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
| Autor: | Yoshio Okada, Beate Heissig, Makoto Ishihara, Yoshihiko Tashiro, Chiemi Nishida, Atsushi Sato, Hiromitsu Nakauchi, Satoshi Takahashi, Yuko Tsuda, Kaori Sato-Kusubata, Ismael Gritli, Shinya Munakata, Koichi Hattori, Akihiro Tojo, Ko Okumura, Hiroshi Shimazu, Hideo Yagita |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Plasmin animal diseases Graft vs Host Disease Enzyme-Linked Immunosorbent Assay Matrix (biology) Effector cell Severity of Illness Index Cell Line Mice Acute graft versus host disease medicine Animals Humans Fibrinolysin DNA Primers Base Sequence Reverse Transcriptase Polymerase Chain Reaction business.industry Disease mortality Biological Transport Matrix metalloproteinase 9 Hematology medicine.disease Mice Inbred C57BL Disease Models Animal Matrix Metalloproteinase 9 Oncology Immunology Female Inflammation Mediators business Cytokine storm medicine.drug |
| Zdroj: | Leukemia. 29:145-156 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2014.151 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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