The Pathogenic Role of NLRP3 Inflammasome Activation in Inflammatory Bowel Diseases of Both Mice and Humans

Abstract

Abnormal activation of NLRP3 inflammasome plays a major pathogenic role in the development of chronic colitis in IL-10-/- mice and humans. Glyburide, an FDA-approved drug, may have great potential in the management of inflammatory bowel diseases.

NLRP3 Inflammasome in Inflammatory Bowel Disease: Friend or Foe?

“…Two other reports, both using IL-10 -/-mice but by different experimental approaches, provided consistent evidence supporting a pathogenic function of the NLRP3 inflammasome in IBD [3,9]: One report in 2014 showed that IL-1b was increased in IL-10 -/-mice and that an IL-1b receptor antagonist or caspase-1 inhibitors ameliorated colitis [9]. The other report published in 2017 using both IL-10 -/-mice and human mucosal explant culture demonstrated that chemically inhibiting the NLRP3 inflammasome potently suppressed the intestinal mucosal inflammation of both mice and humans [3]. The reason for the inconsistency is unknown.…”

“…Although human research is far more challenging to conduct than comparable experimental studies, it is the only means to assure the relevance of conclusions derived from data obtained in experimental models. A recent report in which the expression of the NLRP3 inflammasome by western blot analysis of the colonic mucosa from IBD patients and healthy controls reported that NLRP3, ASC, and IL-1b were all significantly elevated in the mucosae of CD patients, compared with those obtained from of UC and healthy controls, but did not reach statistical significance in UC vs healthy controls [3]. Moreover, inhibition of the NLRP3 inflammasome with glyburide effectively suppressed the release of major proinflammatory cytokines/ chemokines by cultured colonic mucosal explants obtained from Crohn's patients [3].…”

“…A recent report in which the expression of the NLRP3 inflammasome by western blot analysis of the colonic mucosa from IBD patients and healthy controls reported that NLRP3, ASC, and IL-1b were all significantly elevated in the mucosae of CD patients, compared with those obtained from of UC and healthy controls, but did not reach statistical significance in UC vs healthy controls [3]. Moreover, inhibition of the NLRP3 inflammasome with glyburide effectively suppressed the release of major proinflammatory cytokines/ chemokines by cultured colonic mucosal explants obtained from Crohn's patients [3]. These data support the hypothesis that the NLRP3 inflammasome contributes toward the pathogenesis of CD, a conclusion supported by the data reported by Lazaridis et al [10].…”

“…Considering the functions of inflammasomes in sensing microbial or other danger signals, it is conceivable that intestinal inflammasomes must be a key component of the mucosal immune system that mediates host-microbial and host-environmental interactions. Indeed, a considerable number of reports suggest that NLR family inflammasomes, including NLRP1, NLRP3, NLRC4, and AIM2, are involved, one way or another, in the intestinal inflammation characteristic of murine models of experimental colitis [3,4]. Nevertheless, how these different inflammasomes contribute toward IBD pathogenesis remains controversial, as both pathogenic and protective effects have been reported.…”

“…The NLRP3 inflammasome is one of the most studied subfamily members of inflammasomes, sensing and activated by a sizeable spectrum of pathogenassociated patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Little is known about the negative regulator of the NLRP3 inflammasome, except that a recent report has suggested interleukin (IL)-10 functions as a potent suppressor in cultured macrophages and in mice [3]. Activated caspase-1 converts the cytosolic precursors of proinflammatory cytokine IL-1b or IL-18 into biologically active forms (Fig.…”