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

Abstract

The roles of Rev-erbα and circadian clock in colonic inflammation remain unclarified. Here we show colon clock genes (including Rev-erbα) are dysregulated in mice with DSS-induced colitis. In turn, disruption of the circadian clock exacerbates experimental colitis. Rev-erbα-deficient mice are more sensitive to DSS-induced colitis, supporting a critical role of Rev-erbα in disease development. Further, Rev-erbα ablation causes activation of Nlrp3 inflammasome in mice. Cell-based experiments reveal Rev-erbα inactivates Nlrp3 inflammasome mainly at the priming stage. Rev-erbα directly represses Nlrp3 transcription through specific binding to the promoter region. Additionally, Rev-erbα represses p65 transcription and indirectly repressed Nlrp3 via the NF-κB pathway. Interestingly, Rev-erbα activation in wild-type mice by SR9009 attenuates DSS-induced colitis, whereas the protective effects are lost in Nlrp3−/− and Rev-erbα−/− mice. Taken together, Rev-erbα regulates experimental colitis through its repressive action on the NF-κB/Nlrp3 axis. Targeting Rev-erbα may represent a promising approach for prevention and management of colitis.

SR9009 has REV-ERB–independent effects on cell proliferation and metabolism

“…mESCs are similar to cancer cells in terms of their high proliferative capacity. Consistent with a previous report studying cancer cell lines (11), we found that treatment with SR9009 for 2 d at a concentration (10 μM) used in many published studies (24,28,32,34,(42)(43)(44) reduced the viability of immortalized mouse and human cell lines, including some cancer cells (SI Appendix, Fig. S2A) but not fibroblasts (SI Appendix, Fig.…”

“…That study treated cells for longer times (3-7 d), used SR9009 at a concentration of 20 μM, and mainly quantified cytotoxicity via a metabolic assay [NAD(P)H-based: WST-1]. In the present study we used 10 μM, which is the most commonly used concentration among published studies (24,28,32,34,(42)(43)(44), and quantified cytotoxicity via a metabolic assay as well as cell counting and EdU incorporation. Thus, our results demonstrate antiproliferative effects of SR9009 at shorter times of exposure and lower doses, which are seen even when REV-ERBs are drastically depleted from proliferating cells.…”

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

“…The MAPK and NF-κB pathways are implicated in the control of synovial inflammation, hyperplasia, matrix degeneration, and bone destruction. There is a close correlation between NF-κB and NR1D1 16,32 . NR1D1 regulates experimental colitis by repressing the NF-κB/ NLRP3 axis 16 .…”

“…There is a close correlation between NF-κB and NR1D1 16,32 . NR1D1 regulates experimental colitis by repressing the NF-κB/ NLRP3 axis 16 . In addition, Stujanna and colleagues reported that SR9009 inhibited post-MI mortality and improved cardiac function by suppressing the MAPK and NF-κB pathways 33 .…”

“…Recent research has shown that NR1D1 modulates experimental colitis via the NF-κB/NLR family pyrin domain-containing 3 (NLRP3) axis 16 . Griffin and colleagues found that activation of NR1D1 inhibited lipopolysaccharide (LPS)-induced microglial activation and suppressed the development of neurogenic inflammation 17 .…”