REV-ERBα integrates colon clock with experimental colitis through regulation of NF-κB/NLRP3 axis

Area of Science:

• * Chronobiology and immunology
• * Gastroenterology and molecular biology

Background:

• * The role of circadian clock genes, specifically Rev-erbα, in colonic inflammation is not well understood.
• * Circadian clock disruption exacerbates experimental colitis, suggesting a link between biological rhythms and gut inflammation.

Purpose of the Study:

• * To investigate the role of Rev-erbα in the development and progression of colitis.
• * To elucidate the molecular mechanisms by which Rev-erbα influences colonic inflammation, particularly its interaction with the Nlrp3 inflammasome and NF-κB pathway.

Main Methods:

• * Utilized mouse models of dextran sulfate sodium (DSS)-induced colitis, including Rev-erbα-deficient and wild-type mice.
• * Employed cell-based assays to examine the effect of Rev-erbα on Nlrp3 inflammasome activation at the transcriptional and post-transcriptional levels.
• * Investigated the direct binding of Rev-erbα to the Nlrp3 promoter and its impact on NF-κB signaling.

Main Results:

• * Colon clock genes, including Rev-erbα, were dysregulated in DSS-induced colitis.
• * Rev-erbα deficiency exacerbated experimental colitis and led to Nlrp3 inflammasome activation, mediated by direct repression of Nlrp3 transcription and indirect repression via the NF-κB pathway.
• * Pharmacological activation of Rev-erbα with SR9009 attenuated DSS-induced colitis, with protective effects abolished in Nlrp3^-/- and Rev-erbα^-/- mice.

Conclusions:

• * Rev-erbα plays a critical protective role in experimental colitis by inhibiting the NF-κB/Nlrp3 inflammatory axis.
• * Targeting Rev-erbα represents a potential therapeutic strategy for the prevention and management of colitis.