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; 尹哲辉; 张宁; 陈涵; 王卓; 黄玉雪; 黄继钮; 游雅昱; 张晨昀; 鲍沁怡; 雷舒心; 蒋峻; 谢小洁

doi:10.1631/jzus.B2500477

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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

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Research Article | Updated：2026-08-13

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
IL-15 aggravates cardiac ischemic injury via impairing macrophage efferocytosis and driving inflammation
浙江大学学报（英文版）（B辑：生物医学和生物技术） 2026年27卷第8期页码：856-871
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：

the National Natural Science Foundation of China(82270498;81570322)
DOI：10.1631/jzus.B2500477
中图分类号：
CSTR：
收稿：2025-08-09，

修回：2025-11-15，

网络首发：2026-08-13，

纸质出版：2026-08-13
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

Allard-Chamard H , Mishra HK , Nandi M , et al. , 2020 . Interleukin-15 in autoimmunity . Cytokine , 136 : 155258 . https://doi.org/10.1016/j.cyto.2020.155258 https://doi.org/10.1016/j.cyto.2020.155258

Ameri K , Bayardorj D , Samurkashian R , et al. , 2020 . Administration of interleukin-15 peptide improves cardiac function in a mouse model of myocardial infarction . J Cardiovasc Pharmacol , 75 ( 1 ): 98 - 102 . https://doi.org/10.1097/FJC.0000000000000764 https://doi.org/10.1097/FJC.0000000000000764

Cai DQ , Xaymardan M , Holm JM , et al. , 2003 . Age-associated impairment in TNF-α cardioprotection from myocardial infarction . Am J Physiol Heart Circ Physiol , 285 ( 2 ): H463 - H469 . https://doi.org/10.1152/ajpheart.00144.2003 https://doi.org/10.1152/ajpheart.00144.2003

Colpitts SL , Puddington L , Lefrançois L , 2015 . IL-15 receptor α signaling constrains the development of IL-17‒producing γδ T cells . Proc Natl Acad Sci USA , 112 ( 31 ): 9692 - 9697 . https://doi.org/10.1073/pnas.1420741112 https://doi.org/10.1073/pnas.1420741112

Daseke MJ II , Tenkorang-Impraim MAA , Ma YG , et al. , 2020 . Exogenous IL-4 shuts off pro-inflammation in neutrophils while stimulating anti-inflammation in macrophages to induce neutrophil phagocytosis following myocardial infarction . J Mol Cell Cardiol , 145 : 112 - 121 . https://doi.org/10.1016/j.yjmcc.2020.06.006 https://doi.org/10.1016/j.yjmcc.2020.06.006

Dozio E , Malavazos AE , Vianello E , et al. , 2014 . Interleukin-15 and soluble interleukin-15 receptor α in coronary artery disease patients: association with epicardial fat and indices of adipose tissue distribution . PLoS ONE , 9 ( 3 ): e90960 . https://doi.org/10.1371/journal.pone.0090960 https://doi.org/10.1371/journal.pone.0090960

Ghali R , Habeichi NJ , Kaplan A , et al. , 2020 . IL-33 induces type-2-cytokine phenotype but exacerbates cardiac remodeling post-myocardial infarction with eosinophil recruitment, worsened systolic dysfunction, and ventricular wall rupture . Clin Sci , 134 ( 11 ): 1191 - 1218 . https://doi.org/10.1042/CS20200402 https://doi.org/10.1042/CS20200402

Gokkusu C , Aydin M , Ozkok E , et al. , 2010 . Influences of genetic variants in interleukin-15 gene and serum interleukin-15 levels on coronary heart disease . Cytokine , 49 ( 1 ): 58 - 63 . https://doi.org/10.1016/j.cyto.2009.09.004 https://doi.org/10.1016/j.cyto.2009.09.004

Gómez-Nicola D , Valle-Argos B , Suardíaz M , et al. , 2008 . Role of IL-15 in spinal cord and sciatic nerve after chronic constriction injury: regulation of macrophage and T-cell infiltration . J Neurochem , 107 ( 6 ): 1741 - 1752 . https://doi.org/10.1111/j.1471-4159.2008.05746.x https://doi.org/10.1111/j.1471-4159.2008.05746.x

Hamada M , Nakamura M , Tran MTN , et al. , 2014 . MafB promotes atherosclerosis by inhibiting foam-cell apoptosis . Nat Commun , 5 : 3147 . https://doi.org/10.1038/ncomms4147 https://doi.org/10.1038/ncomms4147

