Jin Chao, Gao Bei-Bei, Zhou Wen-Jing, Zhao Bao-Jing, Fang Xing, Yang Chun-Lan, Wang Xiao-Hua, Xia Quan, Liu Ting-Ting
School of Pharmacy, the First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, China.
The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, China.
Front Pharmacol. 2022 Sep 15;13:972397. doi: 10.3389/fphar.2022.972397. eCollection 2022.
Hydroxychloroquine (HCQ) is derivative of the heterocyclic aromatic compound quinoline, which has been used for the treatment of autoimmune diseases. The central purpose of this study was to investigate therapeutic effects and inflammatory immunological molecular mechanism of HCQ in experimental autoimmune hepatitis (AIH). Treatment with HCQ ameliorated hepatic pathologic damage, inflammatory infiltration, while promoted regulatory T cell (T) and down-regulated CD8T cell differentiation in AIH mice induced by S-100 antigen. , HCQ also suppressed pro-inflammatory cytokine (IFN-γ, TNF-α, and IL-12) secretion, promoted anti-inflammatory cytokine (TGF-β) secretion. HCQ mainly impaired T cell lipid metabolism but not glycolysis to promote T differentiation and function. Mechanistically, HCQ down-regulated GRK2 membrane translocation in T cells, inhibited GRK2-PI3K interaction to reduce the PI3K recruiting to the membrane, followed by suppressing the phosphorylation of PI3K-AKT-mTOR signal. Pretreating T cells with paroxetine, a GRK2 inhibitor, disturbed HCQ effect to T cells. HCQ also reversed the activation of the PI3K-AKT axis by 740 Y-P (PI3K agonist). Meanwhile, HCQ inhibited the PI3K-AKT-mTOR, JAK2-STAT3-SOCS3 and increased the AMPK signals in the liver and T cells of AIH mice. In conclusion, HCQ exhibited specific and potent therapeutic effects on AIH and attendant liver injury, which was attributed to HCQ acted on GRK2 translocation, inhibited metabolism-related PI3K-AKT and inflammation-related JAK2-STAT3 signal in T lymphocytes, thereby modulating lipid metabolism of T cell function to regulate T differentiation and function.
羟氯喹啉（HCQ）是杂环芳香化合物喹啉的衍生物，已被用于治疗自身免疫性疾病。本研究的主要目的是探讨HCQ在实验性自身免疫性肝炎（AIH）中的治疗效果及炎症免疫分子机制。用HCQ治疗可改善AIH小鼠肝脏的病理损伤和炎症浸润，同时促进调节性T细胞（Treg）分化并下调CD8+T细胞分化。此外，HCQ还抑制促炎细胞因子（IFN-γ、TNF-α和IL-12）的分泌，促进抗炎细胞因子（TGF-β）的分泌。HCQ主要损害T细胞脂质代谢而非糖酵解，以促进Treg分化和功能。机制上，HCQ下调T细胞中GRK2的膜转位，抑制GRK2与PI3K的相互作用，减少PI3K募集到细胞膜，进而抑制PI3K-AKT-mTOR信号的磷酸化。用GRK2抑制剂帕罗西汀预处理T细胞会干扰HCQ对T细胞的作用。HCQ还可逆转740 Y-P（PI3K激动剂）对PI3K-AKT轴的激活。同时，HCQ抑制AIH小鼠肝脏和T细胞中的PI3K-AKT-mTOR、JAK2-STAT3-SOCS3信号，并增强AMPK信号。总之，HCQ对AIH及伴随的肝损伤具有特异性和强效的治疗作用，这归因于HCQ作用于GRK2转位，抑制T淋巴细胞中与代谢相关 的PI3K-AKT和与炎症相关的JAK2-STAT3信号，从而调节T细胞功能的脂质代谢以调控Treg分化和功能。
