Journal of Zhejiang University

Journal of Zhejiang University SCIENCE B

Accepted manuscript available online (unedited version)

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

Author(s): 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
Affiliation(s): Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; more
Corresponding email(s): xiexj@zju.edu.cn, 2106002@zju.edu.cn
Key Words: Myocardial infarction, Inflammatory phenotype, Macrophage function, Metabolic reprogramming, Interleukin-15 (IL-15)

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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. IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500477

@article{title="IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation",
author="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",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500477"
}

%0 Journal Article
%T IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation
%A Lei GUO
%A Zhehui YIN
%A Ning ZHANG
%A Han CHEN
%A Zhuo WANG
%A Yuxue HUANG
%A Jiniu HUANG
%A Yayu YOU
%A Chenyun ZHANG
%A Qinyi BAO
%A Shuxin LEI
%A Jun JIANG
%A Xiaojie XIE
%J Journal of Zhejiang University SCIENCE B
%P 856-871
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2500477"

TY - JOUR
T1 - IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation
A1 - Lei GUO
A1 - Zhehui YIN
A1 - Ning ZHANG
A1 - Han CHEN
A1 - Zhuo WANG
A1 - Yuxue HUANG
A1 - Jiniu HUANG
A1 - Yayu YOU
A1 - Chenyun ZHANG
A1 - Qinyi BAO
A1 - Shuxin LEI
A1 - Jun JIANG
A1 - Xiaojie XIE
J0 - Journal of Zhejiang University Science B
SP - 856
EP - 871
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2500477"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

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 or 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.

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

郭雷^1,2,3,4，尹哲辉^1,2,3，张宁⁵，陈涵^1,2,3，王卓^1,2,3，黄玉雪⁶，黄继钮^1,2,3，游雅昱⁷，张晨昀^1,2,3，鲍沁怡^1,2,3，雷舒心^1,2,3，蒋峻^1,2,3，谢小洁^1,2,3
¹浙江大学医学院附属第二医院心血管内科，中国杭州， 310009
²经血管植入器械国家重点实验室，中国杭州， 310009
³浙江省心血管介入与再生修复研究重点实验室，中国杭州， 310009
⁴浙江大学医学院附属第二医院全科医学科及国际医学部，中国杭州， 310009
⁵西湖大学医学院附属杭州第一人民医院心血管内科，中国杭州， 310003
⁶重庆医科大学附属第一医院心血管内科，中国重庆， 400016
⁷湖南省人民医院心血管内科，中国长沙， 410000
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。

关键词组：心肌梗死；炎症表型；巨噬细胞功能；代谢重编程；白介素-15（IL-15）

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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