@article{086d59dec828423c8c83e09d4b8768d5,
title = "The role of neutrophil extracellular traps and TLR signaling in skeletal muscle ischemia reperfusion injury",
abstract = "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.",
keywords = "extracellular signal-regulated kinases (ERK) 1/2, hydroxychloroquine, inflammation, muscle fibrosis",
author = "Edwards, {Nicole J.} and Charles Hwang and Simone Marini and Pagani, {Chase A.} and Spreadborough, {Philip J.} and Rowe, {Cassie J.} and Pauline Yu and Annie Mei and Noelle Visser and Shuli Li and Hespe, {Geoffrey E.} and Huber, {Amanda K.} and Strong, {Amy L.} and Shelef, {Miriam A.} and Knight, {Jason S.} and Davis, {Thomas A.} and Benjamin Levi",
note = "Funding Information: NJE was supported by a Ruth L. Kirschstein Institutional National Research Service Award Postdoctoral fellowship (T32‐HD007505). CH was supported by a Howard Hughes Medical Institute Medical Research Fellowship. MS was supported by National Institutes of Health NIAMS K08 AR065500. BL was supported or partially supported by National Institutes of Health (NIH) R01GM123069, R01AR071379, American College of Surgeons Clowes Award, US Department of Defense Grants W81XWH‐18‐1‐0653 (OR170174) and W81XWH‐17‐1‐0655 (OR160105). Mapk t‐ Funding Information: NJE was supported by a Ruth L. Kirschstein Institutional National Research Service Award Postdoctoral fellowship (T32-HD007505). CH was supported by a Howard Hughes Medical Institute Medical Research Fellowship. MS was supported by National Institutes of Health NIAMS K08 AR065500. BL was supported or partially supported by National Institutes of Health (NIH) R01GM123069, R01AR071379, American College of Surgeons Clowes Award, US Department of Defense Grants W81XWH-18-1-0653 (OR170174) and W81XWH-17-1-0655 (OR160105). We acknowledge current and former members of the Levi lab at University of Michigan for thoughtful discussions. We also acknowledge: K. Kessell and members of University of Michigan and Walter Reed Army Institute of Research Unit for Laboratory Animal Medicine for excellent colony management and animal care and the University of Michigan Microscopy Core for expert advice in microscopy presented here. Publisher Copyright: {\textcopyright} 2020 Federation of American Societies for Experimental Biology",
year = "2020",
month = dec,
doi = "10.1096/fj.202000994RR",
language = "English",
volume = "34",
pages = "15753--15770",
journal = "FASEB Journal",
issn = "0892-6638",
number = "12",
}