Immunogenomics and Inflammation Research Unit EA4130, Department of Clinical Immunology and Rheumatology, Edouard Herriot Hospital, University of Lyon, Hospices Civils de Lyon, Lyon, France.
CarMeN Laboratory, University of Lyon, INSERM 1060, INRA 1397, Université Claude Bernard Lyon1, INSA Lyon, Groupement Hospitalier Est, Bron, France.
Front Immunol. 2019 Jan 14;9:3170. doi: 10.3389/fimmu.2018.03170. eCollection 2018.
Muscle inflammation as in idiopathic inflammatory myopathies (IIM) leads to muscle weakness, mononuclear cell infiltration, and myofiber dysfunction affecting calcium channels. The effects of interleukin-17A (IL-17) and tumor necrosis factor-α (TNFα) on inflammation and calcium changes were investigated in human myoblasts. Human myoblasts were exposed to IL-17 and/or TNFα with/without store-operated Ca entry (SOCE) inhibitors (2-ABP or BTP2). For co-cultures, peripheral blood mononuclear cells (PBMC) from healthy donors activated or not with phytohemagglutinin (PHA) were added to myoblasts at a 5:1 ratio. IL-17 and TNFα induced in synergy CCL20 and IL-6 production by myoblasts (>14-fold). PBMC-myoblast co-cultures enhanced CCL20 and IL-6 production in the presence or not of PHA compared to PBMC or myoblast monocultures. Anti-IL-17 and/or anti-TNFα decreased the production of IL-6 in co-cultures ( < 0.05). Transwell system that prevents direct cell-cell contact reduced CCL20 ( < 0.01) but not IL-6 secretion. IL-17 and/or TNFα increased the level of the ER stress marker Grp78, mitochondrial ROS and promoted SOCE activation by 2-fold ( < 0.01) in isolated myoblasts. SOCE inhibitors reduced the IL-6 production induced by IL-17/TNFα. Therefore, muscle inflammation induced by IL-17 and/or TNFα may increase muscle cell dysfunction, which, in turn, increased inflammation. Such close interplay between immune and non-immune mechanisms may drive and increase muscle inflammation and weakness.
肌肉炎症，如特发性炎性肌病 (IIM)，导致肌肉无力、单核细胞浸润和肌纤维功能障碍，影响钙通道。本研究旨在探讨白细胞介素-17A (IL-17) 和肿瘤坏死因子-α (TNFα) 对肌母细胞炎症和钙变化的影响。将人肌母细胞暴露于 IL-17 和/或 TNFα 中，并加入/不加入钙库操纵钙内流 (SOCE) 抑制剂 (2-ABP 或 BTP2)。对于共培养，将来自健康供体的外周血单核细胞 (PBMC) 用植物血球凝集素 (PHA) 激活或不激活，以 5:1 的比例加入肌母细胞。IL-17 和 TNFα 协同诱导肌母细胞产生 CCL20 和 IL-6 (>14 倍)。与 PBMC 或肌母细胞单培养相比，PBMC-肌母细胞共培养在有或没有 PHA 的情况下增强了 CCL20 和 IL-6 的产生。抗 IL-17 和/或抗 TNFα 降低了共培养物中 IL-6 的产生 ( < 0.05)。防止直接细胞-细胞接触的 Transwell 系统降低了 CCL20 ( < 0.01)，但不降低 IL-6 的分泌。IL-17 和/或 TNFα 在分离的肌母细胞中使内质网应激标志物 Grp78、线粒体 ROS 的水平增加 2 倍，并促进 SOCE 激活 ( < 0.01)。SOCE 抑制剂降低了 IL-17/TNFα 诱导的 IL-6 产生。因此，IL-17 和/或 TNFα 诱导的肌肉炎症可能会增加肌肉细胞功能障碍，进而增加炎症。这种免疫和非免疫机制之间的密切相互作用可能会驱动并增加肌肉炎症和虚弱。
