Comprehensive macro and micro views on immune cells in ischemic heart disease

Abstract

Ischemic heart disease (IHD) is a prevalent cardiovascular condition that remains the primary cause of death due to its adverse ventricular remodelling and pathological changes in end-stage heart failure. As a complex pathologic condition, it involves intricate regulatory processes at the cellular and molecular levels. The immune system and cardiovascular system are closely interconnected, with immune cells playing a crucial role in maintaining cardiac health and influencing disease progression. Consequently, alterations in the cardiac microenvironment are influenced and controlled by various immune cells, such as macrophages, neutrophils, dendritic cells, eosinophils, and T-lymphocytes, along with the cytokines they produce. Furthermore, studies have revealed that Gata6⁺ pericardial cavity macrophages play a key role in regulating immune cell migration and subsequent myocardial tissue repair post IHD onset. This review outlines the role of immune cells in orchestrating inflammatory responses and facilitating myocardial repair following IHD, considering both macro and micro views. It also discusses innovative immune cell-based therapeutic strategies, offering new insights for further research on the pathophysiology of ischemic heart disease and immune cell-targeted therapy for IHD.

References

[1] JensenRV, Hjortbak MV, BotkerHE. Ischemic heart disease: an update. Semin Nucl Med. 2020; 50(3):195-207.

[2] LibbyP, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005; 111(25):3481-3488.

[3] DarweshAM, Sosnowski DK, LeeTYT, Keshavarz-BahaghighatH, Seubert JM. Insights into the cardioprotective properties of n-3 PUFAs against ischemic heart disease via modulation of the innate immune system. Chem Biol Interact. 2019; 308:20-44.

[4] HonoldL, Nahrendorf M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ Res. 2018; 122(1):113-127.

[5] PrabhuSD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016; 119(1):91-112.

[6] KuppeC, Ramirez Flores RO, LiZ, et al. Spatial multi-omic map of human myocardial infarction. Nature. 2022; 608(7924):766-777.

[7] SunK, LiYY, JinJ. A double-edged sword of immuno-microenvironment in cardiac homeostasis and injury repair. Signal Transduct Target Ther. 2021; 6(1):79.

[8] JungM, Dodsworth M, ThumT. Inflammatory cells and their non-coding RNAs as targets for treating myocardial infarction. Basic Res Cardiol. 2018; 114(1):4.

[9] WynnTA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016; 44(3):450-462.

[10] Silvestre-RoigC, Braster Q, Ortega-GomezA, SoehnleinO. Neutrophils as regulators of cardiovascular inflammation. Nat Rev Cardiol. 2020; 17(6):327-340.

[11] LiuJ, YangC, LiuT, et al. Eosinophils improve cardiac function after myocardial infarction. Nat Commun. 2020; 11(1):6396.

[12] Moore-MorrisT, Guimarães-Camboa N, BanerjeeI, et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest. 2014; 124(7):2921-2934.

[13] LiuS, ChenJ, ShiJ, et al. M1-like macrophage-derived exosomes suppress angiogenesis and exacerbate cardiac dysfunction in a myocardial infarction microenvironment. Basic Res Cardiol. 2020; 115(2):22.

[14] ZindelJ, Peiseler M, HossainM, et al. Primordial GATA6 macrophages function as extravascular platelets in sterile injury. Science. 2021; 371(6533):eabe0595.

[15] NagareddyPR, Sreejit G, Abo-AlyM, et al. NETosis is required for S100A8/A9-induced granulopoiesis after myocardial infarction. Arterioscler Thromb Vasc Biol. 2020; 40(11):2805-2807.

[16] SreejitG, Abdel-Latif A, AthmanathanB, et al. Neutrophil-derived S100A8/A9 amplify granulopoiesis after myocardial infarction. Circulation. 2020; 141(13):1080-1094.

[17] DinyNL, Baldeviano GC, TalorMV, et al. Eosinophil-derived IL-4 drives progression of myocarditis to inflammatory dilated cardiomyopathy. J Exp Med. 2017; 214(4):943-957.

[18] VieiraJM, NormanS, Villa del CampoC, et al. The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest. 2018; 128(8):3402-3412.

[19] OngSB, Hernández-Reséndiz S, Crespo-AvilanGE, et al. Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol Ther. 2018; 186:73-87.

[20] AndreadouI, Cabrera-Fuentes HA, DevauxY, et al. Immune cells as targets for cardioprotection: new players and novel therapeutic opportunities. Cardiovasc Res. 2019; 115(7):1117-1130.

