Opposing Effects of the Circadian Timing on Acute and Chronic Phases of Sepsis

The circadian clock system has been demonstrated to modulate immune function, thereby resulting in a pronounced diurnal rhythm in the host's response to infection. However, the role of the circadian clock throughout the entire course of sepsis remains unclear. This study aims to investigate whether the endogenous circadian clock mediates differential effects on sepsis at different stages of the disease. We induced sepsis in mice by intraperitoneal injection of lipopolysaccharide (LPS) during the rest phase (Zeitgeber Time 6, ZT6) and the active phase (ZT18). We found a significant time-dependent dual effect: Mice in the ZT18 group exhibited a more intense inflammatory response in the acute phase within 24 h, characterized by more severe hypothermia and elevated serum and tissue levels of tumor necrosis factor (TNF-α), leading to higher acute-phase mortality. However, upon extending the observation period to 5 days, it was observed that ZT18 group had a higher survival rate. The long-term survival advantage of the ZT18 group was associated with stronger metabolic resilience, characterized by faster recovery of the respiratory exchange ratio (RER) and energy expenditure, as well as earlier restoration of daily activity capacity. Lesioning the central clock, the suprachiasmatic nucleus (SCN), eliminated the diurnal differences in LPS-induced mortality and metabolic disturbances, indicating that the phenomenon is driven by the central clock. These findings provide a new theoretical framework for developing stage-specific chronotherapies for sepsis.