Targeting Macrophage-Mediated Mechanisms in Sepsis-Induced Cardiomyopathy: From Pathophysiology to Therapeutic Strategies.

Authors

Jun Wang, Jingyi Zhang, Nianfang Luo, Ziran Zhou, Yue Zhang, Kangyan Guo, Ruiting Li, Chang Li

Published in

Journal of inflammation research. Volume 19. Pages 607880. Epub Jul 15, 2026.

Abstract

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication of sepsis, characterized by dysregulated inflammation, metabolic disturbances, and complex cellular crosstalk. As central innate immune cells, macrophages exert a dual role in this pathology. This review focuses on the key mechanisms by which macrophages contribute to SICM. We discuss macrophage-driven pathogenesis across three interconnected themes. First, inflammatory activation. Macrophages amplify the inflammatory storm through dynamic M1/M2 polarization and activation of Toll-like receptor 4 (TLR4) / nuclear factor κB (NF-κB), as well as multiple inflammasome pathways such as NLR family pyrin domain containing 3 (NLRP3). Second, myocardial injury mechanisms. Activated macrophages promote cardiomyocyte damage via oxidative stress, suppression of mitophagy, direct cytotoxic effects, and indirect networks (such as MMP-9-mediated endothelial disruption). Third, regulatory layers. Immunometabolic reprogramming (enhanced glycolysis and succinate accumulation in M1 macrophages versus fatty acid oxidation in M2 macrophages) serves as an intrinsic driver linking immune activation to cardiomyocyte dysfunction. Additionally, macrophages engage in complex intercellular communication with neutrophils (NETs), T cells (PD-L1/PD-1), and via complement C5a/C5aR1 signaling, all of which amplify cardiac injury. Finally, based on these mechanisms, we discuss therapeutic strategies targeting macrophage polarization, metabolism, specific subsets (e.g. TREM2hi macrophages), and intercellular communication, aiming to offer a theoretical framework for developing precision immunotherapies for SICM.

PMID:
42473475
Bibliographic data and abstract were imported from PubMed on 20 Jul 2026.

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