin D and TLRs

A marked increase in IL-6, TNF-α, and IFN-α cytokine profile was shown in vitamin D-deficient participants after TLR2 stimulation, and this response was reversed after supplementation with vitamin D (Ojaimi et al. 2013). Adding of vitamin D to the cell culture of PBMNs isolated from healthy adults after stimulation with the bacterial ligands showed a significant reduction in inflammatory cytokines TNF-α, IFN-γ, and IL-1β as well as the chemokine IL-8 production while the anti-inflammatory response was promoted through the upregulation of IL-10 (Hoe et al. 2016). Vitamin D was found to downregulate mRNA overexpression of TLR2 and 4 and pro-inflammatory cytokines; TNF-α in cultured human keratinocytes lead to the activation of these cells for further innate immune responses to pathogens (Schauber et al. 2007). It was revealed that vitamin D deficiency and TLR activation were the contributing factors in the pathogenesis of cardiovascular diseases (Adamczak 2007).

Vitamin B12

Vitamin B12 is an essential micronutrient that improves overall function of the immune system (Vázquez et al. 2014). It has been known as anti-inflammatory immunomodulator (Todorova et al. 2017; Hosseinzadeh et al. 2012). It prevents excessive expression and synthesis of inflammatory cytokines in human (Badawi et al. 2013). Deficiency in B12 resulted in reduced white blood cells (Ghatpande et al. 2016) and increased susceptibility to infection and diseases (Maggini et al. 2007). B12 deficiency increased the level of TNF-α in anemic adults (Killen and Brenninger 2013) and in children (Ghatpande et al. 2016).

  • Dietary sources of vitamin B12

Vitamin B12 cannot be obtained from plants or sunlight (Boran et al. 2016), but it should be ingested from animal proteins such as meat, poultry, fish, eggs, milk, and most other dairy products (Kwak et al. 2010); therefore, vegans are at risk for B12 deficiency (Pawlak et al. 2013).

Vitamin A

Since early time, vitamin A has been known as anti-infective vitamin as it is crucial for immune system to function properly (Langan et al. 2014). It helps to maintain the structural and functional integrity of the skin (Green and Mellanby 1928) and mucosal cells of eye and respiratory, gastrointestinal, and genitourinary tracts (Mora et al. 2008). It is also important to the normal function of several types of innate immune system, including NK cells, macrophages, and neutrophils (Sun et al. 2007). In severe inflammation, the body cells increased their abilities to convert retinol form into retinoic acid (RA), the active form (Combs 2008). The inability to make this conversion is considered as a risk factor for increased susceptibility to infection (Spinas et al. 2015). During immune responses, enzymes metabolizing vitamin A are induced in dendritic cells (DCs) and in cells of intestinal mucosa to induce RA production. As a result, the induced RA regulates gene expression, differentiation, and function of immune cells including neutrophils, macrophages, and DCs (Harrison 2005; Hammerschmidt et al. 2011). Vitamin A deficiency (VAD) impaired the components and the inflammatory responses of innate immunity (Kim 2011; Czarnewski et al. 2018). It reduced mucosal epithelial regeneration and killing activity and number of NK cells, as well as the function of neutrophils and macrophages (McDowell et al. 1984). In addition, VAD results in altered cytokine signaling which would affect inflammatory responses of innate immunity (Blomhoff et al. 1992). The risks of VAD can be reversed by supplementation (Semba et al. 2004).

  • Dietary sources of vitamin A

Retinoid forms of vitamin A are provided by animal source of foods, including milk, cheese, yogurt, eggs, livers, shrimp, salmon, sardines, tuna, and chicken, while carotenoid forms are provided by most colored fruits as apricot, papaya, and mango (Semba 2012) and vegetables as sweet potato, tomatoes, spinach, pumpkin, carrots, broccoli, peppers, Kale, and pea (Imdad et al. 2017; Fennema 2008). Fish oil, cod liver oil, and butter contain also high concentration of vitamin A (Tang et al. 2055). Red palm oil (RPO) has been investigated for preventing VAD where low level of PRO intake (≤ 8 g RPO) could increase serum retinol concentrations (Solomons 2006). Sweet potato is a rich source of β-carotene, which the body converts into vitamin A and can treat VAD (Roos et al. 2010).

  • Regulatory role of vitamin A on TLRs

Many clinical trials revealed that vitamin A supplementation downregulate the secretion of pro-inflammatory cytokines (TNF-α, IL-6) by macrophages in response to particular pathogen infections (Blomhoff et al. 1992; Dong et al. 2017). Although VAD resulted in altered cytokine signaling which would affect TLRs response, the exact mechanism by which vitamin A can regulate TLRs is still unknown, and this may be attributed to the fact that vitamin A was tightly to be linked in maintaining the structural and functional integrity of mucosal cells, and for the normal functioning of immune cells including macrophages, NK cells, and neutrophils (McDowell et al. 1984; Low et al. 2017).

Trace elements

Zinc, copper, and iron are essential trace elements for optimal innate immune function, and their nutritional deficiency leads to increased susceptibility to bacterial infection (Djoko et al. 2015).

Zinc

Zinc is an essential micronutrient that is important for maintaining normal physiological functions (Kogan et al. 2017). Zinc has received the most attention for its ability to support immune function (Long et al. 2004). It is needed for basic cell activities such as cell growth, differentiation, and survival (Bhaskaram 2011). Appropriate levels of zinc are required for the proper functioning of the immune system while excessive zinc intake has shown negative effects on it (Wessels et al. 2017). In innate immunity, zinc keeps the epithelial membrane of natural barrier structure and function (Hojyo and Fukada 2016). Acute zinc deficiency causes a decrease in innate immunity (Gruber and Rink 2013; Rink and Gabriel 2000), while chronic deficiency increases inflammation (Maares and Haase 2016; Barnett et al. 2016).

Zinc deficiency received the most important impact on children’s resistance to infectious diseases including the risk, the recurrence, and the severity of infection leading to diarrhea (Bonaventura et al. 2015). Deficiency in zinc impaired the complement system; reduced cytotoxicity of natural killer cells, phagocytic activity of neutrophils, chemotactic responses of both macrophages and monocytes (Gammoh and Rink 2017); and reduced the ability of immune cell to generate oxidants that kill invading pathogens (Krebs 2013; Ibs and Rink 2003). These effects were readily reversible by zinc supplementation (Krebs 2013; Prasad et al. 2011). The main sources of zinc are red meat, poultry, and sea food (Prasad 2013). Nuts, legumes, and wholegrain cereals (Buracco et al. 2018) and dairy products are rich in zinc (Solomons 2001).

  • Regulatory role of zinc on TLRs

There is growing evidence that zinc acts as a signaling molecule, involved in a variety of signaling cascades such as TLR signaling of innate immunity (Bhaskaram 2011). Zinc can modulate inflammation through TLR signaling at different levels and pathways (Maret and Sandstead 2006). The stimulation of TLR4 by LPS changed the expression of zinc transporters in DCs and thereby decreasing intracellular free zinc (Mocchegiani et al. 2013). Zinc is known to inhibit NF-κB activation which in turn decreased the production of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6 (Brieger et al. 2013; Kitamura et al. 2006). It may contribute to the numbers and function of monocyte, macrophage, and NK-mediated host defense through promoting and regulating TLR responses (Haase and Rink 2009; Liu et al. 2013). In monocytes, it has been observed that TLR4 activation initiates zinc-mediated signaling in a MyD88- and TRIF-independent manner (Liu et al. 2013).

