Diurnally-regulated corticosterone and melatonin inversely control endotoxin-induced acute immune responses

The timing of endotoxin administration in mice matters and is associated with diurnal variation in survival; however, underlying mechanisms remain poorly understood. Here, we report that afternoon LPS challenges in mice induce a robust inflammatory response involving increased neutrophil activation and release of cytotoxic mediators, causing higher mortality compared to challenges at midnight. Mechanistically, the cyclic patterns of corticosterone and melatonin hormones differentially modulate neutrophil responses. The afternoon corticosterone peak was associated with heightened incidence and severity of LPS-induced hyperinflammation. Conversely, higher melatonin levels at midnight conferred protection to challenged mice by restraining the magnitude of inflammation. High cortisol and low melatonin profiles detected in septic patients mirror those observed in mice and suggest a novel prognostic marker for sepsis. Our study unveils a regulatory network that links light/dark signals and circadian-regulated hormones to the intensity of the host's inflammatory response to infection. Overall design: To investigate how endotoxin challenges affect neutrophil gene expression, we sorted neutrophils from BM and blood of WT mice 4 hr following LPS administration at ZT10 or ZT18 and subjected them to bulk RNA sequencing