Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells.
Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells.
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抑制 Dot1L 通过骨髓源性抑制细胞缓解暴发性肝炎
DOI：
10.1016/j.jcmgh.2021.01.013
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发表时间：
2021
影响因子：
7.2
通讯作者：
Cai W
中科院分区：
文献类型：
--
作者：
Yang W;Yu H;Huang J;Miao X;Wang Q;Wang Y;Cheng Y;He S;Zhao F;Meng L;Wang B;Qian F;Ren X;Jin M;Gu Y;Zhang Y;Cai W
重型肝炎(FH)是一种以突发性严重肝功能障碍为特征的临床综合征。DOT1L是一种组蛋白甲基转移酶，参与多种生理和病理过程，包括转录调控和白血病。然而，DOT1L在FH期间调节炎症反应中的作用仍然不清楚。用痤疮丙酸杆菌(P.acnes)诱导的脂多糖(LPS)诱导C57BL/6小鼠FH，并用DOT1L抑制剂EPZ-5676治疗。用抗Gr-1抗体去除骨髓来源的抑制细胞(MDSCs)，评价其在DOT1L治疗FH中的作用。采集FH患者和健康对照组外周血，检测其MDSCs中DOT1L-SOCS1-iNOS轴的表达情况。在这里，我们发现DOT1L的药理抑制剂EPZ-5676可以减轻FH所致的小鼠肝损伤。在FH过程中，DOT1L抑制导致辅助性T细胞反应降低，调节性T细胞(Tregs)扩增。有趣的是，DOT1L抑制并不直接针对T细胞，而是显著增强了MDSCs的免疫抑制功能。机制上，DOT1L抑制通过表观遗传抑制SOCS1的表达，从而以STAT1依赖的方式诱导诱导型一氧化氮合酶(INOS)的表达。此外，在人类样本中，与健康对照组相比，FH患者MDSCs中DOT1L和SOCS1的表达水平上调，同时iNOS的表达降低。总之，我们的发现首次确立了DOT1L作为MDSC免疫抑制功能的关键调节因子，并强调了DOT1L抑制剂在FH治疗中的治疗潜力。
Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Propionibacterium acnes (P. acnes)-primed, lipopolysaccharides (LPS)-induced FH was established in C57BL/6 mice and was treated with the Dot1L inhibitor EPZ-5676. Myeloid derived suppressor cells (MDSCs) were depleted by anti-Gr-1 antibody to evaluate their therapeutic roles in Dot1L treatment of FH. Moreover, peripheral blood of patients suffered with FH and healthy controls was collected to determine the expression profile of Dot1L-SOCS1-iNOS axis in their MDSCs. Here we identified that EPZ-5676, pharmacological inhibitor of Dot1L, attenuated the liver injury of mice subjected to FH. Dot1L inhibition led to decreased T helper 1 cell response and expansion of regulatory T cells (Tregs) during FH. Interestingly, Dot1L inhibition didn’t directly target T cells, but dramatically enhanced the immunosuppressive function of MDSCs. Mechanistically, Dot1L inhibition epigenetically suppressed SOCS1 expression, thus inducing inducible nitric oxide synthase (iNOS) expression in a STAT1-dependent manner. Moreover, in human samples, the levels of Dot1L and SOCS1 expression were upregulated in MDSCs, accompanied by decreased expression of iNOS in patients with FH, compared with healthy controls. Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment.
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影响因子：
24.5
作者：
Hardy T;Mann DA
通讯作者：
Mann DA
影响因子：
16.6
作者：
Kagoya Y;Nakatsugawa M;Saso K;Guo T;Anczurowski M;Wang CH;Butler MO;Arrowsmith CH;Hirano N
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Hirano N
影响因子：
24.5
作者：
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Antoniades CG
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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：
4.4
作者：
Huang, Ang;Zhang, Bo;Guo, YaJun
通讯作者：
Guo, YaJun