Copper

Copper is required for different metabolic processes (Stafford et al. 2013), but can be toxic when present in excess (Djoko et al. 2015). It is central to maintain immune system (Haase and Rink 2014). Like zinc, copper is a co-factor for Cu-Zn-superoxide dismutase (SOD) enzyme that is required to maintain immune function (Petris et al. 2003), by catalyzing the production of H2O2 from superoxide in neutrophils and monocytes (Badawi et al. 2013). In addition, copper has been found to modulate macrophage response (Veldhuis et al. 2009). The regulatory effect of copper on macrophages antimicrobial pathways was demonstrated by in vitro studies (Steiger et al. 2010). The elemental analysis of macrophage phagosomes showed that the macrophage-activating cytokines such as TNF-α and IFN-γ promoted the accumulation of copper within the phagosomes of Mycobacterium avium-infected macrophages (Halfdanarson et al. 2008).

Copper deficiency is associated with impaired development of immune cells such as phagocytic cells (Babu and Failla 1990). Early studies recorded that mild copper deficiency in humans and animals resulted in (Wagner et al. 2005; White et al. 2009; Xin et al. 1991). Copper deficiency also resulted in a reduction in the ability of leukocytes to kill ingested microbes that may increase the susceptibility to infection (Percival 1995). The numbers of myeloid precursors in the bone marrow were decreased in copper-deficient patients, as well as vacuolization of these cells (Veldhuis et al. 2009). The best dietary sources of copper include seafood, livers, legumes, whole grain, nuts (including peanuts, hazelnut, and pecans), grains such as wheat and rye, sesame seeds, and fruits including lemon, oranges and raisins (Percival 1998). Cereals, potatoes, peas, red meat, mushrooms, vegetables (like kale, parsley, and turnip), and fruits such as coconuts, papaya and apples were found to contain high quantities of copper (Lazarchick 2012).

  • Regulatory role of copper on TLRs

The direct contribution of copper in macrophage antimicrobial responses was found through regulating innate TLR responses (Haase and Rink 2009). Recently, it was found that Cu/Zn-Mt supplementation decreased the mRNA levels of TLR4 and its downstream signals in MyD88 signaling pathways upon Escherichia coli LPS-induced intestinal injury in weaned piglets, and these finding lead the author to suggest that dietary Cu/Zn-Mt attenuated this injury by alleviating intestinal inflammation, influencing TLR4-MyD88 signaling pathway (Mason 2016).

Iron

Iron is crucial for main cellular functions. It is essential for proper functioning of the immune system (Jiao et al. 2017). It is required to build effective immune responses against invading pathogens such as the differentiation and proliferation of T lymphocytes and production of reactive oxygen species (ROS) to kill pathogens (Beard et al. 2007). Deficiency in iron increases infection susceptibility and causes the reduction in number and action of neutrophils (Doherty 2007), but excessive iron is highly toxic as it increases the severity of some pathogens (Katona and Katona-Apte 2008). Iron is essential for both host and pathogen, and complex systems of acquisition and utilization have evolved in a competition or a battle in between, indicating that iron is a key regulator of host-pathogen interactions, the concept of “nutritional immunity” (de Pontual 2017). Iron sequestration is a vintage host defense against invading pathogens in animal (Johnson and Wessling-Resnick 2012; Weinberg and Weinberg 1995) and in human innate immunity to limit their pathogenicity, where serum iron decrease while iron-storage ferritin increase, keeping iron away from pathogens however available it is to the host (Ong et al. 2006; Cassat and Skaar 2013). Well-adapted microbes have in turn developed techniques to abstract iron from host storage proteins or to interfere with host iron sequestration (Zackular et al. 2017; Ganz and Nemeth 2015). Food rich in iron include spinach, fresh parsley, lettuce, broccoli, cabbage, and spices such as thyme, cumin, turmeric, or cinnamon. Beef, lamb, chicken, turkey, and seafood as oysters and octopus are rich in iron. Soybeans, lentils, and beans are considered also to be food high in iron (Verbon et al. n.d.)

  • Regulatory role of iron on TLRs

Iron was recognized as an extracellular signalling molecule that affects innate immune response via TLR-mediated mechanism (http://wiki-fitness.com/iron-rich-foods/). Macrophages are essential for cellular iron recycling via TLR2 and 4/MyD88-dependent pathway (Figueiredo et al. 2007). TLR signaling mediates hypoferremia-induced activation of innate response by marked iron reduction coupled with iron sequestration within macrophages (Balounová et al. 2014). A strong correlation between enhanced bacterial colonization of the upper respiratory tract of MyD88-deficient mice and the inability to lower serum iron was early described (Layoun et al. 2012). Increased TNF-α and IFN-β is associated with the impaired TLR4 signaling in mice-deficient iron upon LPS stimulation (Albiger et al. 2005). TLR4 plays a role in patients with hereditary hemochromatosis (Wang et al. 2009). TLR2 and 4 upregulated the hepcidin (a key regulator for iron absorbed from diet and iron recycling by macrophages) expression in macrophages via MyD88 and TRIF signaling pathway (Balounová et al. 2014). The regulation of iron accumulation in macrophages by hepcidin may affect the levels of pro-inflammatory cytokine production (Krayenbuehl et al. 2010). Mice lacking MyD88 accumulate iron in their livers in response to dietary iron loading as they are unable to control hepcidin levels (Layoun and Santos 2012; Layoun et al. 2018). Iron potentiated the inflammatory response to LPS by damaging mitochondrial homeostasis and increasing the mitochondrial ROS levels upon incubation with macrophage or injection to mice (Hoeft et al. 2017).

Conclusion

There are several factors affecting the physiological functions of TLRs. Among these are inflammation, cytokines, air pollution, stress, depression, some drugs, genetic polymorphism, nutrition, and micronutrients. Vitamins and trace elements may be considered as important TLR regulators; however, the area concerning the effect of their deficiencies on the function of TLRs is still with less progress. Unlike vitamin D, other vitamins have not yet received the attention that they deserve regarding their effect on the physiological function of TLRs despite their modulatory role to maintain the immune system, and this area remains a point of research in the future.

Recommendation

  • Our main concern should be focused on maintaining TLRs functioning and keeping the integrity of innate immune system, and this could be achieved by avoiding all negative factors including stress, depression, and pollution.

  • Eating healthy food, doing regular exercise, and supplementation with essential micronutrients are recommended to support innate proper immune response.

  • Submitting projects on a wide scale for all governorates to study the effect of micronutrient deficiency on innate immunity, especially in childhood.

  • Producing an awareness program to orient people’s attention to the importance of vitamins and minerals and their impacts on immune system and if it is possible to get the media involved.

  • Nutrition education is a concept that has been taught in many countries as in UK. In schools, there have nutrition classes to teach the importance of healthy food, food pyramid, vitamins, minerals, and physical activity and why processed food, high calories, and malnutrition should be avoided (Lean 2015). The hopeful success is to apply a program such that in Egypt.

