The role of innate immunity receptors in the pathogenesis of inflammatory bowel disease

Abstract

Innate immunity constitutes the first line of defense, fundamental for the recognition and the initiation of an inflammatory response against microorganisms. The innate immune response relies on the sensing of microbial-associated molecular patterns through specialized structures such as toll-like receptors (TLRs) and the nucleotide oligomerization domain- (NOD-) like receptors (NLRs). In the gut, these tasks are performed by the epithelial barrier and the presence of adaptive and innate immune mechanisms. TLRs and NLRs are distributed throughout the gastrointestinal mucosa, being more expressed in the epithelium, and in lamina propria immune and nonimmune cells. These innate immunity receptors exhibit complementary biological functions, with evidence for pathways overlapping. However, as tolerance is the predominant physiological response in the gastrointestinal mucosa, it appears that the TLRs are relatively downregulated, while NLRs play a critical role in mucosal defense in the gut. Over the past two decades, genetic polymorphisms have been associated with several diseases including inflammatory bowel disease. Special emphasis has been given to the susceptibility to Crohn's disease, in association with abnormalities in the NOD2 and in the NLRP3/inflammasome. Nevertheless, the mechanisms underlying innate immune receptors dysfunction that result in the persistent inflammation in inflammatory bowel disease remain to be clarified.

Figure 1

The mechanism of intestinal response against MAMPs and DAMPs in normal conditions. The epithelial barrier recognizes microbial-associated molecular patterns (MAMPs) by the presence of transmembrane TLRs and intracellular microbes and damage-associated molecular patterns (DAMPs), by the cytosolic NLRs. When invading the lamina propria, microorganisms can be recognized through the same mechanisms, by other cells such as dendritic cells, macrophages, lymphocytes, innate lymphoid cells, and stromal cells. The result of the activation of immune cells in the lamina propria and the degree of cell damage, caused by chemokines and cytokines, determine the feedback of the system. TLRs and NLRs drive the immune response and contribute to the maintenance of homeostasis.

Figure 2

TLR and NLR pathways. The TLR pathway is composed of the conserved domain toll-IL-1-resistence (TIR), which senses microbial-associated molecular pattern (MAMPs) and interacts with the myeloid differentiation primary-response protein 88 (MyD88). MyD88 drives signaling through NF-kappa B, by interacting with the IL-1R-associated kinases 1, 2, and 4 (IRAK1, 2, and 4), TNF receptor-associated factor 6 (TRAF6), TGF-β activated kinase 1 (TAK1), and the inhibitor of kappa B (IKKa, b, and y), promoting the activation of proinflammatory cytokines (left). The NLR pathway can be activated by bacterial muramyl dipeptide (MDP), interacting with the leucine-rich repeat-containing protein (LRR) present in NOD1 and NOD2 structures. Both NOD1 and NOD2 can interact with the adaptor molecule RICK (RIP2) via caspase recruitment domains (CARD-CARD) and stimulate TRAF6, which drives the activation of other elements of NF-kappa B and MAPK pathways, with the consequent production of proinflammatory cytokines (right). Additionally, NOD2 can interact with ATG16L1 and stimulate the formation of the autophagosome.

Figure 3

The inflammasome pathway. Depending on the type of stimulus and the type of cell or tissue, signaling through NLR proteins can activate different inflammasomes. Inflammasome is a multiprotein complex composed of NACHT LRR protein (NLRP) and apoptosis-associated speck-like protein containing CARD (ASC), which cleaves procaspase-1 (pro-casp-1) in caspase-1. Once activated, caspase-1 catalyzes the cleavage of pro-IL-18 and pro-IL-1β into IL-18 and IL-1β, respectively, promoting the inflammatory response.