Circadian misalignment and low-grade inflammation: Failure of temporal gating by the molecular clock

Circadian misalignment, from shift work, recurrent sleep-wake disruption, or mistimed behavioral rhythms, tracks with cardiometabolic disease and low-grade systemic inflammation, yet no single account ties the molecular, animal, and human evidence together. This narrative review reads that evidence through one idea: temporal gating of innate immunity by the molecular clock. Clock components, chiefly REV-ERBα and BMAL1, confine NF-κB and NLRP3 inflammasome activity to defined circadian windows through transcriptional and metabolic routes. Misalignment then amounts to internal phase dissociation between central and peripheral clocks, letting inflammation fire at the wrong biological time. Controlled human protocols show that misalignment modestly raises 24-hour high-sensitivity C-reactive protein even when sleep loss is held constant, although cytokine responses are mixed rather than uniformly proinflammatory. Apparent inconsistencies, such as pathway-specific BMAL1 effects, variable biomarkers, and imperfect clock-targeting drugs, reflect biological and methodological heterogeneity and are only partly resolved at present. The mechanistic case for a contribution to chronic inflammation is considerably stronger than the quantitative human case, and causal inference remains incomplete. Behavioral realignment has the firmest translational support; clock-targeted drugs remain largely preclinical. Because low-grade inflammation also figures in mood disorders, mood disorders are discussed here as a hypothesis-generating translational exemplar rather than as evidence of a directly tested circadian-misalignment-inflammation-mood pathway. Standardized circadian-phase assessment and longitudinal human studies are needed.