Availability of data and materials

Not applicable

Abbreviations

CD14:

Cluster of differentiation 14

CS:

Cigarette smoke

DAMPs:

Damage-associated molecular patterns

DCs:

Dendritic cells

EMT:

Epithelial-mesenchymal transition

GC:

Glucocorticoids

HCV:

Hepatitis C virus

HFD:

High-fat diet

HIV:

Human immunodeficiency virus

IFN-α:

Interferon alpha or other symbols

IL-1:

Interleukin 1 or other numbers

IRFs:

Interferon regulatory factors

LPS:

Lipopolysccharides

MDD:

Major depressive disorder

MyD88:

Myeloid differentiation factor 88

NF-κB:

Nuclear factor kappa-B

NK:

Natural killer cells

oxLDL:

Oxidized low-density lipoprotein

PAMPs:

Pathogen-associated molecular patterns

PBMCs:

Peripheral blood mononuclear cells

PM:

Particulate matter

PRRs:

Pattern recognition receptors

PUFA:

Polyunsaturated fatty acids

RA:

Retinoic acid

ROS:

Reactive oxygen species

RPO:

Red palm oil

SFAs:

Saturated fatty acids

SOD:

Cu-Zn-superoxide dismutase

TIR:

Toll/interleukin-1 (IL-1) receptor domain

TLR1:

Toll-like receptor 1 or other numbers

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor alpha or other symbols

TRIF:

TIR-domain-containing adaptor-inducing interferon-β

VAD:

Vitamin A deficiency

VDR:

Vitamin D receptors

References

  1. Adamczak DM (2007) The Role of Toll-Like Receptors and vitamin D in cardiovascular diseases—a review. Int J Mol Sci. 18(11):E2252. https://doi.org/10.3390/ijms18112252

  2. Albiger B, Sandgren A, Katsuragi H, Meyer-Hoffert U, Beiter K, Wartha F, Hornef M, Normark S, Normark BH (2005) Myeloid differentiation factor 88-dependent signalling controls bacterial growth during colonization and systemic pneumococcal disease in mice. Cell Microbiol. 7(11):1603–1615

  3. Arababadi MK, Nosratabadi R, Asadikaram G (2018) Vitamin D and toll like receptors. Life Sci:30146–30142. https://doi.org/10.1016/j.lfs.2018.03.040

  4. Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol. 30:271–294

  5. Babu U, Failla ML (1990) Respiratory burst and candidacidal activity of peritoneal macrophages are impaired in copper-deficient rats. J Nutr. 120:1692–1699

  6. Badawi A, Garcia-Bailo B, Arora P, Al Thani M, Sadoun E, Farid M and El-Shohemy A. The utility of vitamins in the prevention of type 2 diabetes mellitus and its complications. A public Health Perspective, ch. 1: 1- 16. In: Diabetes Mellitus - Insights and Perspectives. Edited by Oluwafemi O. Oguntibeju; Publisher: In Tech, Chapters published January 23, 2013 under CC BY 3.0 license section of royal science B. 369: 1645. doi: 10.1098/rstb.2013.0427. 2013.

  7. Balounová J, Vavrochová T, Benešová M, Ballek O, Kolář M, Filipp D (2014) Toll-like receptors expressed on embryonic macrophages couple inflammatory signals to iron metabolism during early ontogenesis. Eur J Immunol. 44(5):1491–1502. https://doi.org/10.1002/eji.201344040

  8. Barker T, Henriksen VT, Martins TB, Hill HR, Kjeldsberg CR, Schneider ED (2013) Higher serum 25-hydroxyvitamin D concentrations associate with a faster recovery of skeletal muscle strength after muscular injury. Nutrients. 5(4):1253–1275. https://doi.org/10.3390/nu5041253

  9. Barnett JB, Dao MC, Hamer DH, Kandel R, Brandeis G, Wu D, Dallal GE, Jacques PF, Schreiber R, Kong E, Meydani SN (2016) Effect of zinc supplementation on serum zinc concentration and T cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 103(3):942–951. https://doi.org/10.3945/ajcn.115.115188

  10. Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM (2013) Vitamin D metabolism, functions and needs: From science to health claims. Eur J Nutr 52:429–441. https://doi.org/10.1007/s00394-012-0430-5

  11. Bauer RN, Diaz SD, Ilona JL (2012) Effects of air pollutants on innate immunity: the role of Toll-like receptors and nucleotide-binding oligomerization domain–like receptors. J Allergy Clin Immunol 129(1):14–26. https://doi.org/10.1016/j.jaci.2011.11.004

  12. Beard JL, Felt B, Schallert T, Burhans M (2007) Moderate iron deficiency in infancy: biology and behavior in young rats. Behav Brain Res. 170(2):224–232

  13. Bendik I, Friedel A, Roos FF, Weber P, Eggersdorfer M (2014) Vitamin D: a critical and essential micronutrient for human health. Front Physiol. 11(5):248. https://doi.org/10.3389/fphys.2014.00248

  14. Bhaskaram B (2011) Immunology of mild micronutrients deficiencies. Br J Nutr. 85(2):S75–S80

  15. Bivona G, Agnello L, Ciaccio M (2017) Vitamin D and immunomodulation: is it time to change the reference values? Ann Clin Lab Sci. 47(4):508–510

  16. Blomhoff HK, Smeland EB, Erikstein B (1992) Vitamin A is a key regulator for cell growth, cytokine production, and differentiation in normal B cells. J Biol Chem. 267(33):23988–23992

  17. Bode C, Diedrich B, Muenster S, Hentschel V, Weisheit C, Rommelsheim K (2014a) Antibiotics regulate the immune response in both presence and absence of lipopolysaccharide through modulation of Toll-like receptors, cytokine production and phagocytosis in vitro. Int Immunopharmacol. 18(1):27–34. https://doi.org/10.1016/j.intimp.2013.10.025

  18. Boe DM, Boule LA, Kovacs EJ Innate immune responses in the ageing lung. Clin Exp Immunol 16:132–150. https://doi.org/10.1111/cei.12881

  19. Bonaventura P, Benedetti G, Albarède F, Miossec P (2015) Zinc and its role in immunity and inflammation. Autoimmun Rev. 14(4):277–285. https://doi.org/10.1016/j.autrev.2014.11.008

  20. Boran P, Yildirim S, Karakoc-Aydiner E, Ogulur I, Ozen A, Haklar G, Koc A, Akkoc T, Barlan I (2016) Vitamin B12 deficiency among asymptomatic healthy infants: its impact on the immune system. Minerva Pediatr. In press

  21. Brachat A, Pierrat B, BruÈngger A, Heim J (2000) Comparative microarray analysis of gene expression during apoptosis-induction by growth factor deprivation or protein kinase C inhibition. Oncogene. 19(44):5073–5082

  22. Bresnahan KA, Tanumihardjo SA (2014) Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators. Adv Nutr 5(6):702–711 https://doi.org/10.3945/an.114.006361

  23. Brieger A, Rink L, Haase H (2013) Differential regulation of TLR-dependent MyD88 and TRIF signaling pathways by free zinc ions. J Immunol. 191:1808–1817. https://doi.org/10.4049/jimmunol.1301261

  24. Broering R, Montag M, Jiang M, Lu M, Sowa JP, Kleinehr K, Gerken G, Schlaak JF (2011) Corticosteroids shift the Toll-like receptor response pattern of primary-isolated murine liver cells from an inflammatory to an anti-inflammatory state. Int Immunol. 23(9):537–544. https://doi.org/10.1093/intimm/dxr048

  25. Bryant CE, Symmons M, Gay NJ (2015) Toll-like receptor signalling through macromolecular protein complexes. Mol Immunol. 63:162–165. https://doi.org/10.1016/j.molimm.2014.06.033

  26. Buracco S, Peracino B, Andreini C, Bracco E, Bozzaro S (2018) Differential Effects of iron, zinc, and copper on dictyostelium discoideum cell growth and resistance to Legionella pneumophila. Front Cell Infect Microbiol 11(7):536. https://doi.org/10.3389/fcimb.2017.2017

  27. Calder PC (2013) Long chain fatty acids and gene expression in inflammation and immunity. Curr Opin Clin Nutr Metab Care. 16:425–433

  28. Calton EK, Keane KN, Newsholme P, Soares MJ (2015) The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PLoS One. 10(11):e0141770

  29. Cassat JE, Skaar EP (2013) Iron in infection and immunity. Cell Host Microbe. 13:509–519

  30. Cavalcante PAM, Gregnani FM, Henrique JS, Ornellas FH, Araújo RC (2018) Aerobic but not resistance exercise can induce inflammatory pathway via toll-like receptor 2 and 4: a systemic review. Sports Med Open. 3:42

