The IRE1α Arm of UPR Regulates Muscle Cells Immune Characters by Restraining p38 MAPK Activation
The IRE1α Arm of UPR Regulates Muscle Cells Immune Characters by Restraining p38 MAPK Activation
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UPR 的 IRE1 α 臂通过抑制 p38 MAPK 激活来调节肌肉细胞免疫特性
DOI：
10.3389/fphys.2019.01198
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发表时间：
2019-09-19
影响因子：
4
通讯作者：
Liao, Hua
中科院分区：
文献类型：
--
作者：
Gu, RuiCai;Huang, Tao;Liao, Hua
骨骼肌修复和全身炎症/免疫反应与肌病性肌肉中的内质网应激（ER应激）途径相关，并且肌细胞通过在持续促炎症刺激下表现出免疫学特征，在肌肉免疫反应中发挥积极作用。内质网应激是否会影响炎症环境中肌细胞的内在免疫能力，就像它对免疫细胞一样，以及未折叠蛋白反应 (UPR) 的哪些部分主要参与这些过程仍然大多未知。我们研究了这个问题，并表明炎症刺激可以在体内和体外诱导肌细胞中蛋白激酶 R (PKR) 样内质网激酶 (PERK) 和 UPR 肌醇需求酶 1 α (IRE1 α) 臂的激活。在体外，UPR应激源逆转了分化的原代肌管中IFN-γ诱导的MHC-II分子H2-Ea、MHC-I分子H-2K(b)、Toll样受体3 (TLR3)和一些促炎肌因子表达的增加。然而，进一步的 IRE1 α 抑制彻底纠正了 UPR 应激源触发的免疫生物学分子抑制的趋势。在 IFN-γ 处理的肌管中，在 IRE1 α 抑制条件下观察到 p38 MAPK 的显着激活，并且 p38 的药理学抑制逆转了 IRE1 α 抑制诱导的免疫分子上调。与此同时，我们的共培养系统证实，发炎肌管向 OT-I T 细胞的卵清蛋白 (OVA) 抗原呈递能力因 IRE1 α 抑制而增强，但因进一步抑制 p38 而减弱。因此，目前的研究结果表明，p38 MAPK 在炎症应激条件下对肌细胞中 IRE1 α 臂依赖性免疫生物学抑制有很大贡献。
Skeletal muscle repair and systemic inflammation/immune responses are linked to endoplasmic reticulum stress (ER stress) pathways in myopathic muscle, and muscle cells play an active role in muscular immune reactions by exhibiting immunological characteristics under persistent proinflammation stimuli. Whether ER stress affects the intrinsic immunological capacities of myocytes in the inflammatory milieu, as it does to immune cells, and which arms of the unfolded protein response (UPR) mainly participate in these processes remain mostly unknown. We investigated this issue and showed that inflammatory stimuli can induce the activation of the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1 alpha) arms of the UPR in myocytes both in vivo and in vitro. UPR stressor administration reversed the increased IFN-gamma-induced expression of the MHC-II molecule H2-Ea, the MHC-I molecule H-2K(b), toll-like receptor 3 (TLR3) and some proinflammatory myokines in differentiated primary myotubes in vitro. However, further IRE1 alpha inhibition thoroughly corrected the trend in the UPR stressor-triggered suppression of immunobiological molecules. In IFN-gamma-treated myotubes, dramatic p38 MAPK activation was observed under IRE1 alpha inhibitory conditions, and the pharmacological inhibition of p38 reversed the immune molecule upregulation induced by IRE1 alpha inhibition. In parallel, our coculturing system verified that the ovalbumin (OVA) antigen presentation ability of inflamed myotubes to OT-I T cells was enhanced by IRE1 alpha inhibition, but was attenuated by further p38 inhibition. Thus, the present findings demonstrated that p38 MAPK contributes greatly to IRE1 alpha arm-dependent immunobiological suppression in myocytes under inflammatory stress conditions.