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-ERBß 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-ERBß 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.
Subject(s)
Circadian Clocks/immunology , Circadian Rhythm/immunology , Homeostasis/immunology , Immunity, Innate , Nuclear Receptor Subfamily 1, Group D, Member 1/immunology , Pneumonia/immunology , Animals , Circadian Clocks/genetics , Circadian Rhythm/genetics , Homeostasis/genetics , Mice , Mice, Transgenic , Nuclear Receptor Subfamily 1, Group D, Member 1/genetics , Pneumonia/genetics , Pneumonia/pathology , Proteolysis , Sumoylation/genetics , Sumoylation/immunologySubject(s)
Drug Discovery/methods , Molecular Probes/pharmacology , Molecular Targeted Therapy/methods , Pharmaceutical Preparations/chemistry , Small Molecule Libraries/pharmacology , Drug Discovery/standards , Humans , Molecular Probes/chemistry , Molecular Targeted Therapy/standards , Reproducibility of Results , Small Molecule Libraries/chemistryABSTRACT
Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders.
