Circadian clock component REV-ERBα controls homeostatic regulation of pulmonary inflammation

Abstract

Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERBα as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous proinflammatory mechanism in unchallenged cells. However, REV-ERBα plays the dominant role, as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation, and used this to reveal how proinflammatory cytokines trigger rapid degradation of REV-ERBα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERBα protein couple the core clock to innate immunity.

Circadian control of lung inflammation in influenza infection

“…However, in response to Listeria, Nyugen et al(3) noted a preponderance of inflammatory Ly6c hi monocytes in the spleen of Bmal1l Loxp/LoxP Lyz2 Cre mice. More recently, Poullaird et al, noted increased neutrophils in response to LPS in Rev-erbα -/mice at ZT0 but not at ZT4 (41). While it is probable that neutrophils may serve as the effector cells for the circadian regulation of TLR4 signaling pathways (39,41,42) this mechanism does not underlie the response to viruses.…”

“…More recently, Poullaird et al, noted increased neutrophils in response to LPS in Rev-erbα -/mice at ZT0 but not at ZT4 (41). While it is probable that neutrophils may serve as the effector cells for the circadian regulation of TLR4 signaling pathways (39,41,42) this mechanism does not underlie the response to viruses. In fact, in a global Bmal1 -/mice, there was no significant differences between the cellular responses to Sendai Virus (11).In other studies, the effect of Bmal1 on viral nucleic acid expression (9) or mortality(30) was described, but specific cellular mediators in the host's immune repertoire were not examined.…”

NR1D1 modulates synovial inflammation and bone destruction in rheumatoid arthritis

“…NR1D1 is linked to the immune system, as it has been shown to repress Tolllike receptor 4, Cx3cr1, and IL-6 expression in macrophages 15 . Therefore, activated NR1D1 alleviates the progression of pneumonia and fulminant hepatitis 19,20 . NR1D1 regulates the inflammatory response; however, whether NR1D1 mediates the pathogenesis of RA and related mechanisms remain poorly defined.…”

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

“…These proteins drive the transcription of several clock-related genes including Period (Per1/2/3), Cryptochrome (Cry1/2), REV-ERB proteins (Nr1d1/Nr1d2 encode REV-ERBα/REV-ERBβ), and retinoic acid receptor-related orphan receptors (e.g., Rora). Of these, REV-ERBα and β transcriptionally repress Bmal1 by binding to the RORE cis-element in its promoter region (Herzog, Hermanstyne, Smyllie, & Hastings, 2017) and connect the circadian system to macrophage-driven inflammation (Gibbs et al, 2012;Griffin et al, 2019;Pariollaud et al, 2018). Rev-Erbα/β are also nuclear receptors which function as transcriptional repressors and exert a variety of biological functions (Everett & Lazar, 2014;Lam et al, 2013;Woldt et al, 2013).…”