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Immunology

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

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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.

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Acknowledgements

We thank physicians and nurses who cared for the patients and the staff of the FACS core facility at the IMST for their help, and Douaa Dhari for proof-reading of the manuscript. This work was supported by grants from a Grants-in-Aid for Scientific Research (C) from JSPS (KH; BH), a Grant-in-Aid for Scientific Research on Priority Areas from MEXT (KH), a Grant-in-Aid for Scientific Research from MHLW (KH; ST), Mitsubishi Pharma Research Foundation (KH), SENSHIN Medical Research Foundation (KH), Kyowa Hakko Kirin Co., Ltd. (KH), The NOVARATIS Foundation (Japan) for the Promotion of Science (BH) and a Grant-in-Aid for Scientific Research on Innovative Areas from MEXT (BH), Japan.

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Correspondence to K Hattori.

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Sato, A., Nishida, C., Sato-Kusubata, K. et al. 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. Leukemia 29, 145–156 (2015). https://doi.org/10.1038/leu.2014.151

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