  31. Chandra RK (2002) Nutrition and the immune system from birth to old age. Eur J Clini Nut 56(3):S73–S76. https://doi.org/10.1038/sj.ejcn.1601492

  32. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE (2007) Modulatory effects of vitamin D3 on human B cell differentiation. J Immunol. 179:1634–1647

  33. Choi HJ, Hwang S, Lee SH, Lee YR, Shin J, Park KS, Cho YM (2012) Genome-wide identification of palmitate-regulated immediate early genes and target genes in pancreatic beta-cells reveals a central role of NF-kappaB. Mol Biol Rep. 39:6781–6789

  34. Combs GF (2008) The vitamins: fundamental aspects in nutrition and health, 3rd edn. Elsevier Academic Press. ISBN 978-0-12-183493-7, Burlington

  35. Cottey L, Jayasekera N, Haitchi H, Green B, Grainge C, Howarth P (2010) S42 airway epithelial toll receptor expression in asthma and its relationship to disease severity. Thorax. 65:A21–A22

  36. Coussens AK, Martineau AR, Wilkinson RJ (2014) Anti-Inflammatory and antimicrobial actions of vitamin D in combating TB/HIV. Scientifica 903680:13

  37. Czarnewski P, Das S, Parigi SM, Villablanca EJ (2018) Retinoic acid and its role in modulating intestinal innate immunity. Nutrients 9(1):E68. https://doi.org/10.3390/nu9010068

  38. de Pontual L (2017) Iron and susceptibility to infections. Arch Pediatr 24(5S):5S14–5S17. https://doi.org/10.1016/S0929-693X(17)24004-4

  39. Delehanty K, Gibson PG, Wang T (2007) Binding and neutralization of lipopolysaccharides by plant proanthocyanidins. J Nat Prod 70:1718–1724

  40. Delneste Y, Beauvillain C, Jeannin P (2007) Innate immunity: structure and function of TLRs. Med Sci (Paris). 23(1):67–73. https://doi.org/10.1051/medsci/200723167

  41. Devaraj S, Yun JM, DuncanStaley CR, Jialal I (2011) Low vitamin D levels correlate with the proinflammatory state in type 1 diabetic subjects with and without microvascular complications. Am J Clin Pathol. 135:429–433

  42. Djoko KY, Ong CY, Mark J, Walker MJ, McEwan AG (2015) The role of copper and zinc toxicity in innate immune defense against bacterial pathogens. J Biol Chem. 290(31):18954–18961. https://doi.org/10.1074/jbc.R115.647099

  43. Do JE, Kwon SY, Park S, Lee ES (2008) Effects of vitamin D on expression of toll-like receptors of monocytes from patients with Behcet’s disease. Rheumatol Oxf Engl. 47:840–848

  44. Doherty CP (2007) Host-pathogen interactions: the role of iron. J Nutr. 137(5):1341–1344

  45. Dong S, Xia H, Wang F, Sun G (2017) The effect of red palm oil on vitamin A deficiency: a meta-analysis of randomized controlled trials. Nutrients. 9(12):E1281. https://doi.org/10.3390/nu9121281

  46. Dong Z, Xiong L, Zhang W, Gibson PG, Wang T, Lu Y (2016) Holding the inflammatory system in check: TLRs and their targeted therapy in asthma. 2180417. https://doi.org/10.1155/2016/2180417

  47. Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F (2013) Saturated fatty acid and TLR signalling link beta cell dysfunction and islet inflammation. Cell Metab 15:518–533

  48. Ende VDW (2013) Multifunctional fructans and raffinose family oligosaccharides. Front Plant Sci. 4:247

  49. Erickson KL, Medina EA, Hubbard NE (2000) Micronutrients and innate immunity. J Infect Dis. 182(1):S5-10

  50. Erridge C (2010) Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol. 87(6):989–999. https://doi.org/10.1189/jlb.1209775

  51. Erridge C (2011) Stimulants of Toll-like receptor (TLR)-2 and TLR-4 are abundant in certain minimally-processed vegetables. Food Chem Toxicol. 49:1464–1467. https://doi.org/10.1016/j.fct.2011.02.018

  52. Erridge C, Herieka M, Faraj TA (2016) Reduced dietary intake of pro-inflammatory Toll-like receptor stimulants favourably modifies markers of cardiometabolic risk in healthy men. Nutr Metab Cardiovasc Dis. 26(3):194–200. https://doi.org/10.1016/j.numecd.2015.12.001

  53. Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate toll-like receptor signaling. Arterioscler Thromb Vasc Biol. 29:1944–1949

  54. Fang Y, Wang S, Zhu T, Zhang Y, Lian X (2017) Atherogenic high cholesterol/HFD induces TLRs-associated pulmonary inflammation in C57BL/6J mice. Inflamm Res 66(1):39–47. https://doi.org/10.1007/s00011-016-0990-6

  55. Fennema O (2008) Fennema’s Food Chemistry. CRC Press Taylor & Francis, pp 454–455 ISBN 9780849392726

  56. Figueiredo RT, Fernandez PL, Mourao-Sa DS, Porto BN, Dutra FF, Alves LS (2007) Characterization of heme as activator of Toll-like receptor. J Bio Sci. 21(5):159–166

  57. Flammer JR, Rogatsky I (2011) Minireview: Glucocorticoids in autoimmunity: unexpected targets and mechanisms. Mol Endocrinol. 25(7):1075–1086. https://doi.org/10.1210/me.2011-0068

  58. Fuhrman J (2014) The end of Dieting. Harper One (Harper Collins):101–102. ISBN 978-0-06-224932-6

  59. Fulop T, Witkowski JM, Page CA, Fortin FG, Larbi A (2017) Intracellular signalling pathways: targets to reverse immunosenescence. Clin Exp Immunol 14:155–165. https://doi.org/10.1111/cei.12836

  60. Gal-Tanamy M, Bachmetov L, Ravid A, Koren R, Erman A, Tur-Kaspa R, Zemel R (2011) Vitamin D: an innate antiviral agent suppressing hepatitis C virus in human hepatocytes. Hepatology. 54(5):1570–1579

  61. Gambhir V, Yildiz C, Mulder R, Siddiqui S, Guzzo C, Szewczuk M, Gee K, Basta S (2012) The TLR2 agonists’ lipoteichoic acid and Pam3CSK4 induce greater pro-inflammatory responses than inactivated Mycobacterium butyricum. Cell Immunol 280(1):101–107

  62. Gammoh NZ, Rink L (2017) Zinc in infection and inflammation. Nutrients. 9(6):624. https://doi.org/10.3390/nu9060624

  63. Ganz T, Nemeth E (2015) Iron homeostasis in host defense and inflammation. Nat Rev Immunol 15(8):500–510. https://doi.org/10.1038/nri3863

  64. Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Leza JC (2014) Toll-like 4 receptor inhibitor TAK-242 decreases neuroinflammation in rat brain frontal cortex after stress. J Neuroinflammation. 11:8

  65. Gárate I, García-Bueno B, Madrigal JL, Caso JR, Alou L, Gomez-Lus ML, Mico JA, Leza JC (2013) Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway. Biol Psychiatry. 73:32–43

  66. García Bueno B, Caso JR, Madrigal JL, Leza JC (2016) Innate immune receptor Toll-like receptor 4 signalling in neuropsychiatric diseases. Neurosci Biobehav Rev. 64:134–147. https://doi.org/10.1016/j.neubiorev.2016.02.013

  67. Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of Toll-like receptor signalling complexes. Nat Rev Immunol. 14:546–558. https://doi.org/10.1038/nri3713

  68. Ghatpande NS, Apte PP, Naik SS, Joshi BN, Gokhale MK, Kulkarni PP (2016) Association of B12 deficiency and anemia synergistically increases the risk of high TNF-α level among adolescent girls. Metallomics 8:734–738

