Inflammatory Macrophage-derived Plasminogen Activator Inhibitor-1 Exacerbates Inflammation through Efferocytosis Inhibition

Plasminogen activator inhibitor-1 (PAI-1) is significantly upregulated during inflammatory responses, and elevated PAI-1 levels are associated with poor prognosis in various diseases. However, the precise mechanisms by which PAI-1 exacerbates inflammation remain unclear. In this study, we investigated the role of PAI-1 in inflammation using a mouse model of skeletal muscle injury. We found that CCR2⁺Ly6C⁺ inflammatory macrophages infiltrated the injured tissues and produced substantial amounts of PAI-1. Notably, deficiency of PAI-1 specifically in these macrophages resulted in attenuated inflammation and accelerated tissue repair, despite the continued presence of PAI-1 in body fluids, indicating a local, macrophage-driven effect. Low-density lipoprotein receptor-related protein 1 (LRP-1), expressed on macrophages, serves as a common receptor for both PAI-1 and calreticulin (CRT). CRT is exposed on the surface of dead cells and functions as an “eat me” signal recognized by macrophages via LRP-1. We found that PAI-1 binds to LRP-1 with higher affinity than CRT, thereby competitively inhibiting CRT recognition and suppressing efferocytosis—the process by which macrophages clear dead cells—ultimately leading to prolonged inflammation. Importantly, administration of the PAI-1 inhibitor TM5614 restored efferocytosis and significantly improved tissue regeneration. These findings reveal that PAI-1 produced by infiltrating inflammatory macrophages contributes to sustained inflammation by blocking efferocytosis and identify PAI-1 as a promising therapeutic target for the treatment of inflammatory diseases.