Bacterial interactions with cells of the intestinal mucosa: Toll-like receptors and NOD2

Abstract

Toll-like receptors (TLR) and NOD2 are emerging as key mediators of innate host defence in the intestinal mucosa, crucially involved in maintaining mucosal as well as commensal homeostasis. Recent observations suggest new (patho-) physiological mechanisms of how functional versus dysfunctional TLRx/NOD2 pathways may oppose or favour inflammatory bowel disease (IBD). In health, TLRx signalling protects the intestinal epithelial barrier and confers commensal tolerance whereas NOD2 signalling exerts antimicrobial activity and prevents pathogenic invasion. In disease, aberrant TLRx and/or NOD2 signalling may stimulate diverse inflammatory responses leading to acute and chronic intestinal inflammation with many different clinical phenotypes.

Figure 1

Toll-like receptor 4/nucleotide binding oligomerisation domain 2 (TLR4/NOD2) structure and inflammatory bowel disease associated common variants. (A) Mammalian TLRs are a family of type I transmembrane receptors which are all characterised by three common structural features, as exemplified for TLR4 here: a divergent ligand binding extracellular domain with multiple leucine rich repeats (LRR), a short transmembrane region and a highly homologous cytoplasmic Toll-interleukin 1 receptor (TIR) domain. Two common cosegregating missense mutations (D299G and T399I) that affect the extracellular ligand recognition domain of the TLR4 receptor are associated with deregulated immune responses to lipopolysaccharide in humans. (B) NOD1 and NOD2 are members of a family of intracellular proteins that contain an N terminal caspase recruitment domain (CARD), a centrally located nucleotide binding domain (NBD), and a C terminal regulatory domain. As shown here, NOD2 protein contains two N terminal CARDs fused to a central NBD domain followed by 10 tandem LRRs at the C terminus. Three main NOD2 variants (R702W, G908R, and L1007fsinsC) were confirmed to be associated with susceptibility to some types of Crohn’s disease.

Figure 2

TLRx ligand diversity. Different pathogen associated molecular patterns (PAMPs) selectively activate different Toll-like receptors (TLRs) (that is, each TLR binds specific “molecular signatures” of different classes of microorganisms or individual features present on diverse commensals or pathogens). A short list of the main ligands is presented.

Figure 3

TLRx/NOD2 signalling pathways. Toll-like receptor (TLR) signalling is mediated by a complexity of various selective pathways. Rip2 is a direct downstream signal transducer of both TLRx and nucleotide binding oligomerisation domain (NOD2), thus possibly allowing regulatory cross talk between these two distinct pathways. IFN-γ, interferon γ; IRAK, interleukin 1 receptor associated kinase; IL, interleukin; TNF-α, tumour necrosis factor α; NFκB, nuclear factor κB.

Figure 4

TLRx/NOD2 physiology and pathophysiology. In the healthy gut, both Toll-like receptors (TLRx) and nucleotide binding oligomerisation domain 2 (NOD2) are majorly involved in host defence and tissue repair responses, thus maintaining mucosal as well as commensal homeostasis. TLRx signalling protects the intestinal epithelial barrier, confers tolerance, and promotes healing. NOD2 exerts antimicrobial activity through defensin production and prevents intracellular bacterial invasion. When commensal and/or mucosal homeostasis are impaired due to genetic and/or environmental triggers, disease may develop: bacterial dysrecognition and intolerance through aberrant TLR and/or NOD signalling stimulates exaggerated proinflammatory responses leading to chronic inflammation via cytokine and chemokine production. TLR dysfunction induces tissue damage and barrier destruction by loss of commensal mediated colonic epithelial progenitor responses. NOD2 dysfunction leads to defective sensing of microbial threats and loss of bactericidal responses, thus allowing bacterial invasion into the host.

Figure 5

Current concept of how TLRx/NOD2 dysfunctions may contribute to the pathophysiology of Crohn’s disease. Toll-like receptor (TLRs) and nucleotide binding oligomerisation domains (NODs) are present in the intestinal epithelium, the frontline of the mucosal immune system. “Gain of dysfunction” receptor variants may allow commensals to cross the intestinal epithelial barrier and gain access to the antigen presenting cells (APC) of the underlying mucosa. Subsequent commensal mediated stimulation of APC signalling may induce nuclear factor κB (NFκB) dysregulation leading to exaggerated TH1 responses and perpetuation of apoptosis.