2. Academic Validation
  3. Nobiletin alleviates macrophage M2 polarization by activating AMPK-mTOR-mediated autophagy in pulmonary fibrosis mice

Nobiletin alleviates macrophage M2 polarization by activating AMPK-mTOR-mediated autophagy in pulmonary fibrosis mice

  • Int Immunopharmacol. 2024 Sep 30:139:112792. doi: 10.1016/j.intimp.2024.112792.
Yumeng Cheng 1,  Xiaofeng Mei 2,  Wenbo Shao 1,  Jiaping Zheng 1,  Xiaohong Yin 1,  Qin Zhang 3,  Jiansheng Li 4,  Peng Zhao 5
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou 450046, Henan Province, China.
  • 2 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou 450046, Henan Province, China; Department of Respiratory Diseases, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China.
  • 3 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou 450046, Henan Province, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China.
  • 4 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou 450046, Henan Province, China; Department of Respiratory Diseases, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China. Electronic address: li_js8@hactcm.edu.cn.
  • 5 Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China; Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-constructed by Henan Province & Education Ministry of P.R. China, Zhengzhou 450046, Henan Province, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450000, China. Electronic address: zhaopeng871@126.com.
PMID: 39079195 DOI: 10.1016/j.intimp.2024.112792
Abstract

Nobiletin (NOB), a polymethoxylated flavone isolated from citrus peels, is a promising dietary treatment for lung diseases, such as pulmonary fiborsis. In this work, the underlying mechanisms of NOB's preventative effect on pulmonary fibrosis were explored using bleomycin-exposed mice and IL-4-induced M2 polarization of the macrophages. Results showed that NOB treatment could significantly ameliorate lung fibrosis by suppressing pathological damages, collagen deposition, and fibroblat activation. Moreover, NOB obviously reduced the M2 macrophage-related proteins, including CD206, Arg1, and pro-fibrotic mediators such as TGF-β and CTGF, which might contribute to the antifibrosis effect of NOB. Network analysis of the differentially expressed genes in NOB-treated M2 macrophages showed that Autophagy, mTOR signaling pathway, and AMPK signaling pathway might be involved in the effects of NOB. Further exploration illustrated that Autophagy was enhanced in NOB-treated lung and M2 macrophages.The addition of 3MA, an Autophagy Inhibitor, could significantly weaken the effect of NOB on lung fibrosis and macrophage M2 polarization. Additionally, NOB also markedly decreased the expression of p-AMPK, p-mTOR, and p-P70S6K in the M2 macrophages and lung tissues of BLM-exposed mice. Compound C, an AMPK agonist, significantly suppressed NOB-induced activation of AMPK and mTOR signals, as well as its inhibitory effect on Autophagy, M2 macrophages and lung fibrosis both in vitro and in vivo, supporting the requirement of AMPK-mTOR-mediated Autophagy for the NOB's antifibrosis activity. Taken together, this study suggests that NOB ameliorates pulmonary fibrosis likely involving the inhibition of M2 macrophage via activating AMPK-mTOR-mediated Autophagy.

Keywords

AMPK-mTOR signaling；; Autophagy; M2-like polarization of macrophages; Nobiletin; Pulmonary fibrosis.

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