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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\u201010 and TNF\u03b1 were significantly elevated post injury, indicating toll\u2010like 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\u201010, and TNF\u03b1 levels and ultimately mitigated muscle fibrosis and improved myofiber regeneration following IR injury. 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