Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis.
Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis.
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缺乏肝脏 X 受体 α 的骨髓源性抑制细胞可预防自身免疫性肝炎
DOI：
10.3389/fimmu.2021.732102
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发表时间：
2021
影响因子：
7.3
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Li B;Lian M;Li Y;Qian Q;Zhang J;Liu Q;Tang R;Ma X
髓系来源的抑制细胞(MDSCs)有望成为自身免疫性肝炎(AIH)免疫治疗的候选细胞。然而，AIH中调控MDSC的靶点仍在寻找中。肝X受体(LXRs)是连接脂质代谢和免疫反应的重要核受体。尽管LXR在髓系间室有广泛的研究，但目前对其在MDSCs中的作用知之甚少。在本研究中，LXRα在AIH患者中表达上调，并与肝MDSCs共存。在ConA诱导的肝炎中，LxRα的缺失导致MDSCs在肝脏中的扩张增加，从而减轻了肝脏损伤。与WT小鼠相比，LXRα−/−小鼠体内的MDSCs具有更强的增殖和存活能力。T细胞增殖实验和过继细胞转移实验验证了MDSCs在体内外的强大免疫调节作用。从机制上讲，来自α−/−小鼠的MDSCs的干扰素调节因子8(IRF-8)的表达显著降低，IRF-8是MDSC分化的关键负调控因子。本研究进一步证实了LXRα在转录水平上激活了IrF-8。我们报道，取消LXRα可通过下调Irf-8促进MDSCs的扩增，从而显著改善肝脏免疫损伤。我们的工作突出了靶向LXRα在AIH中的治疗潜力。
Myeloid-derived suppressor cells (MDSCs) emerge as a promising candidate for the immunotherapy of autoimmune hepatitis (AIH). However, targets for modulating MDSC in AIH are still being searched. Liver X receptors (LXRs) are important nuclear receptors linking lipid metabolism and immune responses. Despite the extensive studies of LXR in myeloid compartment, its role in MDSCs is currently less understood. Herein, expression of LXRα was found to be upregulated in AIH patients and colocalized with hepatic MDSCs. In ConA-induced hepatitis, deletion of LXRα led to increased expansion of MDSCs in the liver and alleviated the hepatic injury. MDSCs in LXRα−/− mice exhibited enhanced proliferation and survival comparing with WT mice. T-cell proliferation assay and adoptive cell transfer experiment validated the potent immunoregulatory role of MDSCs in vitro and in vivo. Mechanistically, MDSCs from LXRα−/− mice possessed significantly lower expression of interferon regulatory factor 8 (IRF-8), a key negative regulator of MDSC differentiation. Transcriptional activation of IRF-8 by LXRα was further demonstrated We reported that abrogation of LXRα facilitated the expansion of MDSCs via downregulating IRF-8, and thereby ameliorated hepatic immune injury profoundly. Our work highlights the therapeutic potential of targeting LXRα in AIH.
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影响因子：
5.3
作者：
Laffitte, BA;Joseph, SB;Tontonoz, P
通讯作者：
Tontonoz, P
影响因子：
3.8
作者：
Kaffe, Eleanna T.;Rigopoulou, Eirini I.;Moulas, Anargyros N.
通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
21.1
作者：
Diao W;Jin F;Wang B;Zhang CY;Chen J;Zen K;Li L
通讯作者：
Li L
影响因子：
4.8
作者：
Hu, Xiaolin;Bardhan, Kankana;Liu, Kebin
通讯作者：
Liu, Kebin