Farnesoid X Receptor Protects Murine Lung Against IL-6-promoted Ferroptosis Induced by Poly(I:C)
In this study, a intratracheal instillation of poly(I:C) with or without IL-6 neutralizing antibody model combined with metabonomics, transcriptomics and so on to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased IL-6 level, and the up-regulated IL-6 further induced lung ferroptosis, especially in AT2 cells. Meanwhile, the lung regeneration was impaired. Mechanistically, metabolomics analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6 neutralizing antibody. In ferroptosis microenvironment, IL-6 receptor monoclonal antibody, tocilizumab increased FXR expression, and subsequently increased Yes-associated protein (YAP) level by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, present study provides the evidence that IL-6 promotes ferroptosis and impairs regeneration of AT2 cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.PMID:38300138 | DOI:10.1165/rcmb.2023-0172OC
Source: American Journal of Respiratory Cell and Molecular Biology - Category: Molecular Biology Authors: Dongmin Yang Hongbiao Liang Xiangrui Zhu Bochuan Li Chun Li Guizimeng Hu Xing Du Guohui Dang Yuwei Song Xiaolong Ma Peng Zhang Tianqi Chen Bo Liu Li Yan Chunshui Pan Kai Sun Xinmei Huo Yingmei Feng Xian Wang Ding Ai Jingyan Han Juan Feng Source Type: research
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