BMAL1 deficiency in macrophages exacerbates sepsis-induced inflammatory response and organ damage by regulating PGC-1α.

Abstract

BMAL1 is a core gene involved in the regulation of circadian rhythm; however, its role in sepsis remains incompletely understood. In this study, we investigated the molecular mechanisms by which BMAL1 influences sepsis. Sepsis models were established both in vivo using C57BL/6J mice and in vitro using THP-1-derived macrophages. We observed a significant downregulation of BMAL1 expression in peritoneal macrophages and hepatic Kupffer cells during sepsis. Overexpression of BMAL1 in macrophages via plasmid transfection suppressed LPS-induced inflammatory responses and promoted M2 macrophage polarization. Conversely, administration of STL1267, a BMAL1 inhibitor, reduced BMAL1 expression in mice and further exacerbated systemic inflammation and multi-organ injury. Moreover, we identified PGC-1α as a key downstream effector of BMAL1. Knockdown of PGC-1α using short hairpin RNA (shRNA) abrogated BMAL1-mediated anti-inflammatory effects. Collectively, these findings uncover a novel mechanism by which BMAL1 regulates acute inflammatory responses and organ damage in sepsis, highlighting its potential as a therapeutic target.