Ursolic Acid Promotes Autophagy by Inhibiting Akt/mTOR and TNF-α/TNFR1 Signaling Pathways to Alleviate Pyroptosis and Necroptosis in Mycobacterium tuberculosis-Infected Macrophages

上睑下垂 坏死性下垂 自噬 PI3K/AKT/mTOR通路 程序性细胞死亡 生物 蛋白激酶B 细胞内寄生虫 细胞生物学 免疫系统 炎症体 炎症 信号转导 细胞内 微生物学 免疫学 细胞凋亡 生物化学
作者
Jingjing Shen,Yan Fu,Fanglin Liu,Bangzuo Ning,Xin Jiang
出处
期刊:Inflammation [Springer Nature]
卷期号:46 (5): 1749-1763 被引量:11
标识
DOI:10.1007/s10753-023-01839-w
摘要

As a lethal infectious disease, tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb). Its complex pathophysiological process limits the effectiveness of many clinical treatments. By regulating host cell death, Mtb manipulates macrophages, the first line of defense against invading pathogens, to evade host immunity and promote the spread of bacteria and intracellular inflammatory substances to neighboring cells, resulting in widespread chronic inflammation and persistent lung damage. Autophagy, a metabolic pathway by which cells protect themselves, has been shown to fight intracellular microorganisms, such as Mtb, and they also play a crucial role in regulating cell survival and death. Therefore, host-directed therapy (HDT) based on antimicrobial and anti-inflammatory interventions is a pivotal adjunct to current TB treatment, enhancing anti-TB efficacy. In the present study, we showed that a secondary plant metabolite, ursolic acid (UA), inhibited Mtb-induced pyroptosis and necroptosis of macrophages. In addition, UA induced macrophage autophagy and enhanced intracellular killing of Mtb. To investigate the underlying molecular mechanisms, we explored the signaling pathways associated with autophagy as well as cell death. The results showed that UA could synergistically inhibit the Akt/mTOR and TNF-α/TNFR1 signaling pathways and promote autophagy, thus achieving its regulatory effects on pyroptosis and necroptosis of macrophages. Collectively, UA could be a potential adjuvant drug for host-targeted anti-TB therapy, as it could effectively inhibit pyroptosis and necroptosis of macrophages and counteract the excessive inflammatory response caused by Mtb-infected macrophages via modulating the host immune response, potentially improving clinical outcomes.
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