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Rab11b promotes M1-like macrophage polarization by restraining autophagic degradation of NLRP3 in alcohol-associated liver disease

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases. Excessive activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease (ALD) pathology. Rab GTPases play critical roles in regulating vesicular transport. In this study we investigated the role of Rab11b in ALD, aiming to identify effective therapeutic targets. Here, we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice. Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation, injury and steatosis. We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages (BMDM) cells. Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization. Rab11b overexpression in BMDMs inhibited autophagic flux, leading to the suppression of LC3B-mediated NLRP3 degradation. We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.

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Fig. 1: Decreased hepatic Rab11b expression in experimental mice with ALD.
Fig. 2: Up-regulated Rab11b exacerbates macrophages M1-polarization.
Fig. 3: Loss of Rab11b in macrophage promotes M2-polarization in ALD mice.
Fig. 4: Rab11b deficiency ameliorates alcohol induced liver injury.
Fig. 5: NLRP3 inflammasome activation mediates Rab11b-induced M1-macrophage polarization.
Fig. 6: Rab11b inhibits autophagic-mediated degradation of NLRP3.
Fig. 7: Autophagy mediates the protective effect of AAV2/8-Rab11b in alcohol-associated liver disease.

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (82370630, 82100627, 82300722), Research Fund of Anhui Institute of Translational Medicine (2021zhyx-B06, 2022zhyx-B07), Natural Science Foundation of Anhui Province (2108085QH311, 2308085QH248), China Postdoctoral Science Foundation (2022M710178), Anhui Fund for Distinguished Young Scholars (2022AH020050), Postgraduate Innovation Research and Practice Program of Anhui Medical University (YJS20230056), Scientific Research Promotion Fund of Anhui Medical University (2022xkjT010), and Scientific Research Platform Improvement Project of Anhui Medical University (2022xkjT045).

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  1. These authors contributed equally: Yu-xin Zhao, Ying-yin Sun

Authors and Affiliations

  1. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China

    Yu-xin Zhao, Liang-yun Li, Xiao-feng Li, Hai-di Li, Xin Chen, Ying-li Yang, Xiao-ming Meng, Hua Wang, Cheng Huang & Jun Li

  2. Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China

    Yu-xin Zhao, Liang-yun Li, Xiao-feng Li, Hai-di Li, Xin Chen, Ying-li Yang, Cheng Huang & Jun Li

  3. Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei, 230032, China

    Yu-xin Zhao, Liang-yun Li, Hai-di Li, Xin Chen, Ying-li Yang, Cheng Huang & Jun Li

  4. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China

    Ying-yin Sun, Ran Xia & Hua Wang

  5. The Second School of Clinical Medicine, Anhui Medical University, Hefei, 230032, China

    Xin-yu Jiang

  6. Department of Pharmacy, Hospital of Armed Police of Anhui Province, Hefei, 230032, China

    Long-quan Zuo

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Contributions

YXZ and JL designed research; YXZ, LYL, RX, YLY, XYJ, LQZ and XC performed research; YYS and XFL contributed new reagents or analytic tools; XMM, HDL and CH analyzed data; YXZ and HW wrote the paper.

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Correspondence to Cheng Huang or Jun Li.

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Zhao, Yx., Sun, Yy., Li, Ly. et al. Rab11b promotes M1-like macrophage polarization by restraining autophagic degradation of NLRP3 in alcohol-associated liver disease. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01333-5

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