Abstract
Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in regulating the integrity of intestinal homeostasis and shaping innate immune responses during bowel inflammation. Intensive research efforts are being made to achieve an integrated view about the protective/detrimental role of canonical and non-canonical NLRP3 inflammasome activation in the maintenance of intestinal microenvironment integrity. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome could represent a promising molecular target for the therapeutic management of inflammatory immune-mediated gut diseases. The present review has been intended to provide a critical appraisal of the available knowledge about the role of canonical and non-canonical NLRP3 inflammasome activation in the dynamic interplay between microbiota, intestinal epithelium, and innate immune system, taken together as a whole integrated network regulating the maintenance/breakdown of intestinal homeostasis. Moreover, special attention has been paid to the pharmacological modulation of NLRP3 inflammasome, emphasizing the concept that this multiprotein complex could represent a suitable target for the management of inflammatory bowel diseases.
Highlights
A growing body of evidence highlights the relevance of the nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathophysiology of several autoinflammatory syndromes [i.e., cryopyrin-associated autoinflammatory syndromes (CAPS), Schnitzler’s syndrome], as well as metabolic and/or inflammatory disorders [1,2,3]
In the model of dextran sodium sulfate (DSS)-induced acute colitis, which causes a direct damage to the epithelial barrier, with consequent stimulation of innate immune cells by commensal bacteria, infiltration of myeloid cells and massive inflammation, IL-1β and IL-18 appear to be essential for tissue repair and the maintenance of epithelial barrier integrity [56], suggesting a protective role of NLRP3
Studies aimed at characterizing the molecular mechanisms and downstream signaling underlying the canonical and noncanonical NLRP3 inflammasome activation have unraveled the pivotal and dual role of this enzymatic complex in the intestinal homeostasis
Summary
A growing body of evidence highlights the relevance of the nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome in the pathophysiology of several autoinflammatory syndromes [i.e., cryopyrin-associated autoinflammatory syndromes (CAPS), Schnitzler’s syndrome], as well as metabolic and/or inflammatory disorders (i.e., obesity, atherosclerosis, type 2 diabetes, gout, and intestinal inflammation) [1,2,3]. Nlrp3−/−, Asc−/−, and caspase-1−/− mice were found to be more susceptible to colitis induced by dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzenesulfonic acid (TNBS), both characterized by body weight loss, diarrhea, rectal bleeding, and mortality, suggesting a protective role of NLRP3 inflammasome in the digestive tract Such a favorable action was ascribed to the ability of NLRP3 of inducing IL-18 release, a crucial mediator in the repair of colonic mucosal barrier that, through binding IL-18 receptors on intestinal epithelial cells, exerts a restorative effect on the enteric epithelium (Figure 2). These findings highlight the relevance of NLRP3 in modulating the interplay between intestinal epithelium and innate immune cells, suggesting a
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
