Key Points Macrophage deletion of PPARδ reduces inflammation/revascularization of injured muscle. PPARδ expression is not required for M2 macrophage activation in injured muscle. IL-10 is required for M2 macrophage activation after sterile muscle injury. Changes in macrophage phenotype in injured muscle profoundly influence regeneration. In particular, the shift of macrophages from a proinflammatory (M1 biased) phenotype to a proregenerative (M2 biased) phenotype characterized by expression of CD206 and CD163 is essential for normal repair. According to the current canonical mechanism regulating for M1/M2 phenotype transition, signaling through PPARδ is necessary for obtaining the M2-biased phenotype. Our findings confirm that the murine myeloid cell–targeted deletion of Ppard reduces expression in vitro of genes that are activated in M2-biased macrophages; however, the mutation in mice in vivo increased numbers of CD206+ M2-biased macrophages and did not reduce the expression of phenotypic markers of M2-biased macrophages in regenerating muscle. Nevertheless, the mutation impaired CCL2-mediated chemotaxis of macrophages and slowed revascularization of injured muscle. In contrast, null mutation of IL-10 diminished M2-biased macrophages but produced no defects in muscle revascularization. Our results provide two significant findings. First, they illustrate that mechanisms that regulate macrophage phenotype transitions in vitro are not always predictive of mechanisms that are most important in vivo. Second, they show that mechanisms that regulate macrophage phenotype transitions differ in different in vivo environments.

中文翻译：

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骨髓细胞 PPARδ 和 IL-10 在调节急性肌肉损伤后巨噬细胞募集、表型和再生中的差异作用

关键点 PPARδ 的巨噬细胞缺失减少了受伤肌肉的炎症/血运重建。受伤肌肉中 M2 巨噬细胞激活不需要 PPARδ 表达。无菌性肌肉损伤后 M2 巨噬细胞激活需要 IL-10。受伤肌肉中巨噬细胞表型的变化对再生有着深远的影响。特别是，巨噬细胞从促炎（M1 偏向）表型转变为以 CD206 和 CD163 表达为特征的再生（M2 偏向）表型对于正常修复至关重要。根据目前调节 M1/M2 表型转变的典型机制，通过 PPARδ 信号传导是获得 M2 偏向表型所必需的。我们的研究结果证实，Ppard 的小鼠骨髓细胞靶向缺失降低了在 M2 偏向巨噬细胞中激活的基因的体外表达；然而，小鼠体内的突变增加了 CD206+ M2 偏向巨噬细胞的数量，并没有减少再生肌肉中 M2 偏向巨噬细胞表型标志物的表达。然而，该突变损害了 CCL2 介导的巨噬细胞趋化性并减缓了受伤肌肉的血运重建。相比之下，IL-10 的无效突变减少了偏向 M2 的巨噬细胞，但不会产生肌肉血运重建的缺陷。我们的结果提供了两个重要的发现。首先，他们说明体外调节巨噬细胞表型转变的机制并不总是预测体内最重要的机制。第二，