HSF1 Protects Against Sepsis by Transcriptionally Upregulating Neutrophil C5aR1 to Enhance Antimicrobial Defense

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The resulting septic shock and multiple organ dysfunction syndrome (MODS) are the primary drivers of mortality. Heat shock factor 1 (HSF1), a master transcription factor regulating cellular stress responses, has been shown to exert protective effects during sepsis. Here, our RNA-seq analysis revealed a significant downregulation of complement C5a receptor 1 (C5aR1) in both HSF1-deficient and septic mice; however, the precise role of C5aR1 in sepsis progression remains poorly understood. In this study, we demonstrated that both C5aR1 expression on peripheral blood neutrophils and plasma soluble C5aR1 levels are significantly reduced in patients with sepsis. Neutrophil C5aR1 was also markedly decreased in septic mice and inversely correlated with disease severity. Functionally, overexpression of C5aR1 alleviated tissue injury and reduced organ bacterial burden in septic mice. Mechanistically, EMSA and dual-luciferase reporter assays confirmed that HSF1 directly binds to the heat shock element (HSE) within the C5aR1 promoter to positively regulate its transcription. Collectively, our study systematically characterizes the alterations of C5aR1 at the membrane, soluble, and transcriptional levels in sepsis and elucidates a novel molecular mechanism by which HSF1 modulates neutrophil C5aR1 to enhance antimicrobial defense and mitigate multi-organ injury, providing fresh insights into potential diagnostic and therapeutic strategies for sepsis.