NLRP3 inflammasome can be widely found in epithelial cells and immune cells. The NOD-like receptors (NLRs) family member NLRP3 contains a central nucleotide-binding and oligomerization (NACHT) domain which facilitates self-oligomerization and has ATPase activity. The C-terminal conserves a leucine-rich repeats (LRRs) domain which can modulate NLRP3 activity and sense endogenous alarmins and microbial ligands. In contrast, the N-terminal pyrin domain (PYD) can account for homotypic interactions with the adaptor protein-ASC of NLRP3 inflammasome. These characters enable it function in innate immunity. Its downstream effector proteins include caspase-1 and IL-1β etc. which exhibit protective or detrimental roles in mucosal immunity in different studies. Here, we comprehensively review the current literature regarding the physiology of NLRP3 inflammasome and its potential roles in the pathogenesis of IBD. We also discuss about the complex interactions among the NLRP3 inflammasome, mucosal immune response, and gut homeostasis as found in experimental models and IBD patients.

Ulcerative colitis (UC) is a common form of inflammatory bowel disease with a complex aetiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genomewide association scan for UC in 2361 cases and 5417 controls. Loci showing evidence of association at P < 1 × 10 −5 were followed up by genotyping in an independent set of 2321 cases and 4818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10 −17 ), 16q22 (CDH1 and CDH3; P = 2.8 × 10 −8 ) and 7q31 (LAMB1; 3.0 × 10 −8 ). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, which is an established complication of longstanding UC. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of UC.

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Consistent differences in DNA methylation between IBD cases and controls at regulatory sites within these genes suggest that their altered transcription contributes to IBD pathogenesis.