  69. Gleeson M, McFarlin B, Flynn M (2006) Exercise and Toll-like receptors. Immunol Rev. 12:34–53

  70. Green HN, Mellanby E (1928) Vitamin A as an anti-infective agent. Br Med J. 2(3537):691–696

  71. Gruber K, Rink L (2013) The role of zinc in immunity and inflammation. Diet, Immunity and Inflammation. A volume in Wood head Publishing Series in Food Science, Technology and Nutrition, pp 123–156. https://doi.org/10.1533/9780857095749

  72. Haase H, Rink L (2009) Functional significance of zinc-related signaling pathways in immune cells. Annu Rev Nutr. 29:133–152

  73. Haase H, Rink L (2014) Zinc signals and immune function. Biofactors. 40(1):27–40. https://doi.org/10.1002/biof.1114

  74. Halfdanarson TR, Kumar N, Li CY, Phyliky RL, Hogan WJ (2008) Hematological manifestations of copper deficiency: a retrospective review. Eur J Haematol. 80:523–531

  75. Hammerschmidt SI, Friedrichsen M, Boelter J, Lyszkiewicz M, Kremmer E, Pabst O, Förster R (2011) Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice. J Clin Invest. 121(8):3051–3061. https://doi.org/10.1172/JCI44262

  76. Harrison EH (2005) Mechanisms of digestion and absorption of dietary vitamin A. Annu Rev Nutr. 25:87–103

  77. Herrera RE, Sah VP, Williams BO (2011) Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts. Mole Cell Biol. 16(5):2402–2407

  78. Hines DJ, Choi HB, Hines RM, Phillips AG, MacVicar BA (2013) Prevention of LPS-induced microglia activation, cytokine production and sickness behavior with TLR4 receptor interfering peptides. PLoS One. 8:e60388

  79. Hoe E, Nathanielsz J, Toh ZQ, Spry L, Marimla R, Balloch A, Mulholland K, Licciardi PV (2016) Anti-Inflammatory effects of vitamin D on human immune cells in the context of bacterial infection. Nutrients. 8(12):806

  80. Hoeft K, Bloch DB, Graw JA, Malotra R, Ichinose F, Bagchi A (2017) Iron loading exaggerates the inflammatory response to the Toll-like receptor 4 ligand lipopolysaccharide by altering mitochondrial homeostasis. Anesthesiology. 127(1):121–135. https://doi.org/10.1097/ALN.0000000000001653

  81. Hojyo S, Fukada T (2016) Roles of zinc signaling in the immune system. J Immunol Res 6762343. https://doi.org/10.1155/2016/6762343

  82. Hosseinzadeh H, Moallem SA, Moshiri M, Sarnavazi MS, Etemad L (2012) Antinociceptive and anti-inflammatory effects of cyanocobalamin (vitamin B12) against acute and chronic pain and inflammation in mice. Arzneimittelforschung. 62(7):324–329

  83. Hug H, Mohajeri MH, La Fata G (2018) Toll-like receptors: regulators of the immune response in the human gut. Nutrients. 10:203. https://doi.org/10.3390/nu10020203

  84. Hung YY, Huang KW, Kang HY, Ling GY, Huang TL (2016) Antidepressants normalize elevated Toll-like receptor profile in major depressive disorder. J neuropsych. 233(9):1707–1714

  85. Hung YY, Kang HY, Huang KW, Huang TL (2014) Association between toll-like receptors expression and major depressive disorder. Psychiatry Res. 220(1-2):283–286. https://doi.org/10.1016/j.psychres.2014.07.074

  86. Ibs KH, Rink L (2003) Zinc-altered immune function. J Nutr. 133(1):1452S–1456S

  87. Imasato A, Desbois-Mouthon C, Han J, Kai H, Cato AC, Akira S, Li JD (2002) Inhibition of p38 MAPK by glucocorticoids via induction of MAPK phosphatase-1 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J Biol Chem. 277:47444–47450. https://doi.org/10.1074/jbc.M208140200

  88. Imdad A, Mayo-Wilson E, Herzer K, Bhutta ZA (2017) Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev. 11(3):CD008524. https://doi.org/10.1002/14651858

  89. Ina K, Kataoka T, Ando T (2013) The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem. 13:681–688

  90. Jafari M, Nasiri MR, Sanaei R, Anoosheh S, Farnia P, Sepanjnia A, Tajik N (2018) The NRAMP1, VDR, TNF-α, ICAM1, TLR2 and TLR4 gene polymorphisms in Iranian patients with pulmonary tuberculosis: a case-control study. Infect Genet Evol. 39:92–98. https://doi.org/10.1016/j.meegid.2016.01.013

  91. Jeffery LE, Burke F, Mura M (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol. 183:58–67

  92. Jiao L, Wang CC, Wu H, Gong R, Lin FH, Feng J, Hu C (2017) Copper/zinc-loaded montmorillonite influences intestinal integrity, the expression of genes associated with inflammation, TLR4-MyD88 and TGF-β1 signaling pathways in weaned pigs after LPS challenge. Innate Immun. 23(8):648–655. https://doi.org/10.1177/1753425917733033

  93. Jizhong S, Qiaomin W, Chao W, Yanqing L. Corticotropin-releasing factor and toll-like receptor gene expression is associated with inflammation in irritable bowel syndrome patients with depression. Gastroenterol Res Prac. Vol. 2016, ID 7394924, 7 pages. 2016. doi. https://doi.org/10.1155/2016/7394924.

  94. Johnson EE, Wessling-Resnick M (2012) Iron metabolism and the innate immune response to infection. Microbes Infect. 14(3):207–216. https://doi.org/10.1016/j.micinf.2011.10.001

  95. Kamen DL, Tangpricha V (2010) Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med. 88(5):441–450. https://doi.org/10.1007/s00109-010-0590-9

  96. Katona P, Katona-Apte J (2008) The interaction between nutrition and infection. Clin Infect Dis. 46(10):1582–1588. https://doi.org/10.1086/587658

  97. Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 11(5):373–384. https://doi.org/10.1038/ni.1863

  98. Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461. https://doi.org/10.3389/fimmu.2014.00461

  99. Kéri S, Szabo C, Kelemen O (2014) Expression of Toll-Like Receptors in peripheral blood mononuclear cells and response to cognitive-behavioral therapy in major depressive disorder. Brain Behav Immun. 40:235–243

  100. Killen JP, Brenninger VL (2013) Vitamin B12 deficiency. N Engl J Med. 368:2040–2041. https://doi.org/10.1056/NEJMc1304350#SA1

  101. Kim CH (2011) Retinoic acid, immunity, and inflammation. Vitam Horm. 86:83–101. https://doi.org/10.1016/B978-0-12-386960-9

  102. Kitamura H, Morikawa H, Kamon H, Iguchi M, Hojyo S, Fukada T (2006) Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function. Nat Immunol. 7(9):971–977

  103. Klaassen EMM, Thönissen EJT, van Eys G, Dompeling E, Jöbsis Q (2013) A systematic review of CD14 and toll-like receptors in relation to asthma in Caucasian children. Allergy Asthma Clin Immunol. 9(1):10. https://doi.org/10.1186/1710-1492-9-10

  104. Kogan S, Sood A, Garnick MS (2017) Zinc and wound healing: A review of zinc physiology and clinical applications. Wounds. 29(4):102–106

  105. Korf H, Decallonne B, Mathieu C (2014) Vitamin D for infections. Curr Opin Endocrinol Diabetes Obes. 21(6):431–436. https://doi.org/10.1097/MED.0000000000000108