[21] KainV, PrabhuSD, HaladeGV. Inflammation revisited: inflammation versus resolution of inflammation following myocardial infarction. Basic Res Cardiol. 2014; 109(6):444.

[22] PeetC, IveticA, BromageDI, Shah AM. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res. 2020; 116(6):1101-1112.

[23] JakubzickC, Gautier EL, GibbingsSL, et al. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Immunity. 2013; 39(3):599-610.

[24] SagerHB, Hulsmans M, LavineKJ, et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res. 2016; 119(7):853-864.

[25] HeidtT, Courties G, DuttaP, et al. Differential contribution of monocytes to heart macrophages in steady-state and after myocardial infarction. Circ Res. 2014; 115(2):284-295.

[26] DickSA, Macklin JA, NejatS, et al. Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction. Nat Immunol. 2019; 20(1):29-39.

[27] LiuC, HuangJ, QiuJ, et al. Quercitrin improves cardiac remodeling following myocardial infarction by regulating macrophage polarization and metabolic reprogramming. Phytomedicine. 2024; 127:155467.

[28] HanJ, KimYS, LimMY, et al. Dual roles of graphene oxide to attenuate inflammation and elicit timely polarization of macrophage phenotypes for cardiac repair. ACS Nano. 2018; 12(2):1959-1977.

[29] LimSY, ChoDI, JeongHY, et al. Adjuvant role of macrophages in stem cell-induced cardiac repair in rats. Exp Mol Med. 2018; 50(11):1-10.

[30] MaY, MoutonAJ, LindseyML. Cardiac macrophage biology in the steady-state heart, the aging heart, and following myocardial infarction. Transl Res. 2018; 191:15-28.

[31] ter HorstEN, Hakimzadeh N, van der LaanAM, et al. Modulators of macrophage polarization influence healing of the infarcted myocardium. Int J Mol Sci. 2015; 16(12):29583-29591.

[32] PodaruMN, FieldsL, KainumaS, et al. Reparative macrophage transplantation for myocardial repair: a refinement of bone marrow mononuclear cell-based therapy. Basic Res Cardiol. 2019; 114(5):34.

[33] NahrendorfM, Swirski FK, AikawaE, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007; 204(12):3037-3047.

[34] SongE, OuyangN, HörbeltM, AntusB, WangM, ExtonMS. Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol. 2000; 204(1):19-28.

[35] LeblondAL, Klinkert K, MartinK, et al. Systemic and cardiac depletion of M2 macrophage through CSF-1R signaling inhibition alters cardiac function post myocardial infarction. PLoS One. 2015; 10(9):e0137515.

[36] NahrendorfM, PittetMJ, SwirskiFK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010; 121(22):2437-2445.

[37] NahrendorfM, Swirski FK. Monocyte and macrophage heterogeneity in the heart. Circ Res. 2013; 112(12):1624-1633.

[38] GombozhapovaA, Rogovskaya Y, ShurupovV, et al. Macrophage activation and polarization in post-infarction cardiac remodeling. J Biomed Sci. 2017; 24(1):13.

[39] PuginJ, DunnI, JollietP, et al. Activation of human macrophages by mechanical ventilation in vitro. Am J Physiol. 1998; 275(6): L1040-L1050.

[40] LavineKJ, PintoAR, EpelmanS, et al. The macrophage in cardiac homeostasis and disease: JACC macrophage in CVD series (part 4). J Am Coll Cardiol. 2018; 72(18):2213-2230.

[41] ShiraishiM, Shintani Y, ShintaniY, et al. Alternatively activated macrophages determine repair of the infarcted adult murine heart. J Clin Invest. 2016; 126(6):2151-2166.

[42] McLellanMA, SkellyDA, DonaMSI, et al. High-resolution transcriptomic profiling of the heart during chronic stress reveals cellular drivers of cardiac fibrosis and hypertrophy. Circulation. 2020; 142(15):1448-1463.

[43] BoroM, BalajiKN. CXCL1 and CXCL2 regulate NLRP3 inflammasome activation via G-protein-coupled receptor CXCR2. J Immunol. 2017; 199(5):1660-1671.

[44] Mendez-SamperioP. Expression and regulation of chemokines in mycobacterial infection. J Infect. 2008; 57(5):374-384.

[45] DongY, KangZ, ZhangZ, et al. Single-cell profile reveals the landscape of cardiac immunity and identifies a cardio-protective Ym-1(hi) neutrophil in myocardial ischemia-reperfusion injury. Sci Bull (Beijing). 2024; 69(7):949-967.

[46] ZerneckeA, WeberC. Chemokines in atherosclerosis: proceedings resumed. Arterioscler Thromb Vasc Biol. 2014; 34(4):742-750.

[47] KimY, Nurakhayev S, NurkeshA, ZharkinbekovZ, Saparov A. Macrophage polarization in cardiac tissue repair following myocardial infarction. Int J Mol Sci. 2021; 22(5):2715.

[48] HeL, ChenX. Cardiomyocyte induction and regeneration for myocardial infarction treatment: cell sources and administration strategies. Adv Healthc Mater. 2020; 9(22):e2001175.

[49] LiuY, XuR, GuH, et al. Metabolic reprogramming in macrophage responses. Biomark Res. 2021; 9(1):1.

[50] SunX, LiY, DengQ, et al. Macrophage polarization, metabolic reprogramming, and inflammatory effects in ischemic heart disease. Front Immunol. 2022; 13:934040.

[51] ThorpEB. Cardiac macrophages and emerging roles for their metabolism after myocardial infarction. J Clin Invest. 2023; 133(18):e171953.

[52] WangS, LiuG, LiY, PanY. Metabolic reprogramming induces macrophage polarization in the tumor microenvironment. Front Immunol. 2022; 13:840029.

[53] MoutonAJ, LiX, HallME, Hall JE. Obesity, hypertension, and cardiac dysfunction: novel roles of immunometabolism in macrophage activation and inflammation. Circ Res. 2020; 126(6):789-806.

[54] YeL, JiangY, ZhangM. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev. 2022; 68:81-92.

[55] KeshariRS, JyotiA, DubeyM, et al. Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS One. 2012; 7(10):e48111.

[56] OkekeEB, Louttit C, FryC, et al. Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock. Biomaterials. 2020; 238:119836.

[57] MoeKT, YinNO, NaylynnTM, et al. Nox2 and Nox4 mediate tumour necrosis factor-alpha-induced ventricular remodelling in mice. J Cell Mol Med. 2011; 15(12):2601-2613.

[58] GomezD, BaylisRA, DurginBG, et al. Interleukin-1beta has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med. 2018; 24(9):1418-1429.

[59] SwirskiFK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013; 339(6116):161-166.

[60] JiaoY, ZhangT, ZhangC, et al. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care. 2021; 25(1):356.

[61] LeeHD, KimYH, KimDS. Exosomes derived from human macrophages suppress endothelial cell migration by controlling integrin trafficking. Eur J Immunol. 2014; 44(4):1156-1169.

[62] IvashkivLB, DonlinLT. Regulation of type I interferon responses. Nat Rev Immunol. 2014; 14(1):36-49.

[63] TrinchieriG. Type I interferon: friend or foe? J Exp Med. 2010; 207(10):2053-2063.

[64] Lee-KirschMA. The type I interferonopathies. Annu Rev Med. 2017; 68:297-315.

[65] CalcagnoDM, NgRP Jr, ToomuA, et al. The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by Nrf2-activated macrophages. Sci Immunol. 2020; 5(51):eaaz1974.

[66] CaoDJ, Schiattarella GG, VillalobosE, et al. Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation. 2018; 137(24):2613-2634.

[67] KingKR, Aguirre AD, YeYX, et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat Med. 2017; 23(12):1481-1487.

[68] FurieR, Khamashta M, MerrillJT, et al. Anifrolumab, an anti-interferon-alpha receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 2017; 69(2):376-386.

[69] KhamashtaM, Merrill JT, WerthVP, et al. Sifalimumab, an anti-interferon-alpha monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2016; 75(11):1909-1916.

[70] OuyangX, Negishi H, TakedaR, FujitaY, Taniguchi T, HondaK. Cooperation between MyD88 and TRIF pathways in TLR synergy via IRF5 activation. Biochem Biophys Res Commun. 2007; 354(4):1045-1051.

[71] KrausgruberT, BlazekK, SmallieT, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011; 12(3):231-238.

[72] MaD, ShenH, ChenF, et al. Inflammatory microenvironment-responsive nanomaterials promote spinal cord injury repair by targeting IRF5. Adv Healthc Mater. 2022; 11(23):e2201319.

[73] EdsfeldtA, SwartM, SinghP, et al. Interferon regulatory factor-5-dependent CD11c+ macrophages contribute to the formation of rupture-prone atherosclerotic plaques. Eur Heart J. 2022; 43(19):1864-1877.

[74] CourtiesG, HeidtT, SebasM, et al. In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing. J Am Coll Cardiol. 2014; 63(15):1556-1566.

[75] KrogsgaardM, LiQJ, SumenC, Huppa JB, HuseM, DavisMM. Integral role of IRF-5 in the gene induction programme activated by toll-like receptors. Nature. 2005; 434(7030):238-243.

