Toll‐like receptors and their role in gastrointestinal disease

Abstract

The innate immune response to invading pathogens is centred upon a family of non-clonal, germline-encoded pattern recognition receptors (PRRs), the Toll-like receptors (TLRs). These provide specificity for a vast range of microbial pathogens, and offer an immediate anti-microbial response system. Thirteen mammalian TLRs have been described; 10 are expressed in humans, each responsible for the recognition of distinct, invariant microbial structures originating from bacteria, viruses, fungi and protozoa. The two most thoroughly studied are TLR4 and TLR2, the PRRs for Gram-negative and Gram-positive bacterial products, respectively. TLR4 is also the major receptor recognising endogenous ligands released from damaged or dying cells. Activation of a TLR by its relevant ligand rapidly ignites a complex intracellular signaling cascade that ultimately results in upregulation of inflammatory genes and production of proinflammatory cytokines, interferons and recruitment of myeloid cells. It also stimulates expression, upon antigen presenting cells, of co-stimulatory molecules required to induce an adaptive immune response. Whilst a robust TLR response is critical for survival and defence against invading pathogens, inappropriate signaling in response to alterations in the local microflora environment can be detrimental. Such 'unhelpful TLR responses' could form the basis for a large number of gastrointestinal and liver disorders, including inflammatory bowel disease, viral hepatitis, autoimmune liver diseases and hepatic fibrosis. As our understanding of TLRs expands, the pathogenesis of a number of gastrointestinal disorders will be further elucidated, and this offers potential for specific therapies aimed directly at TLR signaling.

Blueprints of Signaling Interactions between Pattern Recognition Receptors: Implications for the Design of Vaccine Adjuvants

“…Unraveling these signaling cascades not only is vital for the understanding of the innate immune system in general, but also could help to identify new targets for immunomodulation (3,30). Furthermore, the consistency of the biological synergistic interactions between several combinations of PRRs may be important to the field of vaccine adjuvant research (18).…”

“…Hence, these receptors can provide highly specific recognition of a vast range of microbes (3). Recognition of a PAMP by a PRR results in the activation of the innate immune system via several intracellular signaling pathways that are described in more detail elsewhere (4)(5)(6).…”

Gut microbiome and nonalcoholic fatty liver diseases

“…With the methionine and choline deficient diet (MCDD) mouse model for NASH, Rivera et al observed portal endotoxemia and elevated expression of Toll-like receptor 4, CD14 and MD2 in Kupffer cells (58). These genes are key components of the LPS/TLR4 signaling pathway leading to the production of pro-inflammatory cytokines (59). One mechanism for hepatic exposure to endotoxin is increased gut permeability such as colitis or celiac disease.…”

Gut–Liver Axis: Role of Inflammasomes

“…78 NLRs are other important membrane-bound receptors besides the TLRs for the detection of proteins. More than twenty NLRs have been known till date, although the best characterized are NOD1 and NOD2.…”