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

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Abstract

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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Availability of Data and Materials

The data used to support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

The authors thank all the members of the laboratory for their help.

Funding

This study was supported by National Key Research and Development Program of China (2021YFE0200900), National Natural Science Foundation of China (81873069), and Shanghai Municipal Science and Technology Major Project (ZD2021CY001).

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Authors and Affiliations

  1. Department of Immunology and Microbiology, Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Jingjing Shen, Yan Fu, Fanglin Liu, Bangzuo Ning & Xin Jiang

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  1. Jingjing Shen
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  2. Yan Fu
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  3. Fanglin Liu
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  4. Bangzuo Ning
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  5. Xin Jiang
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Contributions

XJ conceived and designed the experiments. JS, YF, FL, and BN performed the experiments. JS and YF analyzed the data. JS and XJ wrote the paper. All authors have read and approved the final manuscript.

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Correspondence to Xin Jiang.

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Shen, J., Fu, Y., Liu, F. et al. Ursolic Acid Promotes Autophagy by Inhibiting Akt/mTOR and TNF-α/TNFR1 Signaling Pathways to Alleviate Pyroptosis and Necroptosis in Mycobacterium tuberculosis-Infected Macrophages. Inflammation 46, 1749–1763 (2023). https://doi.org/10.1007/s10753-023-01839-w

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