ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1623486
Myeloid-Specific S100A8/A9 Deficiency Attenuates Atrial Fibrillation through Prevention of TLR4/NF-kB-Mediated Immune Cell Recruitment and Inflammation
Provisionally accepted
- 1Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
- 2Chinese PLA General Hospital, Beijing, China
- 3shuguang hospital, Shanghai, China
- 4Xinxiang City No.1 People's Hospital, Xinxiang City, China
- 5Shanghai Changzheng Hospital, Shanghai, China
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Atrial fibrillation (AF) is the most common sustained arrhythmia, frequently associated with inflammation and atrial remodeling. S100A8/A9, a calcium-binding protein complex enriched in myeloid cells, has been implicated in cardiovascular inflammation, yet its role in AF remains unexplored. This study aims to investigate the mechanistic contribution of myeloid-derived S100A8/A9 to AF pathogenesis and assess its therapeutic potential through targeted genetic deletion.Transcriptomic and single-cell RNA sequencing data from AF patients were analyzed to identify differentially expressed genes (DEGs) and immune cell signatures. S100A8/A9 emerged as top hub genes. Monocyte/macrophage-specific S100A9 conditional knockout (CKO) mice were subjected to Ach-CaCl₂-induced AF, with assessments of electrophysiology, fibrosis, inflammation, and TLR4/NF-κB signaling.The functional role of this pathway was further tested using the NF-κB activator HY-18739.S100A8/A9 expression was significantly elevated in atrial tissues and myeloid cell clusters of AF patients. S100A9 CKO mice exhibited reduced AF inducibility and duration, accompanied by attenuation of atrial fibrosis, inflammatory cytokine production, and monocyte infiltration. Mechanistically, S100A9 deletion suppressed activation of the TLR4/IRAK1/TRAF6/NF-κB pathway. These effects were reversed by pharmacologic NF-κB reactivation with HY-18739, confirming the centrality of this pathway.Myeloid-derived S100A8/A9 amplifies AF by promoting monocyte recruitment and inflammation via the TLR4/NF-κB axis. Targeting this pathway may offer a promising therapeutic strategy for AF prevention and treatment.
Keywords: Atrial Fibrillation, S100A8/A9, Monocytes, Inflammation, TLR4/NF-κB signaling, conditional knockout
Received: 06 May 2025; Accepted: 15 Aug 2025.
Copyright: © 2025 Wang, Shen, Wang, Wang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yufeng Zhang, Shanghai Changzheng Hospital, Shanghai, China
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