RIPK3-MLKL依赖的程序性坏死通路在炎性肌病非免疫机制中的作用

Inflammatory myopathies are a group of autoimmune diseases that preferentially affect the skeletal muscle, with great severity and poor prognosis. Predominate muscle fiber necrosis and macrophage invasion are characteristic in some patients, indicating their pathogenicity. The inducing and modulation of necroptosis is the highlight of the medical research in recent years, which is involved in many process of chronic inflammation and tissue injury. We previously demonstrated that the key molecule receptor-interacting protein kinase 3 (RIPK3) is overexpressed in the muscle biopsies of patients with inflammatory myopathies. In this study, we first aim to use biopsy samples and in vitro myotube culture to investigate the necroptosis pathway and its modulation. Secondly we will utilize the myotube-macrophage transwell co-culture assay to investigate the role of macrophage in necroptosis modulation. This study will shed light on the signaling pathway and related molecular network of myocyte necrosis, thus will provide scientific basis for screening new therapeutic strategies targeting necroptosis and macrophage.

炎性肌病是一种好累及骨骼肌的自身免疫性疾病，病情重，治疗效果差。部分患者存在明显的肌纤维坏死和巨噬细胞浸润，提示其在发病机制中有重要作用。近年来程序性坏死在各种慢性炎症和损伤中的作用日益受到关注。我们的前期研究发现，程序性坏死通路的关键分子受体交互蛋白激酶3（RIPK3）在炎性肌病患者肌肉组织中明显上调。本研究首先以程序性坏死为切入点，利用患者肌肉活检组织和体外细胞学实验，研究该通路在炎性肌病中的上调情况和调控因子。然后利用体外肌管细胞-巨噬细胞共培养体系，探讨巨噬细胞对程序性坏死的调控和作用途径。通过研究以期发现炎性肌病的肌肉坏死发生发展机制，为探索针对程序性坏死和巨噬细胞的治疗策略提供理论和实验依据。

特发性炎性肌病是一种好累及骨骼肌的自身免疫性疾病，患者病情重、疗效差，往往遗留肌无力、肌萎缩等肢体功能障碍，亟需特异性治疗和预防再发手段。以免疫介导坏死性肌病为代表，患者肌肉标本中常见明显的肌纤维坏死和巨噬细胞浸润，提示其在发病机制中有重要作用。我们的前期研究发现其机制可能与程序性坏死通路激活有关，并在后续工作中建立特发性炎性肌病临床队列，在免疫介导坏死性肌病活检组织中明确TNF-α诱导的程序性坏死通路关键分子上调、通路激活，在体外细胞学实验中证明从SRP和HMGCR抗体阳性的病人血浆中分离出的总IgG并不单独致病，而可以增敏人横纹肌肉瘤细胞系使其经TNF-α诱导产生坏死性凋亡。该研究为程序性坏死通路在免疫介导坏死性肌病中介导肌肉坏死假说提供了理论和实验依据，研究过程中建立的临床队列、细胞模型将为后续发病机制研究、药物临床试验等奠定基础。