The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis

By Hasan Zaki, K. Boyd, M. Kastan, M. Lamkanfi, T. Kanneganti. Immunity, 2010

992 citations recorded by the source corpus.

SUMMARY Crohn’s disease and ulcerative colitis are inflammatory bowel diseases with high prevalence in humans. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, protein complexes responsible for the maturation and secretion of IL-1β and IL-18. Decreased expression of the NOD-like receptor (NLR) Nlrp3 was recently associated with susceptibility to Crohn’s disease. However, the role of Nlrp3 in colitis has not been characterized. Here, we show that mice deficient for Nlrp3 or the inflammasome effectors ASC and caspase-1 are highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation leads to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration and increased chemokine production in the colon. As a consequence, significantly higher mortality rates were noted for mice lacking components of the Nlrp3 inflammasome. Therefore, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/0e783c5bda49b8c6b067feea5dc3f3ffb9748403

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Citations in the corpus

Intestinal homeostasis and its breakdown in inflammatory bowel disease (2011, background): “Recent studies have indicated that NLR-mediated inflammasome activation also contributes to protection after damage of the epithelium, because mice deficient in NLRP3, its adaptor ASC or caspase-1 showed enhanced colitis and mortality after DSS administratio”
NLRP6 inflammasome is a regulator of colonic microbial ecology and risk for colitis (2011, positive): “Four previous reports indicated that caspase-1, ASC, or NLRP3 deficiencies were associated with an increased severity of acute DSS colitis in mice and suggested that exacerbated disease was mediated, in part, by a defect in repair of the intestinal mucosa (Allen et al., 2010; Dupaul-Chicoine et al.,”
Genetics and pathogenesis of inflammatory bowel disease (2011, background): “For example, mouse knockout studies of Nlrp3 or RIG - I (also known as Ddx58 ) show increased susceptibility to experimental coliti”
Inflammasome is a central player in the induction of obesity and insulin resistance (2011, background): “Nlrp3, ASC, and Casp1 mice backcrossed to C57BL/6 background for at least 10 generations have been described previously (33, 34).”
Lipotoxicity and the gut-liver axis in NASH pathogenesis. (2018, background): “These studies have reported that deficiency in inflammasome components (Nlrp3-/- and caspase-1-/mice) was associated with loss of epithelial integrity and gut inflammation that was associated with dysbiosis and bacteremia [101, 102].”
Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease (2018, background): “Endogenous alcoholic production by alcohol-producing bacteria [89]”
Nek7 is an essential mediator of NLRP3 activation downstream of potassium efflux (2016, neutral): “Consistent with additional NLRP3 function in radio-resistant recipient cells 27 , chimeric Nlrp3 −/− recipients transplanted with Nek −/− or Nlrp3 −/− fetal liver cells showed further reduction in IL-1 β production (Fig.”
Inflammasomes in health and disease (2012, background): “Using the same model, other groups found that mice deficient in NLRP3, ASC and caspase-1 show an exacerbated disease severit”