Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells.
Inflammation-induced inhibition of chaperone-mediated autophagy maintains the immunosuppressive function of murine mesenchymal stromal cells.
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炎症诱导的伴侣介导的自噬抑制维持小鼠间充质基质细胞的免疫抑制功能
DOI：
10.1038/s41423-019-0345-7
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发表时间：
2021-06
影响因子：
24.1
通讯作者：
Zhang Y
中科院分区：
文献类型：
--
作者：
Zhang J;Huang J;Gu Y;Xue M;Qian F;Wang B;Yang W;Yu H;Wang Q;Guo X;Ding X;Wang J;Jin M;Zhang Y
巨噬参与调节间充质间质细胞（MSCs）的治疗功能。然而，MSCs中伴侣介导的自噬（CMA）的生物学功能仍然是未知的。在这里，我们发现CMA在MSCs中受到促炎细胞因子干扰素-γ (IFN-γ)和肿瘤坏死因子-α (TNF-α)的抑制。此外，通过敲低MSCs中CMA相关溶酶体受体溶酶体相关膜蛋白2 （LAMP-2A）来抑制CMA，可显著增强MSCs对T细胞增殖的免疫抑制作用，正如预期的那样，MSCs中LAMP-2A过表达对T细胞增殖产生相反的作用。CMA对MSCs免疫抑制功能的影响归因于其对趋化因子C-X-C基序配体10 （CXCL10）表达的负调控，CXCL10可向MSCs招募炎症细胞，尤其是T细胞，并可诱导一氧化氮合酶（iNOS）的表达，从而通过一氧化氮（NO）抑制T细胞增殖。机制上，CMA抑制显著促进IFN-γ + TNF-α-诱导的NF-κB和STAT1的激活，导致MSCs中CXCL10和iNOS的表达增强。此外，我们发现IFN-γ + TNF-α-诱导的AKT激活有助于MSCs中CMA的抑制。更有趣的是，缺乏cma的MSCs在炎症性肝损伤中表现出更好的治疗效果。综上所述，我们的研究结果确定了CMA抑制是炎症细胞因子诱导的MSCs免疫抑制功能的关键因素，并强调了CMA以前未知的功能。
Macroautophagy has been implicated in modulating the therapeutic function of mesenchymal stromal cells (MSCs). However, the biological function of chaperone-mediated autophagy (CMA) in MSCs remains elusive. Here, we found that CMA was inhibited in MSCs in response to the proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). In addition, suppression of CMA by knocking down the CMA-related lysosomal receptor lysosomal-associated membrane protein 2 (LAMP-2A) in MSCs significantly enhanced the immunosuppressive effect of MSCs on T cell proliferation, and as expected, LAMP-2A overexpression in MSCs exerted the opposite effect on T cell proliferation. This effect of CMA on the immunosuppressive function of MSCs was attributed to its negative regulation of the expression of chemokine C-X-C motif ligand 10 (CXCL10), which recruits inflammatory cells, especially T cells, to MSCs, and inducible nitric oxide synthase (iNOS), which leads to the subsequent inhibition of T cell proliferation via nitric oxide (NO). Mechanistically, CMA inhibition dramatically promoted IFN-γ plus TNF-α-induced activation of NF-κB and STAT1, leading to the enhanced expression of CXCL10 and iNOS in MSCs. Furthermore, we found that IFN-γ plus TNF-α-induced AKT activation contributed to CMA inhibition in MSCs. More interestingly, CMA-deficient MSCs exhibited improved therapeutic efficacy in inflammatory liver injury. Taken together, our findings established CMA inhibition as a critical contributor to the immunosuppressive function of MSCs induced by inflammatory cytokines and highlighted a previously unknown function of CMA.
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