2. Academic Validation
  3. Esaxerenone Inhibits Interferon-γ Induced Pyroptosis of Macrophages in the Lungs of Aldosterone-treated Mice

Esaxerenone Inhibits Interferon-γ Induced Pyroptosis of Macrophages in the Lungs of Aldosterone-treated Mice

  • Inflammation. 2024 May 7. doi: 10.1007/s10753-024-02030-5.
Jingyue Chang # 1 2,  Xiaomeng Gao # 1 2,  Fan Yang # 2 3,  Panpan Qiang 2 3,  Lili Fan 1 2,  Ziqian Liu 1 2,  Tatsuo Shimosawa 4,  Qingyou Xu 5 6 7,  Yi Chang 8 9
Affiliations

Affiliations

  • 1 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 2 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 3 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 4 Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, 286-8686, Japan.
  • 5 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. qingyouxu@hebcm.edu.cn.
  • 6 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. qingyouxu@hebcm.edu.cn.
  • 7 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. qingyouxu@hebcm.edu.cn.
  • 8 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. changyiyi@hebcm.edu.cn.
  • 9 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. changyiyi@hebcm.edu.cn.
  • # Contributed equally.
PMID: 38713304 DOI: 10.1007/s10753-024-02030-5
Abstract

Lung immune cells such as lymphocytes and macrophages can induce an inflammatory response due to the activation of Mineralocorticoid Receptor (MR), which is manifested by the infiltration of inflammatory cells and the secretion of inflammatory cytokines and subsequent Apoptosis, Pyroptosis and necrosis of intrinsic lung cells and immune cells. Macrophages are immune cells that are abundant in the lung and act as the first line of defense against pathogens but are also aggravating factors of Infection. The activation of the renin-angiotensin-aldosterone system (RAAS), especially aldosterone-stimulated MR activation, can induce macrophage and CD8+ T cell aggregation and the secretion of cytokines such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ). Increased IFN-γ secretion can induce macrophage Pyroptosis and the release of interleukin 1-β (IL-1β), aggravating lung injury. In this study, lung injury in C57BL/6 mice was induced by subcutaneous micro-osmotic pump infusion of aldosterone. After 12 weeks of administration, the kidney, heart, blood vessels and lungs all showed obvious inflammatory injury, which manifested as rapid accumulation of macrophages. The overexpression of IFN-γ in the lungs of aldosterone-treated mice and the stimulation of MH-S and RAW264.7 alveolar macrophages (AMs) with aldosterone in vitro showed that IFN-γ induced Pyroptosis of macrophages via the activation of the inflammasome, and the MR blocker esaxerenone effectively inhibited this effect and alleviated lung injury. In addition, IFN-γ secreted by CD8+ T cells is associated with macrophage Pyroptosis. In conclusion, the inhibition of macrophage Pyroptosis can effectively alleviate lung injury.

Keywords

aldosterone; interferon-gamma; lung injury; macrophage pyroptosis; mineralocorticoid receptor blocker.

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