Spontaneous and persistent activation of NLRP3/NALP3 inflammasome plays a critical pathological role in colitis of IL-10 deficient (IL-10-/-) mice (P3240)

Abstract

Abstract IL-10-/- mice spontaneously develop chronic colitis. Our study was to evaluate the role and regulation of NLRP3 inflammasome in colitis of IL-10-/- mice and Crohn’s disease (CD). Two major NLRP3 complex proteins, NLRP3 and ASC, were upregulated in colonic mucosa of both IL-10-/- mice and CD. Importantly, NLRP3 inflammasome in IL-10-/- mice was activated prior to the onset of colitis; it progressively increased as disease worsened, peaking as macroscopic disease emerged. NOD2, a major IBD susceptible gene product, was upregulated only at a later stage of colitis when NLRP3 inflammasome was fully activated. The NLRP3 complex, including NLRP3, ASC and caspase-1, was demonstrated in vivo in colonic mucosa and increased in IL-10-/- mice, using 3 independent approaches (density fractionation, crosslinking, and co-IP). NLRP3 inflammasome activation occurred spontaneously in macrophages of IL-10-/- but not WT mice, and was effectively inhibited by IL-10. Glyburide, an inflammasome inhibitor, suppressed NLRP3 inflammasome expression/activation in IL-10-/- mice, resulting in not only alleviation of preexisting colitis, but also prevention of colitis development when given before disease onset. Thus, spontaneous and persistent activation of NLRP3 inflammasome, which is negatively regulated by IL-10, plays a major pathogenic role in colitis, it functions as a disease initiator whereas NOD2 may act as an accelerator. Inhibitors of the NLRP3 inflammasome may have utility in IBD therapy.