ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1654688
This article is part of the Research TopicMetabolic Implications in Sepsis and Inflammation-related Critical IllnessesView all 3 articles
ADAM8 in Macrophages Exacerbates Sepsis-induced Cardiomyopathy by Impeding Efferocytosis
Provisionally accepted
Zhenjun Ji*
Jiaqi GuoMi Wang
Rui ZhangRong Dong
Zulong Sheng
Pengfei Zuo
Kongbo Zhu
Yongjun LiYuyu YaoHongliang HeGenshan Ma- Southeast University, Nanjing, China
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Abstract Introduction: Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication characterized by acute cardiac dysfunction during sepsis., and macrophages play a crucial role in SICM pathogenesis. ADAM8 has been implicated in inflammation-driven diseases, yet its role in SICM remains uncharted. Methods: Mouse models of SICM were established using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP). Macrophage-specific ADAM8 knockout (CKO) mice were generated. RNA transcriptome sequencing was conducted on left ventricular tissues sourced from ADAM8 CKO mice, as well as on RAW264.7 cell lines that were treated with both ADAM8 knockdown (KD) lentivirus and LPS. Results: Here, we demonstrate that ADAM8 expression is significantly upregulated in cardiac macrophages of SICM mice using single-cell transcriptomics and immunofluorescence. Macrophage-specific ADAM8 CKO mice exhibited preserved cardiac function, reduced myocardial injury markers, attenuated apoptosis (decreased Bax/Bcl2 ratio), and enhanced survival in both LPS-induced and CLP sepsis models. Transcriptomic analysis revealed downregulation of cytokine-cytokine receptor pathways in CKO hearts, suggesting diminished inflammatory responses. Mechanistically, ADAM8 deficiency promoted macrophage efferocytosis by increasing phagocytic receptors (MerTK) while reducing soluble Mer (sMer) generation. Conversely, sMer administration abolished the cardioprotective effects in CKO mice, exacerbating cardiac dysfunction and mortality. Conclusions: Our findings identify ADAM8 as a critical regulator of macrophage-mediated inflammation and impaired macrophage efferocytosis in SICM. Targeting ADAM8 or its downstream effectors may represent a novel therapeutic strategy for sepsis-induced cardiac complications.
Keywords: Sepsis-induced cardiomyopathy, Macrophages, ADAM8, Efferocytosis, Inflammation
Received: 26 Jun 2025; Accepted: 26 Sep 2025.
Copyright: © 2025 Ji, Guo, Wang, Zhang, Dong, Sheng, Zuo, Zhu, Li, Yao, He and Ma. 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: Zhenjun Ji, ji_zhenjun@126.com
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