  106. Krayenbuehl PA, Hersberger M, Truninger K, Müllhaupt B, Maly FE, Bargetzi M, Schulthess G (2010) Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis. Eur J Gastroenterol Hepatol. 22(7):835–841. https://doi.org/10.1097/MEG.0b013e3283322067

  107. Krebs NF (2013) Update on zinc deficiency and excess in clinical pediatric practice. Ann Nutr Metab 62(1):19–29

  108. Kwak CS, Lee MS, Oh S, Park SC (2010) Discovery of novel sources of vitamin B12 in traditional Korean foods from nutritional surveys of centenarians. Curr Gerontol Geriatr Res 3:374897. https://doi.org/10.1155/2010/374897

  109. Lafferty EI, Qureshi ST, Schnare M (2010) The role of toll-like receptors in acute and chronic lung inflammation. J Inflamm. 7(3):57

  110. Lancaster GI, Khan Q, Drysdale P, Wallace W, Jeukendrup AE, Drayson MT, Gleeson M (2005) The physiological regulation of toll-like receptor expression and function in humans. J Physiol. 563(3):945–955. https://doi.org/10.1113/jphysiol.2004.081224

  111. Langan RC, Goodbred AJ, Linton DM (2014) Vitamin B12 deficiency. Alesia Hunt Susan Robinson 96(6):384–389. https://doi.org/10.1136/bmj.g5226

  112. Lauffenburger DA, Horwitz AF, Heim J (1996) Cell migration: a physically integrated molecular process. Cell. 84(3):359–369

  113. Layoun A, Huang H, Calvé A, Santos MM (2012) Toll-like receptor signal adaptor protein MyD88 is required for sustained endotoxin-induced acute hypoferremic response in mice. Am J Pathol. 180(6):2340–2350. https://doi.org/10.1016/j.ajpath.2012.01.046

  114. Layoun A, Samba-Mondonga M, Fragoso G, Calvé A, Santos MM (2018) MyD88 adaptor protein is required for appropriate hepcidin induction in response to dietary iron overload in mice. Front Physiol. 5(9):159. https://doi.org/10.3389/fphys.2018.00159

  115. Layoun A, Santos MM (2012) Bacterial cell wall constituents induce hepcidin expression in macrophages through MyD88 signaling. Inflammation. 35(4):1500–1506. https://doi.org/10.1007/s10753-012-9463-4

  116. Lazarchick J (2012) Update on anemia and neutropenia in copper deficiency. Curr Opin Hematol. 19(1):58–60. https://doi.org/10.1097/MOH.0b013e32834da9d2

  117. Lean MEJ (2015) Principles of human nutrition. Medicine. 43(2):61–65. https://doi.org/10.1016/j.2014.11.009

  118. Lee JY, Sohn KH, Rhee SH, Hwang D (2015) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem. 276:16683–16689

  119. Liu JJ, Buisman-Pijlman F, Hutchinson MR (2014) Toll-like receptor 4: innate immune regulator of neuroimmune and neuroendocrine interactions in stress and major depressive disorder. Front Neurosci. 8:309

  120. Liu MJ, Bao S, Gálvez-Peralta M, Rudawsky AC, Pavlovicz RE (2013) ZIP8 regulates host defense through zinc-mediated inhibition of NF-κB. Cell Reports 3(2):386–400. https://doi.org/10.1016/j.celrep.2013.01.009

  121. Liu PT, Stenger S, Li H (2006) Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 311:1770–1773

  122. Long KZ, Hass M, Young C, Estrada T, Firestone M, Fawzi W, Bhagwat J, Rosado JL, Santos JE, Nanthakumar N (2004) Impact of vitamin A on the intestinal immune response in pathogen induced diarrhea of children in Mexico City Mexico. FASEB J 18:A9

  123. Low JW, Mwanga RM, Andrade M, Carey E, Ball AM (2017) Tackling vitamin A deficiency with bio-fortified sweet potato in sub-Saharan Africa. Glob Food Sec. 14:23–30. https://doi.org/10.1016/j.gfs.2017.01.004

  124. Maares M and Haase H. Zinc and immunity: an essential interrelation. Arch Biochem Biophys. 2016. pii: S00039861 (16):30074-1.

  125. Maggini S, Wintergerst ES, Beveridge S, Hornig DH (2007) Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humeral immune responses. Br J Nutr 98(1):S29–S35 PMID: 17922955

  126. Maret W, Sandstead HH (2006) Zinc requirements and the risks and benefits of zinc supplementation. J Trace Elem Med Biol 20(1):3–18. https://doi.org/10.1016/j.jtemb.2006.01.006

  127. Mason JB (2016) Vitamins, trace minerals, and other micronutrients. In: Goldman L, Schafer AI (eds) Goldman-Cecil Medicine, 25th edn. Elsevier Saunders, Philadelphia, p 218

  128. McDowell EM, Keenan KP, Huang M (1984) Effects of vitamin A-deprivation on hamster tracheal epithelium. A quantitative morphologic study. Virchows Arch B Cell Pathol Incl Mol Pathol. 45(2):197–219

  129. McFarlin BK, Flynn MG, Campbell WW, Stewart LK, Timmerman KL (2004) TLR4 is lower in resistance-trained older women and related to inflammatory cytokines. Med Sci Sports Exerc. 36(11):1876–1883

  130. Miettinen M, Sareneva T, Julkunen I, Matikainen S (2001) IFN activate toll-like receptor gene expression in viral infections. Genes Immun. 2:349–355. https://doi.org/10.1038/sj.gene.6363791

  131. Mikkelsen K, Stojanovska L, Polenakovic M, Bosevski M, Apostolopoulos V (2017) Exercise and mental health. Maturitas. 106:48–56

  132. Mocchegiani E, Romeo J, Malavolta M, Costarelli L, Giacconi R, Diaz LE, Marcos A (2013) Zinc: dietary intake and impact of supplementation on immune function in elderly. Age (Dordr). 35(3):839–860. https://doi.org/10.1007/s11357-011-9377-3

  133. Montgomery RR (2016) Age-related alterations in immune responses to West Nile virus infection. Clin Exp Immunol 22:187–200. https://doi.org/10.1111/cei.12863

  134. Mora JR, Iwata M, von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take center stage. Nat Rev Immunol 8(9):685–698. https://doi.org/10.1038/nri2378

  135. Mora JR, Iwata M, Von Andrian UH (2010) Vitamin effects on immune system: vitamin A and D take centre stage. Nat Rev Immunol. 8(5):685–698

  136. Moresco EM, LaVine D, Beutler B (2011) Toll-like receptors. Curr Biol 21:R488–R493. https://doi.org/10.1016/j.cub.2011.05.039

  137. Murad S (2014) Toll-like receptor 4 in inflammation and angiogenesis: a double-edged sword. Front Immunol. 5:313

  138. Myszka M, Klinger M (2014) The immunomodulatory role of Vitamin D. Postepy Hig Med Dosw. 68:865–878

  139. Noppert SJ, Fitzgerald KA, Hertzog PJ (2007) The role of type I interferon in TLR responses immunology and cell biology. Immunol Cell Biol 85:446–457

  140. Ojaimi S, Skinner NA, Strauss BJ, Sundararajan V, Woolley I, Visvanathan K (2013) Vitamin D deficiency impacts on expression of toll-like receptor-2 and cytokine profile: a pilot study. J Transl Med 11:176

  141. Ong ST, Ho JZS, Ho B, Ding JL (2006) Iron-withholding strategy in innate immunity. Immunobiology. 211:295–314

  142. Pandey GN, Rizavi HS, Ren X, Bhaumik R, Dwivedi Y (2014) Toll-like receptors in the depressed and suicide brain. J Psychiatr Res. 53:62–68. https://doi.org/10.1016/j.jpsychires.2014.01.021

