Urokinase-Type Plasminogen Activator Plays Essential Roles in Macrophage Chemotaxis and Skeletal Muscle Regeneration

Abstract

Although macrophages are thought to play important roles in tissue repair, the molecular mechanisms involved remain to be elucidated. Mice deficient in urokinase-type plasminogen activator (uPA−/−) exhibit decreased accumulation of macrophages following muscle injury and severely impaired muscle regeneration. We tested whether macrophage-derived uPA plays essential roles in macrophage chemotaxis and skeletal muscle regeneration. Macrophage uPA was required for chemotaxis, even when invasion through matrix was not necessary. The mechanism by which macrophage uPA promoted chemotaxis was independent of receptor binding but appeared to depend on proteolytic activity. Exogenous uPA restored chemotaxis to uPA−/− macrophages and rescued muscle regeneration in uPA−/− mice. Macrophage depletion in wild-type (WT) mice using clodronate liposomes resulted in impaired muscle regeneration, confirming that macrophages are required for efficient healing. Furthermore, transfer of WT bone marrow cells to uPA−/− mice restored macrophage accumulation and muscle regeneration. In this rescue, transferred WT cells appeared to contribute to IGF-1 expression but did not fuse to regenerating fibers. These data indicate that WT leukocytes, including macrophages, that express uPA were sufficient to rescue muscle regeneration in uPA−/− mice. Overall, the results indicate that uPA plays a fundamental role in macrophage chemotaxis and that macrophage-derived uPA promotes efficient muscle regeneration.