NLRP3 Inflammasome and Inflammatory Bowel Disease

Abstract

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.

Keywords: Crohn's disease; NLRP3 inflammasome; gut homeostasis; mucosal immune; ulcerative colitis.

Figure 1

NLRP3 Inflammasome complex and pathology of the IBD. (Part 1) The production of proinflammatory cytokines IL-1β and IL-18 is a two-step process. NF-κB activation can rapidly prime the expressions of pro-IL-1β and pro-IL-18, which are then cleaved into the mature IL-1β and IL-18 by caspase-1 in the Inflammasome. The second signal can directly activate inflammasome assembly. And cleavage of gasdermin D by caspase-11 and caspase-1 is essential for pyroptosis of innate immune cells and endothelial cells harboring LPS-tainted cytoplasm. (Part 2) The intestinal epithelial barrier protects underlying mucosal tissues from commensal bacteria present in the gut. But in susceptible hosts, the epithelial barrier is compromised allowing commensal bacteria to invade lamina propria and mucosa. Infiltrated bacteria interact with macrophages, Dendritic cells(DC) and neutrophils via innate recognition receptors such as NLRs. Activation of NLRs induces the production of proinflammatory cytokines which further recruit immune cells to the infected tissue accelerating inflammatory response.

Figure 2

Polymorphisms of NLRP3 inflammasome related gene that affect genetic susceptibility to IBD.