  143. Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D (2013) How prevalent is vitamin B(12) deficiency among vegetarians? Nutr Rev. 71(2):110–117. https://doi.org/10.1111/nure.12001

  144. Percival SS (1995) Neutropenia caused by copper deficiency: possible mechanisms of action. Nutr Rev. 53:59–66

  145. Percival SS (1998) Copper and immunity. Am J Clin Nutr. 67:1064S–1068S

  146. Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD (1993) Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr. 57:170–174

  147. Petris MJ, Smith K, Lee J, Thiele DJ (2003) Copper-stimulated endocytosis and degradation of the human copper transporter, hCtr1. J Biol Chem. 278:9639–9646

  148. Pettengill MA, van Haren SD, Levy O (2014) Soluble mediators regulating immunity in early life. Front Immunol 5:457

  149. Plummer LE, Smiley-Jewell S, Pinkerton KE (2012) Impact of air pollution on lung inflammation and the role of Toll-like receptors. Int J Interf Cyt Media Res 4:43–57. https://doi.org/10.2147/IJIMR.S29352

  150. Polyak K, Weinberg RA (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 9(4):265–273

  151. Prasad AS (2013) Discovery of human zinc deficiency: its impact on human health and disease. Adv Nutr. 4:176–190

  152. Prasad AS, Beck FW, Bao B, Fitzgerald JT, Snell DC, Steinberg JD, Cardozo LJ (2011) Zinc supplementation decreases incidence of infections in the elderly: effect of zinc on generation of cytokines and oxidative stress. Am J Clin Nutr. 85(3):837–844

  153. Prietl B, Treiber G, Pieber TR, Amrein K (2013) Vitamin D and immune function. Nutrients 5(7):2502–2521. https://doi.org/10.3390/nu5072502

  154. Rada I, Deldicque L, Francaux M, Zbinden-Foncea H (2018) Toll like receptor expression induced by exercise in obesity and metabolic syndrome: a systematic review. Exerc Immunol Rev. 24:60–71

  155. Ragab D, Soliman D, Samaha D, Yassin A (2016) Vitamin D status and its modulatory effect on interferon gamma and interleukin-10 production by peripheral blood mononuclear cells in culture. Cytokine. 85:5–10

  156. Rathinam VA, Vanaja SK, Waggoner L, Kolovska AS, Becker C, Stuart LM (2012) TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by Gram-negative bacteria. Cell 150(3):606–619

  157. Rink L, Gabriel P (2000) Zinc and the immune system. Proc Nutr Soc 59(4):541–552. https://doi.org/10.1017/S0029665100000781

  158. Rocha DM, Caldas AP, Oliveira LL, Bressan J, Hermsdorff HH (2016) Saturated fatty acids trigger TLR4-mediated inflammatory response. Atherosclerosis. 244:211–215

  159. Roos N, Wahab MA, Chamnan C, Thilsted SH (2010) The role of fish in food-based strategies to combat vitamin A and mineral deficiencies in developing countries. J Nutr 137(4):1106–1109

  160. Sadeghi K, Wessner B, Laggner U (2016) Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol. 36:61–70

  161. Schauber J, Dorschner RA, Coda AB (2007) Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 117:803

  162. Schnetzke U, Spies-Weisshart B, Yomade O, Fischer M, Rachow T, Schrenk K, Glaser A, von Lilienfeld-Toal M (2015) Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia. Genes Immun 16(1):83–88. https://doi.org/10.1038/gene.2014.47

  163. Schroeder JT (2009) Basophils: beyond effector cells of allergic inflammation. Adv Immunol. 101:123–161

  164. Semba RD (2012) On the ‘discovery’ of vitamin A. Ann Nutr Metabol 61(3):192–198. https://doi.org/10.1159/000343124

  165. Semba RD, Dancheck B, Gamble MV, Palafox NA, Briand K (2004) Vitamin A deficiency and inflammatory markers among preschool children in the Republic of the Marshall Islands. Nutr J. 3:21. https://doi.org/10.1186/1475-2891-3-21

  166. Shaw AC, Panda A, Joshi SR, Qian F, Allore H, Gand R, Montgomery RR (2011a) Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev. 10(3):346–353. https://doi.org/10.1016/j.arr.2010.10.007

  167. Singh K, Kant S, Gupta SK, Singh VK (2014) Toll-like receptor 4 polymorphisms and their haplotypes modulate the risk of developing diabetic retinopathy in type 2 diabetes patients. Mol Vision 20:704–713

  168. Slusher AL, McAllister MJ, Huang CJ (2015) A therapeutic role for vitamin D on obesity-associated inflammation and weight-loss intervention. Inflamm Res. 64(8):565–575. https://doi.org/10.1007/s00011-015-0847-4

  169. Smith TJ, Tripkovic L, Lanham-New SA, Hart KH (2017) Vitamin D in adolescence: evidence-based dietary requirements and implications for public health policy. Proc Nutr Soc:1–10. https://doi.org/10.1017/S0029665117004104

  170. So EY, Ouchi T (2010) The application of toll like receptors for cancer therapy. Int J Biol Sci 6(7):675–681

  171. Solomons NW (2001) Dietary Sources of zinc and factors affecting its bioavailability. Food Nutr Bull. 22:138–154

  172. Solomons NW (2006) Vitamin A. In: Bowman B, Russell R (eds) Present Knowledge in Nutrition, 9th edn. International Life Sciences Institute, Washington, DC, pp 157–183

  173. Spinas E, Saggini A, Cerulli G, Caraffa A (2015) Can vitamin a mediate immunity and inflammation? J Biol Regul Homeost Agents. 29(1):1–6

  174. Stafford SL, Bokil NJ, Achard MES, Kapetanovic R, Mark A, Schembri MA, Mc Ewan AM, Sweet MJ (2013) Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci Rep. 33(4):e00049. https://doi.org/10.1042/BSR20130014

  175. Steiger D, Fetchko M, Vardanyan A, Atanesyan L, Steiner K, Turski ML, Thiele DJ, Georgiev O, Schaffner W (2010) The Drosophila copper transporter Ctr1C functions in male fertility. J Biol Chem. 285:17089–17097

  176. Stewart LK, Flynn MG, Campbell WW, Craig BA, Robinson JP, McFarlin BK (2005) Influence of exercise training and age on CD14+ cell surface expression of toll-like receptor 2 and 4. Brain Behav Immunol. 19:389–397

  177. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785. https://doi.org/10.1084/jem.20070602

  178. Tang G, Qin J, Dolnikowski GG, Russell RM, Grusak MA (2055) Spinach or carrots can supply significant amounts of vitamin A as assessed by feeding with intrinsically deuterated vegetables. Am J Clin Nutr 82(4):821–828

  179. Tang X, Pan Y, Zhao Y (2012) Vitamin D inhibits the expression of interleukin-8 in human periodontal ligament cells stimulated with Porphyromonas gingivalis. Arch Oral Biol 58:397–407

  180. Tizaoui K, Kaabachi W, Hamzaoui K, Hamzaoui A (2015) Association of single nucleotide polymorphisms in Toll-like receptor genes with asthma risk: a systematic review and meta-analysis. Allergy Asthma Immunol Res 7(2):130–140. https://doi.org/10.4168/aair.2015.7.2.130

  181. Todorova TT, Ermenlieva N, Tsankova G. (2017) Vitamin B12; Could it be a promising immunotherapy? Immunology and microbiology “Immunotherapy – Myths, Reality ideas, Future” book edited by Krassimir Metodiev. ISBN 978-953-51-3106-9 print ISBN 078-953-51-3105-2.

