Role of NLRP3 inflammasome in inflammatory bowel diseases

Abstract

Inflammasomes are multiprotein intracellular complexes which are responsible for the activation of inflammatory responses. Among various subtypes of inflammasomes, NLRP3 has been a subject of intensive investigation. NLRP3 is considered to be a sensor of microbial and other danger signals and plays a crucial role in mucosal immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β (IL-1β) and IL-18. NLRP3 inflammasome has been associated with a variety of inflammatory and autoimmune conditions, including inflammatory bowel diseases (IBD). The role of NLRP3 in IBD is not yet fully elucidated as it seems to demonstrate both pathogenic and protective effects. Studies have shown a relationship between genetic variants and mutations in NLRP3 gene with IBD pathogenesis. A complex interaction between the NLRP3 inflammasome and the mucosal immune response has been reported. Activation of the inflammasome is a key function mediated by the innate immune response and in parallel the signaling through IL-1β and IL-18 is implicated in adaptive immunity. Further research is needed to delineate the precise mechanisms of NLRP3 function in regulating immune responses. Targeting NLRP3 inflammasome and its downstream signaling will provide new insights into the development of future therapeutic strategies.

Keywords: Inflammatory bowel diseases; Interleukin 18; Interleukin 1β; Mucosal immune system; NLRP3 gene polymorphisms; NLRP3 inflammasome.

Figure 1

NLRP3 inflammasome structure. NLRP3 inflammasome consists of three major components-the sensor NLRP3 protein, the adaptor-apoptosis-associated speck-like protein (ASC) which contains a N-terminal PYRIN-PAAD-DAPIN domain (PYD) and a C-terminal caspase recruitment domain (CARD) and the effector protein-caspase-1. Activation of NLRP3 occurs when the cell is subjected to pathogen-associated molecular patterns and damage-associated molecular patterns. The stimulated NLRP3 interacts through PYD domain with ASC and pro-caspase-1 binds to ASC via CARD to assemble into a large cytosolic complex, which triggers activation of caspase-1. Active caspase-1 cleaves the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18 from their precursors to their biologically active forms inducing inflammation. ASC: Adaptor-apoptosis-associated speck-like protein; CARD: C-terminal caspase recruitment domain; PYD: PYRIN-PAAD-DAPIN domain; IL: Interleukin; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns.