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Chronoregulation of innate immune cell fibrinolytic activity

ABSTRACT: Peritoneal macrophages are important for pathogen clearance, forming cell-pathogen aggregates held together by fibrin. This can be beneficial in limiting the spread of pathogens, however, persistent fibrin deposits can lead to abdominal adhesions which give rise to multiple comorbidities. How this process is regulated is poorly understood. Under inflammatory conditions, macrophages secrete PAI-1, a potent inhibitor of fibrinolysis. We found that macrophage fibrinolytic activity is dependent on the time of day. PAI 1 secretion by peritoneal macrophages was increased at the onset of activity (ZT13) compared to at the onset of rest (ZT1), both basally and following in vivo LPS stimulation. Furthermore, the fibrinolytic response was reduced at ZT13 compared to ZT1. We also establish a novel role for the Rev-erbα agonist SR9009 in reversing macrophage anti-fibrinolytic activity. The chrono-dependency of macrophage fibrinolytic activity was confirmed using SR9009, which potently inhibited PAI-1 and PAI-2 secretion from LPS-stimulated macrophages, boosting plasmin generation and fibrin clot lysis in the presence of both macrophages and endothelial cells. Moreover, SR9009 promoted intraperitoneal fibrinolysis in LPS-administered mice. Collectively, these data highlight a novel role for circadian regulation of macrophage fibrinolytic activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE324312 | GEO | 2026/08/09

REPOSITORIES: GEO

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