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 mechanism through which PAI-1 exacerbates inflammation remains unclear. In the present study, we have 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, PAI-1 deficiency 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, is a common receptor for both PAI-1 and calreticulin (CRT). CRT is exposed on the surface of dying 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 that to 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 a PAI-1 Inhibitor, TM5614, restored efferocytosis and significantly improved tissue regeneration. These findings therefore reveal that PAI-1 produced by infiltrating inflammatory macrophages contributes to sustained inflammation by blocking efferocytosis, and that PAI-1 is a promising therapeutic target for the treatment of inflammatory diseases. Dead cells expose an "eat-me" signal molecule CRT, which is recognized by the LRP-1 receptor on macrophages, leading to their phagocytosis through a process known as efferocytosis. However, PAI-1, secreted by infiltrating CCR2⁺Ly6c⁺ macrophages, impairs tissue regeneration after injury by inhibiting efferocytosis through competitive binding to LRP-1, thereby prolonging inflammation.