REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome

Jul 29, 2021Biochemical pharmacology

REV-ERBα activator SR9009 reduces inflammatory IL-1β in immune cells by blocking inflammasome through BMAL1

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Abstract

The production of the inflammatory cytokine IL-1β in macrophages is influenced by the timing of lipopolysaccharide stimulation.

Circadian clock components, particularly BMAL1 and REV-ERBα, regulate inflammatory responses in macrophages.
Pharmacological activation of REV-ERBα with SR9009 significantly reduces inflammation caused by lipopolysaccharide in vitro and in vivo.
The inhibitory effect of SR9009 on IL-1β and IL-18 production in macrophages is dependent on the presence of BMAL1.
Knockout of BMAL1 in macrophages worsens the hypometabolic state and delays recovery from lipopolysaccharide-induced endotoxemia.
These findings suggest a role for BMAL1 in regulating inflammation and metabolic responses during endotoxin exposure.

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The circadian clock plays an important role in adapting organisms to the daily light/dark cycling environment. Recent research findings reveal the involvement of the circadian clock not only in physiological functions but also in regulating inflammatory responses under pathological situations. Previous studies showed that the time-of-day variance of leucocyte circulation and pro-inflammatory cytokines secretion could be directly regulated by the clock-related proteins, including BMAL1 and REV-ERBα in a 24-hour oscillation pattern. To investigate the molecular mechanism behind the regulation of inflammation by the core clock components, we focus on the inflammatory responses in macrophages. Using bone marrow-derived macrophages from wild type and myeloid selective BMAL1-knockout mice, we found that the production of inflammatory cytokines, particularly IL-1β, was dependent on the timing of the lipopolysaccharide (LPS) stimulation in macrophages. Pharmacological activation of REV-ERBα with SR9009 significantly suppressed the LPS-induced inflammation in vitro and in vivo. Particularly, the effect of SR9009 on inhibiting NLRP3-mediated IL-1β and IL-18 production in macrophages was dependent on BMAL1 expression. Further analysis of the metabolic activity in LPS-treated mice showed that knockout of BMAL1 in macrophages exacerbated the hypometabolic state and delayed the recovery from LPS-induced endotoxemia even in the presence of SR9009. These results demonstrated an anti-inflammatory role of REV-ERBα in endotoxin-induced inflammation, during which the secretion of IL-1β through the NLRP3 inflammasome pathway inhibited by SR9009 was regulated by BMAL1.

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REV-ERBα agonist SR9009 suppresses IL-1β production in macrophages through BMAL1-dependent inhibition of inflammasome

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