Circadian Disruption Exacerbates Innate Immune Responses by Modulating the Bistability of Pro-Inflammatory Signaling:...

Background/Objectives: Circadian disruption resulting from factors such as jet lag, shift work, or aging leads to exaggerated inflammatory responses and increased disease susceptibility. However, the core dynamical mechanism by which circadian disruption exacerbates innate immune responses remains poorly understood. Methods: We develop an integrated mathematical model coupling the mammalian circadian clock with antigen-induced innate immune responses, incorporating key regulatory interactions including glucocorticoid modulation and pro-inflammatory positive feedback loops. Results: The model successfully recapitulates experimental data regarding homeostatic immune circadian oscillations and time-dependent gating of acute inflammatory responses. Dynamic analyses reveal that the circadian clock exerts its gating function by modulating the bistable characteristics within pro-inflammatory positive feedback loops. Circadian disruption, simulated as jet lag or age-related reduction in clock gene amplitude, reshapes this bistable landscape and prolongs residence duration in the pathological hyperinflammatory state. Conclusions: This shift not only amplifies acute cytokine bursts but also sustains exaggerated inflammatory activity, providing a mechanistic explanation for acute tissue injury and chronic low-grade inflammation (inflammaging) under these circadian disruption scenarios.