The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury.

Autor: Edwards NJ; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Hwang C; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Marini S; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Pagani CA; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Spreadborough PJ; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Rowe CJ; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Yu P; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Mei A; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Visser N; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Li S; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Hespe GE; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Huber AK; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Strong AL; Department of Surgery, University of Michigan, Ann Arbor, MI, USA., Shelef MA; Division of Rheumatology, University of Wisconsin and William S. Middleton Memorial Veterans Hospital, Madison, WI, USA., Knight JS; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA., Davis TA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA., Levi B; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Dec; Vol. 34 (12), pp. 15753-15770. Date of Electronic Publication: 2020 Oct 22.
DOI: 10.1096/fj.202000994RR
Abstrakt: Ischemia reperfusion (IR) injury results in devastating skeletal muscle fibrosis. Here, we recapitulate this injury with a mouse model of hindlimb IR injury which leads to skeletal muscle fibrosis. Injury resulted in extensive immune infiltration with robust neutrophil extracellular trap (NET) formation in the skeletal muscle, however, direct targeting of NETs via the peptidylarginine deiminase 4 (PAD4) mechanism was insufficient to reduce muscle fibrosis. Circulating levels of IL-10 and TNFα were significantly elevated post injury, indicating toll-like receptor (TLR) signaling may be involved in muscle injury. Administration of hydroxychloroquine (HCQ), a small molecule inhibitor of TLR7/8/9, following injury reduced NET formation, IL-10, and TNFα levels and ultimately mitigated muscle fibrosis and improved myofiber regeneration following IR injury. HCQ treatment decreased fibroadipogenic progenitor cell proliferation and partially inhibited ERK1/2 phosphorylation in the injured tissue, suggesting it may act through a combination of TLR7/8/9 and ERK signaling mechanisms. We demonstrate that treatment with FDA-approved HCQ leads to decreased muscle fibrosis and increased myofiber regeneration following IR injury, suggesting short-term HCQ treatment may be a viable treatment to prevent muscle fibrosis in ischemia reperfusion and traumatic extremity injury.
(© 2020 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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