TNFR2/14-3-3 signaling complex instructs macrophage plasticity in inflammation and autoimmunity
TNFR2/14-3-3 signaling complex instructs macrophage plasticity in inflammation and autoimmunity
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DOI：
10.1172/jci144016
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发表时间：
2021-08-16
影响因子：
15.9
通讯作者：
Liu, Chuan-ju
中科院分区：
文献类型：
--
作者：
Fu, Wenyu;Hu, Wenhuo;Liu, Chuan-ju
TNFR 1和TNFR 2由于在炎症和自身免疫的发病机制中占主导地位而受到了突出的关注。TNFR 1已被广泛研究，主要介导炎症。TNFR 2的研究仍然少得多，尽管新出现的证据表明TNFR 2在各种病症和疾病中发挥免疫调节作用。在此，我们报告TNFR 2调节巨噬细胞极化，这是一个高度动态的过程，由大量未鉴定的细胞内调节因子控制。使用生物化学共纯化和质谱方法，我们分离出信号分子14-3-3c作为TNFR 2复合物的组分，其响应于巨噬细胞中的颗粒蛋白前体刺激。此外，14-3-3c对于TNFR 2信号介导的巨噬细胞极化和转换的调节是必需的。14-3-3c的整体和骨髓特异性缺失导致炎症性关节炎加重，并抵消了前颗粒蛋白介导的TNFR 2活化对炎症和自身免疫的保护作用。TNFR 2/14-3-3c通过PI 3 K/ Akt/mTOR信号传导以限制NF-κ B活化，同时刺激C/EBP β活化，从而指示巨噬细胞可塑性。总的来说，这项研究确定了14-3-3c作为TNFR 2受体复合物的一个以前未被认识到的重要组成部分，并提供了新的见解TNFR 2信号，特别是其在巨噬细胞极化中的作用，对各种炎症和自身免疫性疾病具有治疗意义，并激活TNFR 2/14-3-3c信号通路。
TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3c as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3c was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3c resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3c signaled through PI3K/ Akt/mTOR to restrict NF-KB activation while simultaneously stimulating C/EBPp activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3c as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3c antiinflammatory pathway.