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首页> 外文期刊>Skeletal Muscle >Upregulated IL-1β in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages
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Upregulated IL-1β in dysferlin-deficient muscle attenuates regeneration by blunting the response to pro-inflammatory macrophages

机译：dysferlin缺陷型肌肉中IL-1β上调通过减弱对促炎性巨噬细胞的反应而减弱了再生

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Background Loss-of-function mutations in the dysferlin gene (DYSF) result in a family of muscle disorders known collectively as the dysferlinopathies. Dysferlin-deficient muscle is characterized by inflammatory foci and macrophage infiltration with subsequent decline in muscle function. Whereas macrophages function to remove necrotic tissue in acute injury, their prevalence in chronic myopathy is thought to inhibit resolution of muscle regeneration. Two major classes of macrophages, classical (M1) and alternative (M2a), play distinct roles during the acute injury process. However, their individual roles in chronic myopathy remain unclear and were explored in this study. Methods To test the roles of the two macrophage phenotypes on regeneration in dysferlin-deficient muscle, we developed an in vitro co-culture model of macrophages and muscle cells. We assayed the co-cultures using ELISA and cytokine arrays to identify secreted factors and performed transcriptome analysis of molecular networks induced in the myoblasts. Results Dysferlin-deficient muscle contained an excess of M1 macrophage markers, compared with WT, and regenerated poorly in response to toxin injury. Co-culturing macrophages with muscle cells showed that M1 macrophages inhibit muscle regeneration whereas M2a macrophages promote it, especially in dysferlin-deficient muscle cells. Examination of soluble factors released in the co-cultures and transcriptome analysis implicated two soluble factors in mediating the effects: IL-1β and IL-4, which during acute injury are secreted from M1 and M2a macrophages, respectively. To test the roles of these two factors in dysferlin-deficient muscle, myoblasts were treated with IL-4, which improved muscle differentiation, or IL-1β, which inhibited it. Importantly, blockade of IL-1β signaling significantly improved differentiation of dysferlin-deficient cells. Conclusions We propose that the inhibitory effects of M1 macrophages on myogenesis are mediated by IL-1β signals and suppression of the M1-mediated immune response may improve muscle regeneration in dysferlin deficiency. Our studies identify a potential therapeutic approach to promote muscle regeneration in dystrophic muscle.
机译：背景dysferlin基因（DYSF）的功能丧失突变导致了一系列肌肉疾病，统称为dysferlinopathies。缺乏铁蛋白的肌肉的特征在于炎性灶和巨噬细胞浸润，随后肌肉功能下降。尽管巨噬细胞在急性损伤中起着去除坏死组织的作用，但是它们在慢性肌病中的流行被认为抑制了肌肉再生的能力。在急性损伤过程中，巨噬细胞的两个主要类别为经典（M1）和另类（M2a）。然而，它们在慢性肌病中的个体作用仍不清楚，并在本研究中进行了探讨。方法为了测试这两种巨噬细胞表型在dysferlin缺陷型肌肉再生中的作用，我们建立了一个巨噬细胞和肌肉细胞体外共培养模型。我们使用ELISA和细胞因子阵列分析了共培养物以鉴定分泌因子，并对成肌细胞中诱导的分子网络进行了转录组分析。结果与WT相比，Dysferlin缺陷型肌肉含有过量的M1巨噬细胞标志物，并且对毒素损伤的反应再生较差。巨噬细胞与肌肉细胞共培养显示，M1巨噬细胞抑制肌肉再生，而M2a巨噬细胞促进肌肉再生，特别是在缺乏铁蛋白的肌细胞中。共培养物中释放的可溶性因子的检查和转录组分析涉及介导作用的两种可溶性因子：IL-1β和IL-4，它们在急性损伤中分别从M1和M2a巨噬细胞分泌。为了测试这两个因素在dysferlin缺陷型肌肉中的作用，用改善肌肉分化的IL-4或抑制它的IL-1β处理成肌细胞。重要的是，IL-1β信号传导的阻断显着改善了dysferlin缺陷细胞的分化。结论我们认为M1巨噬细胞对肌生成的抑制作用是由IL-1β信号介导的，而M1介导的免疫反应的抑制可能会改善dysferlin缺乏症的肌肉再生。我们的研究确定了促进营养不良性肌肉再生的潜在治疗方法。

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