α2-antiplasmin is a key regulator of macrophage activation syndrome progression through modulation of IFN-γ-induced responses and fibrin deposition

Abstract

Abstract Background: Macrophage activation syndrome (MAS) is a life-threatening condition, characterized by cytopenia, multi-organ dysfunction, and coagulopathy associated with excessive activation of macrophages. The aim of this study was to clarify the role of a2-antiplasmin (α2AP) in the pathogenesis of MAS. Methods: We investigated the role of α2AP in the progression of MAS using fulminant MAS mouse model induced by Toll-like receptor-9 (TLR-9) agonist (CpG) and d-galactosamine (DG). Results: α2AP deficiency attenuated macrophage accumulation, hypocellular bone marrow (BM), liver damage, and fibrin deposition in the MAS model mice. Interferon-g (IFN-γ) is associated with macrophage activation, including phagocytosis, invasion, and migration, and plays a pivotal role in MAS progression. α2AP enhanced the IFN-γ-induced phagocytosis, invasion, migration, and tissue factor (TF) production. Additionally, we showed that fibrin induced macrophage activation and tumor necrosis factor-a (TNF-α) production. Moreover, the blockade of α2AP by neutralizing antibodies attenuated macrophage accumulation, hypocellular BM, liver damage, and fibrin deposition in the MAS model mice. Conclusion: α2AP regulates macrophage activation through modulation of IFN-γ-induced responses and fibrin deposition and is associated with MAS progression.