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Macrophages evoke autophagy of hepatic stellate cells to promote liver fibrosis in NAFLD mice via the PGE2/EP4 pathway

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Abstract

The pathogenesis of liver fibrosis in nonalcoholic fatty liver disease (NAFLD) remains unclear and the effective treatments have not been explored yet. The activation of hepatic stellate cells (HSCs) is considered as the most critical factor in the progression of liver fibrosis and cirrhosis. Autophagy has recently been identified as a new mechanism to regulate HSC activation. Here, we found that liver macrophages were polarized toward type 2 (M2) during the progression of nonalcoholic steatohepatitis (NASH) and liver fibrosis in both patients and NAFLD mice. Using the methionine–choline-deficient (MCD) diet NAFLD murine model and the in vitro cell culture system, we identified that the M2 macrophages promoted HSC autophagy by secreting prostaglandin E2 (PGE2) and binding its receptor EP4 on the surface of HSCs, which consequently enhanced HSC activation, extracellular matrix deposition, and liver fibrosis. Mechanistically, PGE2/EP4 signals enhanced HSC autophagy through the Erk pathway. A specific PGE2/EP4 antagonist E7046 significantly inhibited M2 macrophage-mediated HSC autophagy and improved liver fibrosis and histopathology in NAFLD mice. Our study provides novel mechanistic insights into the regulation of HSC activation and liver fibrosis. Our findings suggest that the PGE2/EP4 pathway is a promising therapeutic target to prevent NASH progression into cirrhosis.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely thank Prof. Xiangying Kong from Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences for providing laboratory equipment, technical assistance and critically reading the manuscript and discussions.

Funding

This work was funded by grants from the National Natural Science Foundation of China (81600454, 81671940, 81871586 and 81770577), Beijing Municipal Excellent Talents Foundation (2018000021223ZK27) and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201828).

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  1. Ying Cao, Weili Mai and Rui Li contribute equally to this work and are co-first authors.

Authors and Affiliations

  1. Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Ying Cao, Weili Mai, Wen Xie & Jie Yan

  2. Department of Gastroenterology, General Hospital of the Southern Theater of the Chinese People’s Liberation Army, Guangzhou, 510030, China

    Weili Mai

  3. Beijing Institute of Infectious Diseases, Beijing, 100015, China

    Rui Li, Shuwei Deng, Lan Li, Yanxi Zhou, Yue Zhang, Ming Han, Pu Liang, Yonghong Yan, Yu Hao & Liuluan Zhu

  4. Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Rui Li, Shuwei Deng, Lan Li, Yanxi Zhou, Qiushi Qin, Yue Zhang, Ming Han, Pu Liang, Yonghong Yan, Yu Hao & Liuluan Zhu

  5. National Center for Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Rui Li, Shuwei Deng, Lan Li, Yanxi Zhou, Yue Zhang, Ming Han, Pu Liang, Yonghong Yan, Yu Hao & Liuluan Zhu

  6. Institute of Infectious Diseases, Peking University Ditan Teaching Hospital, Beijing, 100015, China

    Qiushi Qin

  7. Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China

    Xingang Zhou

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  1. Ying Cao
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Contributions

LZ, YC and JY designed the research; WM, RL, SD, LL, YZ, QQ, YZ, YY and YH conducted the research; MH and PL provided critical advice; LZ, WM, YC and RL analyzed the data; LZ, WM and YC wrote the paper; XZ provided clinical pathological resources. MH and WX provided essential materials.

Corresponding authors

Correspondence to Wen Xie, Jie Yan or Liuluan Zhu.

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The study on human patients was approved by the Ethics Committee of the Beijing Ditan Hospital, Capital Medical University (approval number: 2018-047-01). All the individuals involved in the study have signed the written informed consent. The study on animals was conducted according to the 1998 XXVIII Hungarian law about animal protection and welfare.

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Cao, Y., Mai, W., Li, R. et al. Macrophages evoke autophagy of hepatic stellate cells to promote liver fibrosis in NAFLD mice via the PGE2/EP4 pathway. Cell. Mol. Life Sci. 79, 303 (2022). https://doi.org/10.1007/s00018-022-04319-w

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