Nuclear receptor Rev‐erbα alleviates intervertebral disc degeneration by recruiting NCoR–HDAC3 co‐repressor and inhibiting NLRP3 inflammasome

Abstract

AbstractIntervertebral discs (IVDs) are rhythmic tissues that experience daily low‐load recovery. Notably, aging and abnormal mechanical stress predispose IVDs to degeneration due to dysrhythmia‐induced disordered metabolism. Meanwhile, Rev‐erbα acts as a transcriptional repressor in maintaining biorhythms and homeostasis; however, its function in IVD homeostasis and degeneration remains unclear. This study assessed the relationship between low Rev‐erbα expression levels and IVD degeneration. Rev‐erbα deficiency accelerated needle puncture or aging‐induced IVD degeneration, characterized by increased extracellular matrix (ECM) catabolism and nucleus pulposus (NP) cell apoptosis. Mechanistically, Rev‐erbα knockdown in NP cells aggravated rhIL1β‐induced NOD‐like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, exacerbating the imbalanced ECM and NP cell apoptosis. Meanwhile, blocking NLRP3 inflammasome activation mitigated Rev‐erbα deficiency and needle puncture‐induced IVD degeneration. Particularly, Rev‐erbα mediated the transcriptional repression of the NLRP3 inflammasome via the ligand heme‐binding of nuclear receptor co‐repressor (NCoR) and histone deacetylase 3 (HDAC3) complex. Thus, the increased expression of Rev‐erbα in NP cells following short‐term rhIL1β treatment failed to inhibit NLRP3 transcription in vitro owing to heme depletion. Pharmacological activation of Rev‐erbα in vivo and in vitro alleviated IVD degeneration by altering the NLRP3 inflammasome. Taken together, targeting Rev‐erbα may be a potential therapeutic strategy for alleviating IVD degeneration and its related diseases.