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Background  Macrophages, key regulators of healing/regeneration processes, strongly infiltrate ischemic tissues from patients suffering from critical limb ischemia (CLI). However pro-inflammatory markers correlate with disease progression and risk of amputation, suggesting that modulating macrophage activation state might be beneficial. We previously reported that thrombospondin-1 (TSP-1) is highly expressed in ischemic tissues during CLI in humans. TSP-1 is a matricellular protein that displays well-known angiostatic properties in cancer, and regulates inflammation  in vivo  and macrophages properties  in vitro . We therefore sought to investigate its function in a mouse model of CLI.    Methods and Findings  Using a genetic model of  tsp-1   −/−  mice subjected to femoral artery excision, we report that  tsp-1   −/−  mice were clinically and histologically protected from necrosis compared to controls. Tissue protection was associated with increased postischemic angiogenesis and muscle regeneration. We next showed that macrophages present in ischemic tissues exhibited distinct phenotypes in  tsp-1   −/−  and  wt  mice. A strong reduction of necrotic myofibers phagocytosis was observed in  tsp-1   −/−  mice. We next demonstrated that phagocytosis of muscle cell debris is a potent pro-inflammatory signal for macrophages  in vitro . Consistently with these findings, macrophages that infiltrated ischemic tissues exhibited a reduced postischemic pro-inflammatory activation state in  tsp-1   −/−  mice, characterized by a reduced Ly-6C expression and a less pro-inflammatory cytokine expression profile. Finally, we showed that monocyte depletion reversed clinical and histological protection from necrosis observed in  tsp-1   −/−  mice, thereby demonstrating that macrophages mediated tissue protection in these mice.    Conclusion  This study defines targeting postischemic macrophage activation state as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI. Furthermore, our data suggest that phagocytosis plays a crucial role in promoting a deleterious intra-tissular pro-inflammatory macrophage activation state during critical injuries. Finally, our results describe TSP-1 as a new relevant physiological target during critical leg ischemia.

Modulation of Macrophage Activation State Protects Tissue from Necrosis during Critical Limb Ischemia in Thrombospondin-1-Deficient Mice