Hao ZY , Ma J , Dai JJ , et al. , 2020 . A real-world analysis of cardiac rupture on incidence, risk factors and in-hospital outcomes in 4190 ST-elevation myocardial infarction patients from 2004 to 2015 . Coron Artery Dis , 31 ( 5 ): 424 - 429 . https://doi.org/10.1097/MCA.0000000000000877 https://doi.org/10.1097/MCA.0000000000000877

Irwin MW , Mak S , Mann DL , et al. , 1999 . Tissue expression and immunolocalization of tumor necrosis factor-α in postinfarction dysfunctional myocardium . Circulation , 99 ( 11 ): 1492 - 1498 . https://doi.org/10.1161/01.cir.99.11.1492 https://doi.org/10.1161/01.cir.99.11.1492

Jakubzick CV , Randolph GJ , Henson PM , 2017 . Monocyte differentiation and antigen-presenting functions . Nat Rev Immunol , 17 ( 6 ): 349 - 362 . https://doi.org/10.1038/nri.2017.28 https://doi.org/10.1038/nri.2017.28

Jung M , Ma YG , Iyer RP , et al. , 2017 . IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation . Basic Res Cardiol , 112 ( 3 ): 33 . https://doi.org/10.1007/s00395-017-0622-5 https://doi.org/10.1007/s00395-017-0622-5

Lambert JM , Lopez EF , Lindsey ML , 2008 . Macrophage roles following myocardial infarction . Int J Cardiol , 130 ( 2 ): 147 - 158 . https://doi.org/10.1016/j.ijcard.2008.04.059 https://doi.org/10.1016/j.ijcard.2008.04.059

Li YF , Feng LF , Li GR , et al. , 2020 . Resveratrol prevents ISO-induced myocardial remodeling associated with regulating polarization of macrophages through VEGF-B/AMPK/NF-κB pathway . Int Immunopharmacol , 84 : 106508 . https://doi.org/10.1016/j.intimp.2020.106508 https://doi.org/10.1016/j.intimp.2020.106508

Li YQ , Sun XQ , Liu XN , et al. , 2022 . P2X7R-NEK7-NLRP3 inflammasome activation: a novel therapeutic pathway of Qishen granule in the treatment of acute myocardial ischemia . J Inflamm Res , 15 : 5309 - 5326 . https://doi.org/10.2147/JIR.S373962 https://doi.org/10.2147/JIR.S373962

Luan Y , Yang Y , Luan Y , et al. , 2024 . Targeting ferroptosis and ferritinophagy: new targets for cardiovascular diseases . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 25 ( 1 ): 1 - 22 . https://doi.org/10.1631/jzus.B2300097 https://doi.org/10.1631/jzus.B2300097

McDonald PP , Russo MP , Ferrini S , et al. , 1998 . Interleukin-15 (IL-15) induces NF-κB activation and IL-8 production in human neutrophils . Blood , 92 ( 12 ): 4828 - 4835 . https://doi.org/10.1182/blood.V92.12.4828 https://doi.org/10.1182/blood.V92.12.4828

Mortier E , Bernard J , Plet A , et al. , 2004 . Natural, proteolytic release of a soluble form of human IL-15 receptor α-chain that behaves as a specific, high affinity IL-15 antagonist . J Immunol , 173 ( 3 ): 1681 - 1688 . https://doi.org/10.4049/jimmunol.173.3.1681 https://doi.org/10.4049/jimmunol.173.3.1681

Mortier E , Woo T , Advincula R , et al. , 2008 . IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation . J Exp Med , 205 ( 5 ): 1213 - 1225 . https://doi.org/10.1084/jem.20071913 https://doi.org/10.1084/jem.20071913

Ngai D , Schilperoort M , Tabas I , 2023 . Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair . Nat Metab , 5 ( 12 ): 2206 - 2219 . https://doi.org/10.1038/s42255-023-00921-9 https://doi.org/10.1038/s42255-023-00921-9

Patidar M , Yadav N , Dalai SK , 2016 . Interleukin 15: a key cytokine for immunotherapy . Cytokine Growth Factor Rev , 31 : 49 - 59 . https://doi.org/10.1016/j.cytogfr.2016.06.001 https://doi.org/10.1016/j.cytogfr.2016.06.001

Perera PY , Lichy JH , Waldmann TA , et al. , 2012 . The role of interleukin-15 in inflammation and immune responses to infection: implications for its therapeutic use . Microbes Infect , 14 ( 3 ): 247 - 261 . https://doi.org/10.1016/j.micinf.2011.10.006 https://doi.org/10.1016/j.micinf.2011.10.006

