CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome
CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4+ T cells in Sjogren’s syndrome
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DOI：
10.1007/s10238-022-00939-5
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发表时间：
2022-11
影响因子：
4.6
通讯作者：
J. Yin;Jiayao Fu;Yanxiong Shao;Jiabao Xu;Hui Li;Chan Chen;Yijie Zhao;Zhanglong Zheng;
中科院分区：
文献类型：
--
作者：
J. Yin;Jiayao Fu;Yanxiong Shao;Jiabao Xu;Hui Li;Chan Chen;Yijie Zhao;Zhanglong Zheng;
细胞色素P450家族51（CYP 51）是哺乳动物细胞中胆固醇从头合成的重要酶。在本研究中，我们发现CYP 51的表达与体内和体外的CD 4 +T细胞活化呈正相关。添加酮康唑（一种CYP 51的药理学抑制剂）以剂量依赖性方式阻止抗CD 3/CD 28扩增的小鼠CD 4 +T细胞的增殖和活化。液相色谱-串联质谱法表明，在活化过程中用酮康唑处理的T细胞中羊毛甾醇水平增加。酮康唑诱导的胆固醇合成途径的阻断也引起了CD 4 +T细胞中固醇调节元件结合蛋白2（SREBP 2）的激活。此外，酮康唑治疗引起T细胞中的整合应激反应，其在翻译水平上上调活化转录因子4（ATF 4）和DNA损伤诱导转录本3（DDIT 3/CHOP）。此外，酮康唑治疗显着降低了NOD/Ltj小鼠下颌下腺浸润病变的CD 4 +T细胞的数量。总之，我们的结果表明，CYP 51在CD 4 +T细胞的增殖和生存中发挥着至关重要的作用，这使得酮康唑通过调节胆固醇的生物合成和诱导综合应激反应而成为CD 4 +T细胞增殖和SS样自身免疫反应的抑制剂。
CYtochrome P450, family 51 (CYP51) is an important enzyme for de novo cholesterol synthesis in mammalian cells. In the present study, we found that the expression of CYP51 positively correlated with CD4+T cell activation both in vivo and in vitro. The addition of ketoconazole, a pharmacological inhibitor of CYP51, prevented the proliferation and activation of anti-CD3/CD28-expanded mouse CD4+T cells in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry indicated an increase in levels of lanosterol in T cells treated with ketoconazole during activation. Ketoconazole-induced blockade of the cholesterol synthesis pathway also caused Sterol regulatory element binding protein 2 (SREBP2) activation in CD4+T cells. Additionally, ketoconazole treatment elicited an integrated stress response in T cells that up-regulated activating transcription factor 4 (ATF4) and DNA-damage inducible transcript 3 (DDIT3/CHOP) at the translational level. Furthermore, treatment with ketoconazole significantly decreased the amount of CD4+T cells infiltrating lesions in the submandibular glands of NOD/Ltj mice. In summary, our results suggest that CYP51 plays an essential role in the proliferation and survival of CD4+T cells, which makes ketoconazole an inhibitor of CD4+T cell proliferation and of the SS-like autoimmune response through regulating the biosynthesis of cholesterol and inducing the integrated stress response.