IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation

Lei GUO; Zhehui YIN; Ning ZHANG; Han CHEN; Zhuo WANG; Yuxue HUANG; Jiniu HUANG; Yayu YOU; Chenyun ZHANG; Qinyi BAO; Shuxin LEI; Jun JIANG; Xiaojie XIE

doi:10.1631/jzus.B2500477

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Research Article | Updated：2026-08-13

IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation
IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation
白介素-15通过损害巨噬细胞胞葬并驱动炎症加重心脏缺血损伤
Journal of Zhejiang University-SCIENCE B Vol. 27, Issue 8, Pages: 856-871(2026)
Affiliations：

1.Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
2.State Key Laboratory of Transvascular Implantation Devices, Hangzhou 310009, China
3.Heart Regeneration and Repair Key Laboratory of Zhejiang Province, Hangzhou 310009, China
4.Department of General Practice and International Medicine, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
5.Department of Cardiology, Hangzhou First Affiliated People’s Hospital, Westlake University School of Medicine, Hangzhou 310003, China
6.Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
7.Department of Cardiology, Hunan Provincial People’s Hospital, Changsha 410000, China
Funds：
DOI：10.1631/jzus.B2500477
CLC：
CSTR：
Received：09 August 2025，

Revised：2025-11-15，

Online First：13 August 2026，

Published：13 August 2026
Accepted：

郭雷,尹哲辉,张宁等.白介素-15通过损害巨噬细胞胞葬并驱动炎症加重心脏缺血损伤[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(08):856-871.

Lei GUO, Zhehui YIN, Ning ZHANG, et al. IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(8): 856-871.
郭雷,尹哲辉,张宁等.白介素-15通过损害巨噬细胞胞葬并驱动炎症加重心脏缺血损伤[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2026,27(08):856-871. DOI： 10.1631/jzus.B2500477.

Lei GUO, Zhehui YIN, Ning ZHANG, et al. IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation[J]. Journal of Zhejiang University-SCIENCE B, 2026, 27(8): 856-871. DOI： 10.1631/jzus.B2500477.

摘要

急性心肌梗死仍然是全球范围内一项重要健康负担，其主要特征包括严重的心脏炎症、细胞凋亡和心肌功能受损。虽然白介素-15（IL-15）与免疫调节相关，但其在急性心肌梗死发病机制中的具体作用尚未明确。因此，本研究旨在阐明IL-15在急性心肌梗死进展中的具体功能，重点关注其对巨噬细胞驱动的炎症反应、凋亡细胞清除和代谢重编程的影响。本研究检测了急性心肌梗死患者及小鼠模型中IL-15表达水平。为了评估IL-15对心脏炎症、凋亡及急性心肌梗死后功能的影响，采用

IL-15

和IL-15受体α亚基(

IL-15Rα

)基因敲除小鼠模型进行了机制研究，探讨IL-15介导对巨噬细胞清除凋亡细胞、细胞极化和代谢重塑的影响，特别关注核因子κB (NF-κB)信号通路和糖酵解通量的变化。研究结果显示，在急性心肌梗死患者的血浆及急性心肌梗死模型小鼠的心脏组织中，检测到IL-15水平升高，且其与疾病严重程度增加相关。

IL-15

或

IL-15Rα

的基因缺失显著改善了心脏损伤，减少了炎症和凋亡，同时保持了心肌功能。机制研究表明，IL-15通过下调MERTK表达抑制巨噬细胞对凋亡细胞的清除，并通过激活NF-κB通路促进M1极化。此外，IL-15还通过增强糖酵解活性对巨噬细胞代谢进行重新编程。最终，IL-15的恢复加重了急性心肌梗死后的心脏缺血损伤，提示IL-15作为巨噬细胞介导炎症的关键调节因子。综上所述，这些发现突显了IL-15作为潜在治疗和预后靶点的作用，旨在减轻心脏炎症并改善急性心肌梗死中的心肌损伤。

Abstract

Acute myocardial infarction (AMI) remains a major global health burden and is characterized by profound cardiac inflammation

apoptotic cell death

and impaired myocardial function. While interleukin-15 (IL-15) has been implicated in immune regulation

its precise role in the pathogenesis of AMI has not been clarified. Therefore

this study sought to delineate the functional role of IL-15 in the progression of AMI

with a particular focus on its influence on macrophage-driven inflammation

efferocytosis

and metabolic reprogramming. IL-15 levels were assessed in AMI patients and murine models. To evaluate the impact of IL-15 on cardiac inflammation

apoptosis

and functional outcomes following AMI

IL-15

and IL-15 receptor α (

IL-15Rα

) knockout (KO) mouse models were employed. Mechanistic studies were conducted to investigate IL-15-mediated effects on macrophage efferocytosis

polarization

and metabolic remodeling

with an emphasis on nuclear factor-κB (NF-κB) signaling and glycolytic flux. Elevated IL-15 levels were detected in both the plasma of AMI patients and the cardiac tissues of murine AMI models

correlating with increased disease severity. The genetic deletion of

IL-15

IL-15Rα

significantly ameliorated cardiac injury by reducing inflammation and apoptosis while preserving myocardial function. Mechanistic analyses revealed that IL-15 impaired macrophage efferocytosis via Mer tyrosine kinase (MERTK) downregulation and promoted M1 polarization via NF-κB pathway activation. Furthermore

IL-15 reprogrammed macrophage metabolism by enhancing glycolytic activity. Ultimately

IL-15 restoration exacerbated cardiac ischemic injury following AMI

serving as a critical regulator of macrophage-mediated inflammation in AMI. These findings highlight the role of IL-15 as a potential therapeutic and prognostic target for mitigating cardiac inflammation and improving myocardial recovery in AMI.

关键词

Keywords

references

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Related Institution

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Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

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