Role of Inflammasomes in Intestinal Inflammation and Crohnʼs Disease

Abstract

: Inflammasomes are multiprotein complexes that process procytokines into mature forms of interleukin 1β and interleukin 18 and induce pyroptotic cell death. Evidence linking NLRP3, NLRC4, and NLRP6 inflammasomes to intestinal inflammation is reviewed to provide a basis to understand how the innate immune system discriminates pathogenic bacteria from commensal bacteria and shapes microbial ecology. Inflammasomes have a direct and important role limiting colitis by directing effective immune responses against pathogenic bacterial infections in the intestine. Chronic granulomatous disease is presented to reveal a contrasting proinflammatory effect of inflammasomes. This pathogenic effect is unmasked in a state of immunodeficiency where bacterial growth is poorly controlled increasing inflammasome activity. The role of inflammasomes in inflammation associated with Crohn's disease and ulcerative colitis is discussed. Finally, mechanistic studies linking genetic polymorphisms in ATG16L and NOD2 to inflammasome activation provide a basis for new hypotheses to explain how genetic polymorphism associated with Crohn's disease modulate intestinal inflammation. A deeper understanding of the role of inflammasomes in intestinal inflammation is expected to identify new ways of treating inflammatory bowel disease.

Host Genotype and Microbiota Contribute Asymmetrically to Transcriptional Variation in the Threespine Stickleback Gut

“…2015), and inflammasome dysfunction is associated with inflammatory bowel disease (Levy et al. 2015; Opipari and Franchi 2015), so genotype-dependent, microbe-sensitive gene expression of NLRC3 orthologs in stickleback may be relevant in an evolutionary mutant model context. Given the expression patterns for complement and NLRC3 genes, it is likely that multiple components of stickleback innate immunity react to microbes in fundamentally different ways depending on the genetic background of the host.…”

Enhanced Expression of NLRP3 Inflammasome-Related Inflammation in Diabetic Retinopathy

“…[21][22][23] In addition, previous studies showed that the NLRP3 inflammasome complex and cytokines IL-1b and IL-18 play essential roles in the development of T2DM and its major complica- . Data represent means 6 SD.…”

Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

“…It has been shown, for instance, that several gene polymorphisms associated with increased risk for development of CD, most notably loss-of-function polymorphisms involving NOD2 and ATG16L1, have been associated with changes in NLRP3 activity and could thus be contributors to gut inflammation via their effect on inflammasome function (32). In addition, patients with intestinal inflammation associated with gene abnormalities' leading to mevalonate kinase deficiency and chronic granulomatous disease (CGD) have benefited from treatment with agents that block IL-1β (33,34).…”