Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy.
Itaconate attenuates autoimmune hepatitis via PI3K/AKT/mTOR pathway-mediated inhibition of dendritic cell maturation and autophagy.
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ITACONATE通过PI3K/AKT/MTOR途径介导的树突状细胞成熟和自噬的抑制作用可减弱自身免疫性肝炎。
DOI：
10.1016/j.heliyon.2023.e17551
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发表时间：
2023-07
期刊：
影响因子：
4
通讯作者：
Li, Xun
中科院分区：
文献类型：
--
作者：
Zhang, Qiyu;Luo, Yang;Zheng, Qiuxia;Zhao, Haixia;Wei, Xiaofeng;Li, Xun
自身免疫性肝炎（AIH）是由自身免疫介导的针对肝细胞的慢性炎症反应引起的。自身免疫耐受缺陷和功能失调的树突状细胞（DCs）在AIH中起调节作用。衣康酸酯最近在免疫代谢领域引起了关注，因为它作为抗炎代谢物的重要作用，负调节炎症反应。然而，在AIH中衣康酸介导DC的潜在机制仍不清楚。在这项研究中，我们发现衣康酸在肝脏中起抗炎因子的作用。内源性衣康酸水平显着增加与S100诱导的AIH模型的小鼠，并与上调的免疫应答基因1表达。然而，内源性衣康酸盐的抗炎反应可能并不代表外源性衣康酸盐的作用。我们研究了外源性衣康酸在S100诱导的AIH中的抗炎反应，我们的结果表明，衣康酸治疗减轻了S100诱导的AIH模型中的肝组织病理学损伤、肝细胞凋亡、转氨酶升高和IL-6产生。此外，衣康酸减少糖酵解，以抑制AIH模型的肝脏和脾脏中的DC的成熟，从而直接调节体内Th 17和TcB的分化。Th 17细胞在CD 4+细胞中的比例降低，T细胞亚群升高（P < 0.05）。此外，衣康酸诱导的骨髓来源的单核细胞抑制CD 4+细胞增殖。在体外和体内实验中，我们发现衣康酸通过激活骨髓来源的DC和肝组织中的PI 3 K/AKT/mTOR信号通路来抑制自噬。我们进一步研究了衣康酸对DC特异性mTOR缺陷小鼠的功能。mTOR缺陷型DC增强mTORDC-AIH小鼠的炎症反应并诱导自噬。MHY 1485（mTOR的激动剂）和衣康酸盐显著减轻炎症反应和自噬信号传导。总之，衣康酸通过调节PI 3 K/AKT/mTOR通路减少DCs自噬和成熟来改善S100诱导的AIH小鼠的肝脏炎症。这些结果为治疗AIH提供了有用的见解。衣康酸减轻s100诱导的自身免疫性肝炎小鼠的肝脏炎症。衣康酸可抑制树突状细胞的成熟并调节自噬。衣康酸通过PI 3 K/AKT/mTOR途径抑制树突状细胞自噬发挥抗炎作用。
Autoimmune hepatitis (AIH) results from an autoimmune-mediated chronic inflammatory response against liver cells. Defective self-tolerance and dysfunctional dendritic cells (DCs) play a regulatory role in AIH. Itaconate has recently attracted attention in the field of immunometabolism because of its crucial role as an anti-inflammatory metabolite that negatively regulates the inflammatory response. However, the underlying mechanism of itaconate mediation of DCs in AIH remains unclear. In this study, we found that itaconate acts as an anti-inflammatory factor in the liver. Endogenous itaconate levels were significantly increased in mice with S100-induced AIH model and correlated with upregulation of the immune-responsive gene 1 expression. However, the anti-inflammatory response from endogenously itaconate may not represent the effects exogenously-produced itaconate. We investigated the anti-inflammatory response from exogenous itaconate in S100-induced AIH, and our results showed that itaconate treatment attenuated liver histopathological damage, hepatocyte apoptosis, aminotransferase elevation, and IL-6 production in the S100-induced AIH model. In addition, Itaconate decreased glycolysis to suppress the maturation of DCs in the liver and spleen of AIH models, thereby directly regulating differentiation of Th17 and Tregs in vivo. The percentage of Th17 cells among the CD4+ population were decreased and Tregs were increased (P < 0.05). Furthermore, Itaconate-induced bone marrow-derived monocytes suppressed CD4+cells proliferation. In vitro and in vivo, we found that itaconate suppressed autophagy via activating the PI3K/AKT/mTOR signalling pathway in bone marrow-derived DCs and liver tissues. We further investigated the function of Itaconate on DC-specific mTOR-deficient mice. mTOR-deficient DCs augmented inflammatory reactions in mTORDC−/− AIH mice and induced autophagy. MHY1485 (an agonist of mTOR) and itaconate significantly alleviated the inflammatory reaction and autophagy signalling. In conclusion, itaconate ameliorate liver inflammation in S100-induced AIH mice by regulating the PI3K/AKT/mTOR pathway to decrease DCs autophagy and maturation. These results provide insight useful for treating AIH. Itaconate alleviated liver inflammation in s100 induced-autoimmune hepatitis mice. Itaconate suppressed the maturation of dendritic cells and regulated the autophagy. Itaconate exerted anti-inflammatory effect by PI3K/AKT/mTOR pathway to decrease dendritic cells autophagy.
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Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
综合代谢组学和转录组学将Itaconate鉴定为治疗眼细菌感染的辅助疗法。
DOI：
10.1016/j.xcrm.2021.100277
发表时间：
2021-05-18
期刊：
Cell reports. Medicine
影响因子：
--
作者：
Singh S;Singh PK;Jha A;Naik P;Joseph J;Giri S;Kumar A
通讯作者：
Kumar A
影响因子：
8
作者：
Jaiswal AK;Yadav J;Makhija S;Mazumder S;Mitra AK;Suryawanshi A;Sandey M;Mishra A
通讯作者：
Mishra A
影响因子：
7.3
作者：
Sridhar, Sunandini;Botbol, Yair;Macian, Fernando;Cuervo, Ana Maria
通讯作者：
Cuervo, Ana Maria
影响因子：
13.5
作者：
KNODELL, RG;ISHAK, KG;WOLLMAN, J
通讯作者：
WOLLMAN, J