Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking

Abstract

The systemic inflammatory response observed during acute graft-versus-host disease (aGVHD) is driven by proinflammatory cytokines, a 'cytokine storm'. The function of plasmin in regulating the inflammatory response is not fully understood, and its role in the development of aGVHD remains unresolved. Here we show that plasmin is activated during the early phase of aGVHD in mice, and its activation correlated with aGVHD severity in humans. Pharmacological plasmin inhibition protected against aGVHD-associated lethality in mice. Mechanistically, plasmin inhibition impaired the infiltration of inflammatory cells, the release of membrane-associated proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and Fas-ligand directly, or indirectly via matrix metalloproteinases (MMPs) and alters monocyte chemoattractant protein-1 (MCP-1) signaling. We propose that plasmin and potentially MMP-9 inhibition offers a novel therapeutic strategy to control the deadly cytokine storm in patients with aGVHD, thereby preventing tissue destruction.

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

“…Outside the realm of biological products, CRS is also common and could occur in conditions like severe infection, hemophagocytic syndrome (HLH), or graft versus host disease (GvHD) [29–31]. It is generally accepted that CRS is an immune-mediated disorder.…”

Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines

“…mmol,6.0 equiv), compound 10 (56.4 mg, 0.245 mmol,1.2 equiv), and HATU (186 mg, 0.489 mmol, 2.4 equiv) in 150 mL of DMF. The crude product was purified via flash chromatography (silica gel, DCM/MeOH 15:1 with 0.5% NH 4 OH (25%)).…”

Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

“…5,18,[21][22][23][24][25][26][27] In addition, MMP-9 is also a key molecule involved in the infiltration of inflammatory cells. 28 Although the binding of CXCL10 onto its receptors, CXCR3A and CXCR3B, regulates immune responses through the recruitment and activation of leukocytes, such as lymphocytes, eosinophils, monocytes, and neutrophils, the main infiltrated cells observed in the lesional skin of patients with BP, [29][30][31] its involvement in MMP-9 secretion from these cells has still not been investigated.…”