Ridker PM , Everett BM , Thuren T , et al. , 2017 . Antiinflammatory therapy with canakinumab for atherosclerotic disease . N Engl J Med , 377 ( 12 ): 1119 - 1131 . https://doi.org/10.1056/NEJMoa1707914 https://doi.org/10.1056/NEJMoa1707914

Roth GA , Mensah GA , Johnson CO , et al. , 2020 . Global burden of cardiovascular diseases and risk factors , 1990 ‒ 2019: update from the GBD 2019 study . J Am Coll Cardiol, 76 ( 25 ): 2982 - 3021 . https://doi.org/10.1016/j.jacc.2020.11.010 https://doi.org/10.1016/j.jacc.2020.11.010

Stone KP , Kastin AJ , Pan WH , 2011 . NFκB is an unexpected major mediator of interleukin-15 signaling in cerebral endothelia . Cell Physiol Biochem , 28 ( 1 ): 115 - 124 . https://doi.org/10.1159/000331720 https://doi.org/10.1159/000331720

van den Bossche J , Baardman J , Otto NA , et al. , 2016 . Mitochondrial dysfunction prevents repolarization of inflammatory macrophages . Cell Rep , 17 ( 3 ): 684 - 696 . https://doi.org/10.1016/j.celrep.2016.09.008 https://doi.org/10.1016/j.celrep.2016.09.008

Wang YC , Zheng Y , Qi BC , et al. , 2023 . α-Lipoic acid alleviates myocardial injury and induces M2b macrophage polarization after myocardial infarction via HMGB1/NF-κB signaling pathway . Int Immunopharmacol , 121 : 110435 . https://doi.org/10.1016/j.intimp.2023.110435 https://doi.org/10.1016/j.intimp.2023.110435

Wei YZ , Lan Y , Zhong YC , et al. , 2020 . Interleukin-38 alleviates cardiac remodelling after myocardial infarction . J Cell Mol Med , 24 ( 1 ): 371 - 384 . https://doi.org/10.1111/jcmm.14741 https://doi.org/10.1111/jcmm.14741

Westman PC , Lipinski MJ , Luger D , et al. , 2016 . Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction . J Am Coll Cardiol , 67 ( 17 ): 2050 - 2060 . https://doi.org/10.1016/j.jacc.2016.01.073 https://doi.org/10.1016/j.jacc.2016.01.073

Wuttge DM , Eriksson P , Sirsjö A , et al. , 2001 . Expression of interleukin-15 in mouse and human atherosclerotic lesions . Am J Pathol , 159 ( 2 ): 417 - 423 . https://doi.org/10.1016/S0002-9440(10)61712-9 https://doi.org/10.1016/S0002-9440(10)61712-9

Xuan WL , Huang WX , Wang RJ , et al. , 2017 . Elevated circulating IL-32 presents a poor prognostic outcome in patients with heart failure after myocardial infarction . Int J Cardiol , 243 : 367 - 373 . https://doi.org/10.1016/j.ijcard.2017.03.065 https://doi.org/10.1016/j.ijcard.2017.03.065

Yan XX , Anzai A , Katsumata Y , et al. , 2013 . Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction . J Mol Cell Cardiol , 62 : 24 - 35 . https://doi.org/10.1016/j.yjmcc.2013.04.023 https://doi.org/10.1016/j.yjmcc.2013.04.023

Zhang YQ , Zhao JL , Lau WB , et al. , 2013 . Tumor necrosis factor-α and lymphotoxin-α mediate myocardial ischemic injury via TNF receptor 1, but are cardioprotective when activating TNF receptor 2 . PLoS ONE , 8 ( 5 ): e60227 . https://doi.org/10.1371/journal.pone.0060227 https://doi.org/10.1371/journal.pone.0060227

Zhou SF , Yuan J , Liao MY , et al. , 2014 . IL-17A promotes ventricular remodeling after myocardial infarction . J Mol Med , 92 ( 10 ): 1105 - 1116 . https://doi.org/10.1007/s00109-014-1176-8 https://doi.org/10.1007/s00109-014-1176-8

Zou H , Zhang MY , Yang X , et al. , 2024 . Cynaroside regulates the AMPK/SIRT3/Nrf2 pathway to inhibit doxorubicin-induced cardiomyocyte pyroptosis . J Zhejiang Univ-Sci B (Biomed & Biotechnol) , 25 ( 9 ): 756 - 772 . https://doi.org/10.1631/jzus.B2300691 https://doi.org/10.1631/jzus.B2300691

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