  182. Trotta T, Porro C, Calvello R, Panaro MA (2014) Biological role of Toll-like receptor 4 in the brain. Polymorphisms in toll-like receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J Neuroimmunol. 268:1–12

  183. Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H (2008) Role of Toll-like receptors in the development of sepsis. Shock 29(3):315–321. https://doi.org/10.1097/SHK.0b013e318157ee55

  184. Urry Z, Xystrakis E, Richards DF, McDonald J, Sattar Z, Cousins DJ, Corrigan CJ, Hickman E, Brown Z, Hawrylowicz CM (2009) Ligation of TLR9 induced on human IL-10-secreting Tregs by 1alpha,25-dihydroxyvitamin D3 abrogates regulatory function. J Clin Invest. 119:387–398

  185. Vanherwegen AS, Gysemans C, Mathieu C (2017) Regulation of immune function by vitamin D and its use in diseases of immunity. Endocrinol Metab Clin North Am. 46(4):1061–1094. https://doi.org/10.1016/j.ecl.2017.07.010

  186. Vázquez CMP, Netto RSM, Barbosa KBF (2014) Micronutrients influencing the immune response in leprosy. Nutrición Hospitalaria. 29(1):26–36

  187. Veldhuis NA, Valova VA, Gaeth AP, Palstra N, Hannan KM, Michell BJ, Kelly LE (2009) Phosphorylation regulates copper-responsive trafficking of the Menkes copper transporting P-type ATP-ase. Int J Biochem Cell Biol. 41:2403–2412

  188. Verbon EH, Trapet PL, Stringlis IA, Kruijs S, Bakker P, Pieterse C Iron and immunity. Microbes Infect 14(3):207–216. https://doi.org/10.1016/j.micinf.2011.10.001

  189. Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R (2017) Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. 37(3):1–17. https://doi.org/10.1080/08830185.2017.1380200

  190. Vogt L, Ramasamy U, Meyer D, Pullens G, Venema K, Faas MM, Schols HA, de Vos P (2013) Immune modulation by different types of beta2-->1-fructans is toll-like receptor dependent. PLoS ONE. 8:e68367

  191. Vogt LM, Meyer D, Pullens G, Faas MM, Venema K, Ramasamy U, Schols HA, de Vos P (2014) Toll-like receptor 2 activation by beta2-->1-fructans protects barrier function of T84 human intestinal epithelial cells in a chain length-dependent manner. J Nutr. 144:1002–1008

  192. Vogt LM, Sahasrabudhe NM, Ramasamy U, Meyer D, Pullens G, Faas MM (2016) The impact of lemon pectin characteristics on TLR activation and T84 intestinal epithelial cell barrier function. J Funct Foods. 22:398–407

  193. Wagner D, Maser J, Lai B, Cai ZH, Barry CE, Bentrup KHZ, Russell DG, Bermudez LE (2005) Elemental analysis of Mycobacterium avium-, Mycobacterium tuberculosis-, and Mycobacterium smegmatis-containing phagosomes indicates pathogen-induced microenvironments within the host cell’s endosomal system. J Immunol. 174:1491–1500

  194. Wan Z, Durrer C, Mah D, Simtchouk S, Little JP (2014) One-week high-fat diet leads to reduced toll-like receptor 2 expression and function in young healthy men. Nutr Res. 34(12):1045–1051. https://doi.org/10.1016/j.nutres.2014.08.012

  195. Wang J, Grishin AV, Ford HR, Fritsche K, Petris MJ, Nakahira K, Hwang DH (2016) Experimental anti-inflammatory drug semapimod inhibits TLR signaling by targeting the TLR Chaperone gp96. J immunol. 196(12):5130–5137. https://doi.org/10.4049/jimmunol.1502135

  196. Wang L, Harrington L, Trebicka E, Shi HN, Kagan JC, Hong CC, Lin HY, Babitt JL, Cherayil BJ (2009) Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice. J Clin Invest 119(11):3322–3328. https://doi.org/10.1172/JCI39939

  197. Wang TT (2004) Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 173(5):2909–2912

  198. Wang Y, Song E, Bai B, Vanhoutte PM (2015). Toll-like receptors mediating vascular malfunction: lessons from receptor subtypes. Pharm Therap. In press. doi. https://doi.org/10.1016/j.pharmthera.2015.12.005.

  199. Wei R, Christakos S (2015) Mechanisms underlying the regulation of innate and adaptive immunity by vitamin D. Nutrients 7:8251–8260. https://doi.org/10.3390/nu7105392

  200. Weinberg ED, Weinberg GA (1995) The role of iron in infection. Curr Opin Infect Dis. 8:164–169

  201. Wessels I, Maywald M, Rink L (2017) Zinc as a gatekeeper of immune function. Nutrients. 9(12):1286

  202. White C, Lee J, Kambe T, Fritsche K, Petris MJ (2009) A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem. 284:33949–33956

  203. Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH (2009) Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem. 284:27384–27392

  204. Xin Z, Waterman DF, Hemken RW, Harmon RJ (1991) Effects of copper status on neutrophil function, superoxide dismutase, and copper distribution in steers. J Dairy Sci. 74:3078–3085

  205. Yi C, Bai X, Chen J, Li J, Liu P, Liao Y (2011) Effect of w-3 polyunsaturated fatty acid on Toll-like receptors in patients with severe multiple trauma. J Huazhong Univ Sci Technolog Med Sci. 31(4):504–508

  206. Yu L, Feng Z (2018) The role of Toll-like receptor signalling in the progression of heart failure. Mediators Inflamm. 8:9874109. https://doi.org/10.1155/2018/9874109

  207. Yuk JM, Shin DM, Lee HM (2011) Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe. 6:31–43

  208. Zackular JP, Chazin WJ, Skaar EP (2017) Nutritional immunity: S100 proteins at the host-pathogen interface. J Biol Chem. 290(31):18991–18998. https://doi.org/10.1074/jbc.R115.645085b

  209. Zandieh Z, Amjadi F, Ashrafi M, Aflatoonian A, Fazeli A, Aflatoonian R (2016) The effect of estradiol and progesterone on Toll like receptor gene expression in a human fallopian tube epithelial cell line. Cell J. 17(4):678–691

  210. Zhang J, Dou W, Zhang E, Sun A, Ding L, Wei X (2014) Paeoniflorin abrogates dss-induced colitis via a TLR4-dependent pathway. Am J Physiol Gastrointest Liver Physiol 306:G27–G36

  211. Zhang LJ, Gallo RL (2016) Antimicrobial peptides. Curr Biol 26(1):R14–R19

  212. Zhang Q, Qian FH, Zhou LF, Wei GZ, Jin GF, Bai JL, Yin KS (2011) Polymorphisms in toll-like receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J Investig Allergol Clin Immunol. 21(5):370–377

  213. Zhang X, Qi C, Guo Y, Zhou W, Zhang Y (2016) Toll-like receptor 4-related immunostimulatory polysaccharides: primary structure, activity relationships, and possible interaction models. Carbohydr Polym. 149:186–206

  214. Zhang Y, Liang C (2016) Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci. 59(12):1210–1217. https://doi.org/10.1007/s11427-016-0325-6

Download references

Acknowledgements

The authors would like to thank National Research Centre where they work.

Funding

Not applicable

Author information

SRE-Z collected the scientific material and wrote the whole manuscript. HS participated in the scientific material collection and reviewed the whole manuscript. FAM reviewed the whole manuscript. All authors read and approved the final manuscript.

Correspondence to Salwa Refat El-Zayat.

Ethics declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

El-Zayat, S.R., Sibaii, H. & Mannaa, F.A. Micronutrients and many important factors that affect the physiological functions of toll-like receptors. Bull Natl Res Cent 43, 123 (2019) doi:10.1186/s42269-019-0165-z

Download citation

Keywords

  • Toll-like receptors
  • Pollution
  • Stress
  • Nutrition
  • Micronutrients