Mini Review
The role of innate signaling in the homeostasis of tolerance and immunity in the intestine

https://doi.org/10.1016/j.ijmm.2009.08.008Get rights and content

Abstract

In the intestine innate recognition of microbes is achieved through pattern recognition receptor (PRR) families expressed in immune cells and different cell lineages of the intestinal epithelium. Toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-like receptor (NLR) families are emerging as key mediators of immunity through their role as maturation factors of immune cells and triggers for the production of cytokines and chemokines and antimicrobial factors. At the mucosal surface chronic activation of the immune system is avoided through the epithelial production of a glycocalyx, steady-state production of antimicrobial factors as well as the selective expression and localization of PRRs. Additionally, the polarization of epithelial TLR signaling and suppression of NF-κB activation by luminal commensals appears to contribute to the homeostasis of tolerance and immunity. Several studies have demonstrated that TLR signaling in epithelial cells contributes to a range of homeostatic mechanisms including proliferation, wound healing, epithelial integrity, and regulation of mucosal immune functions. The intestinal epithelium appears to have uniquely evolved to maintain mucosal tolerance and immunity, and future efforts to further understand the molecular mechanisms of intestinal homeostasis may have a major impact on human health.

Introduction

Epithelial cells can reabsorb nutrients from the digested food stream and on the other hand act as a barrier to the intestinal microbiota and opportunistic pathogens. The density of bacteria increases along the intestinal tract starting with 103 to 105 bacteria per ml of luminal contents in the stomach and duodenum to approximately 109 to 1012 per ml in the ileum and colon. This intestinal community encompasses eukarya, archea and bacteria, and comprises at least 500 to 1000 species (Artis, 2008). In mammals and other metazoans these host-microbe relationships have formed over millions of years of evolution and are mutualistic and symbiotic in nature. The symbiotic benefits are diverse and include host defense from infection, energy and nutrient metabolism, and tissue development and repair. In contrast, pathogens have by definition the capacity to cause harm to the host and may also be able to spread from the mucosa to other tissues in the body. This creates a need for the host to maintain homeostatic balance between tolerance to commensals and immunity to pathogens. The necessity to regulate immune responses to commensal organisms is evident from research on inflammatory bowel disease (IBD) where loss of tolerance to the microbiota causes chronic inflammation and loss of epithelial integrity (Salzman and Bevins, 2008).

The epithelial cell barrier is reinforced by numerous chemical factors including a heavily glycosylated mucin-rich layer and a range of antimicrobial peptides and proteins that prevent intimate contact with the commensal and pathogenic bacteria. Specialized lymphoid structures, including Peyer's patches (PP) and isolated lymphoid follicles permit the sampling of luminal antigens and the induction of immunity and secretory IgA (sIgA) via specialized M cells in the follicular epithelium (Mowat, 2003). Humans secrete several grams per day of sIgA into the intestinal lumen which exerts considerable immune pressure on the luminal microbiota. Dendritic cells play a key role in the induction of tolerance and immunity, reside in the PP but can also sample luminal antigen in the lamina propria by extending dendrites through the epithelial tight junctions (Rescigno et al., 2001). Epithelial cells and immune cells in the lamina propria recognize microbes through the expression of pathogen recognition receptors (PRRs) that recognize common structures on microorganisms often referred to as pathogen-associated molecular patterns (PAMPs). As these molecular structures are also found on non-pathogenic and commensal microorganisms the term microbe-associated molecular patterns (MAMPs) is increasingly used. The best characterized family of PRRs is the Toll like receptors (TLRs) that are expressed on cells of the myeloid and lymphoid lineages as well non-immune cells such as enterocytes and fibroblasts. In this review we discuss PRR signaling in the intestinal epithelium with a focus on its regulation and role in homeostasis and immunity.

Section snippets

PRR signaling pathways

The molecular structures recognized by the known human TLRs are shown in Table 1. With respect to microbial recognition, TLR 2 4, 5, and 9 function to detect common bacterial and fungal structures, whereas TLR, 3, 7 and 8 are aimed primarily at viral detection. TLRs participate in innate signaling at the cell surface and in endosomes whereas a different set of receptors known as the nucleotide-binding and oligomerization domain-like receptors (NLRs) of which there are more than 20 family

Expression and compartmentalization of PRRs in the intestine

Our current view of TLR expression in the intestine is not comprehensive with respect to tissue localization and in vivo studies. Intestinal cell lines have been frequently used to study PRR localization and signaling but the results can differ between cell lines and in vivo to in vitro (Abreu et al., 2005; Furrie et al., 2005). For example, the mouse small intestine TLR5 has been shown to be located at the apical surface of the villi and crypts epithelium (Chabot et al., 2006) but is reported

Regulation of PPR signaling by microbes

The relationship between humans and their intestinal microbiota is largely symbiotic in nature, and over eons of co-evolution multiple adaptations appear to have developed to help maintain this peaceful co-existence. On the other hand multiple viral and bacterial pathogens have also evolved mechanisms to subdue recognition by PRRs and avoid innate immunity (Rahman and McFadden, 2006). Members of the genus Bacteroides that are abundant commensals in the colon were shown to induce expression of

The role of PRR signaling in intestinal homeostasis

One of the established outcomes of PRR signaling is the activation of NF-κB and transcription of pro-inflammatory cytokines and chemokines. In the mucosal epithelium this serves to recruit phagocytes including neutrophils, macrophages and dendritic cells to the site of invading pathogens. Here dendritic cells play a crucial role in the induction of adaptive immune responses via the presentation of antigens and activation of naïve T cells in the peripheral lymph nodes. It was not surprising,

Effects of TLR signaling on epithelial barrier function

Increased permeability of the intestinal epithelium is recognized as having a role in the pathophysiology of a variety of gastrointestinal disorders and is observed in IBD, irritable bowel syndrome (IBS), celiac disease and the early stages of colon cancer development in mouse (Clayburgh et al., 2004; Wyatt et al., 1993; Arslan et al., 2001; Vilela et al., 2007; Barbara, 2006). Alterations to tight junctions (TJs) are associated with changes in epithelial permeability as confirmed by studies on

Regulation of antimicrobial peptides and proteins by PRRs

Paneth cells are specialized small intestinal cells found at the base of the crypts of Lieberkuhn that secrete a diverse range of peptides and proteins with antimicrobial activities. Among these are two of the known α-defensins (HD5 and HD6). Defensins are small antimicrobial peptides of 2-6 kDa with a β-sheet structure and six cysteine residues, which are disulfide linked (Ayabe et al., 2000; Dann and Eckmann, 2007). Defensins show antimicrobial activity against Gram-positive and Gram-negative

Conclusions

The human intestinal microbiota makes numerous symbiotic contributions but has the potential to trigger chronic inflammation via the perpetual activation of PRR signaling in the mucosa. As PRRs are crucial for the innate defense against pathogens, there is a necessity for host mechanisms to distinguish between commensals and pathogens and balance tolerance and immunity. To a large extent mucus secreted by goblet cells in the intestinal wall prevents intimate contact with the vast majority of

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