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Activating α7nAChR helps post-myocardial infarction healing by regulating macrophage polarization via the STAT3 signaling pathway

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Abstract

Background

Monocytes/macrophages play critical roles in inflammation and cardiac remodeling following myocardial infarction (MI). The cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses by activating α7 nicotinic acetylcholine receptors (α7nAChR) in monocytes/macrophages. We investigated the effect of α7nAChR on MI-induced monocyte/macrophage recruitment and polarization and its contribution to cardiac remodeling and dysfunction.

Methods

Adult male Sprague Dawley rats underwent coronary ligation and were intraperitoneally injected with the α7nAChR-selective agonist PNU282987 or the antagonist methyllycaconitine (MLA). RAW264.7 cells were stimulated with lipopolysaccharide (LPS) + interferon-gamma (IFN-γ) and treated with PNU282987, MLA, and S3I-201 (a STAT3 inhibitor). Cardiac function was evaluated by echocardiography. Masson’s trichrome and immunofluorescence were used to detect cardiac fibrosis, myocardial capillary density, and M1/M2 macrophages. Western blotting was used to detect protein expression, and the proportion of monocytes was measured using flow cytometry.

Results

Activating the CAP with PNU282987 significantly improved cardiac function and reduced cardiac fibrosis and 28-day mortality after MI. On days 3 and 7 post-MI, PNU282987 reduced the percentage of peripheral CD172a + CD43low monocytes and the infiltration of M1 macrophages in the infarcted hearts, whereas it increased the recruitment of peripheral CD172a + CD43high monocytes and M2 macrophages. Conversely, MLA exerted the opposite effects. In vitro, PNU282987 inhibited M1 macrophage polarization and promoted M2 macrophage polarization in LPS + IFN-γ-stimulated RAW264.7 cells. These PNU282987-induced changes in LPS + IFN-γ-stimulated RAW264.7 cells were reversed by administering S3I-201.

Conclusion

Activating α7nAChR inhibits the early recruitment of pro-inflammatory monocytes/macrophages during MI and improves cardiac function and remodeling. Our findings suggest a promising therapeutic target for regulating monocyte/macrophage phenotypes and promoting healing after MI.

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Funding

This study was supported by the National Natural Science Foundation of China (No.82070333), the Zhejiang Provincial Natural Science Foundation of China (No.LY21H020011), and the Wenzhou Science and Technology Bureau Major Scientific Research Project (No.ZY2020018).

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Author notes

  1. Xiao-Hui Niu and Rong-Hua Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Xiao-Hui Niu, Rong-Hua Liu, Xiao Lv, Rui-Lin He, Shu-Jie Wu, Lei Li & Jia-Feng Lin

  2. Key Laboratory of Structural Malformations in Children of Zhejiang Province, Wenzhou, 325000, China

    Xiao-Hui Niu, Rong-Hua Liu, Xiao Lv, Rui-Lin He, Shu-Jie Wu, Lei Li & Jia-Feng Lin

  3. Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China

    Fang-Zhou Lv

  4. Rehabilitation Medicine Center, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, China

    Xu-Qing Li

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  1. Xiao-Hui Niu
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Contributions

JL and LL designed the research, wrote the paper; XN and RL conducted animal experiments; XL, RH and XL conducted cell experiments; SW and FL analyzed the data and contributed to revise the paper. All authors read and approved the final manuscript.

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Correspondence to Lei Li or Jia-Feng Lin.

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Niu, XH., Liu, RH., Lv, X. et al. Activating α7nAChR helps post-myocardial infarction healing by regulating macrophage polarization via the STAT3 signaling pathway. Inflamm. Res. 72, 879–892 (2023). https://doi.org/10.1007/s00011-023-01714-2

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