ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice

Tao Zhuang, Mei-Hua Chen, Ruo-Xi Wu, Jing Wang, Xi- De Hu, Ting Meng, Ai-Hua Wu, Yan Li, Yong-Feng Yang, Yu Lei, Dong-Hua Hu, Yan-Xiu Li, Li Zhang, Ai-Jun Sun, Wei Lu (), Guan-Nan Zhang (), Jun-Li Zuo () and Cheng-Chao Ruan ()
Additional contact information
Tao Zhuang: Fudan University
Mei-Hua Chen: Fudan University
Ruo-Xi Wu: Fudan University
Jing Wang: Fudan University
Xi- De Hu: Fudan University
Ting Meng: Fudan University
Ai-Hua Wu: Fudan University
Yan Li: Shanghai Jiao Tong University School of Medicine
Yong-Feng Yang: Fudan University
Yu Lei: Fudan University
Dong-Hua Hu: Fudan University
Yan-Xiu Li: The First Affiliated Hospital of Nanjing Medical University
Li Zhang: Shanghai Jiaotong University School of Medicine
Ai-Jun Sun: Shanghai Institute of Cardiovascular Diseases
Wei Lu: Fudan University
Guan-Nan Zhang: Nanjing Medical University
Jun-Li Zuo: Shanghai Jiao Tong University School of Medicine
Cheng-Chao Ruan: Fudan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Date: 2024
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DOI: 10.1038/s41467-024-46357-x

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