[76] DavisJ, Molkentin JD. Myofibroblasts: trust your heart and let fate decide. J Mol Cell Cardiol. 2014; 70:9-18.

[77] FisherSA, Periasamy M. Collagen synthesis inhibitors disrupt embryonic cardiocyte myofibrillogenesis and alter the expression of cardiac specific genes in vitro. J Mol Cell Cardiol. 1994; 26(6):721-731.

[78] WuX, RebollMR, Korf-KlingebielM, WollertKC. Angiogenesis after acute myocardial infarction. Cardiovasc Res. 2021; 117(5):1257-1273.

[79] HaiderN, Boscá L, ZandbergenHR, et al. Transition of macrophages to fibroblast-like cells in healing myocardial infarction. J Am Coll Cardiol. 2019; 74(25):3124-3135.

[80] LeaskA. Getting to the heart of the matter: new insights into cardiac fibrosis. Circ Res. 2015; 116(7):1269-1276.

[81] HumeresC, ShindeAV, HannaA, et al. Smad7 effects on TGF-beta and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure. J Clin Invest. 2022; 132(3):e146926.

[82] Schultz JelJ, WittSA, GlascockBJ, et al. TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest. 2002; 109(6):787-796.

[83] FrangogiannisNG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012; 92(2):635-688.

[84] FrangogiannisNG, RenG, DewaldO, et al. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation. 2005; 111(22):2935-2942.

[85] FrangogiannisNG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014; 11(5):255-265.

[86] KongP, ShindeAV, SuY, et al. Opposing actions of fibroblast and cardiomyocyte Smad3 signaling in the infarcted myocardium. Circulation. 2018; 137(7):707-724.

[87] RussoI, Cavalera M, HuangS, et al. Protective effects of activated myofibroblasts in the pressure-overloaded myocardium are mediated through Smad-dependent activation of a matrix-preserving program. Circ Res. 2019; 124(8):1214-1227.

[88] YinX, YinX, PanX, et al. Post-myocardial infarction fibrosis: pathophysiology, examination, and intervention. Front Pharmacol. 2023; 14:1070973.

[89] FrangogiannisNG. Cardiac fibrosis. Cardiovasc Res. 2021; 117(6):1450-1488.

[90] DenisetJF, BelkeD, LeeWY, et al. Gata6(+) pericardial cavity macrophages relocate to the injured heart and prevent cardiac fibrosis. Immunity. 2019; 51(1):131-140-e5.

[91] JinH, LiuK, HuangX, et al. Genetic lineage tracing of pericardial cavity macrophages in the injured heart. Circ Res. 2022; 130(11):1682-1697.

[92] MewhortHEM, Svystonyuk DA, TurnbullJD, et al. Bioactive extracellular matrix scaffold promotes adaptive cardiac remodeling and repair. JACC Basic Transl Sci. 2017; 2(4):450-464.

[93] ZhouB, HonorLB, HeH, et al. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors. J Clin Invest. 2011; 121(5):1894-1904.

[94] DasekeMJ 2nd, Valerio FM, KaluscheWJ, et al. Neutrophil proteome shifts over the myocardial infarction time continuum. Basic Res Cardiol. 2019; 114(5):37.

[95] Vinten-JohansenJ. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res. 2004; 61(3):481-497.

[96] SreejitG, Johnson J, JaggersRM, et al. Neutrophils in cardiovascular disease: warmongers, peacemakers, or both? Cardiovasc Res. 2022; 118(12):2596-2609.

[97] NauseefWM, Borregaard N. Neutrophils at work. Nat Immunol. 2014; 15(7):602-611.

[98] ScapiniP, Cassatella MA. Social networking of human neutrophils within the immune system. Blood. 2014; 124(5):710-719.

[99] KhoyrattyTE, AiZ, BallesterosI, et al. Distinct transcription factor networks control neutrophil-driven inflammation. Nat Immunol. 2021; 22(9):1093-1106.

[100] KatakuraF, Nishiya K, WentzelAS, et al. Paralogs of common carp granulocyte colony-stimulating factor (G-CSF) have different functions regarding development, trafficking and activation of neutrophils. Front Immunol. 2019; 10:255.

[101] LeyK, Hoffman HM, KubesP, et al. Neutrophils: new insights and open questions. Sci Immunol. 2018; 3(30):eaat4579.

[102] SoehnleinO, Zernecke A, ErikssonEE, et al. Neutrophil secretion products pave the way for inflammatory monocytes. Blood. 2008; 112(4):1461-1471.

[103] SorensenOE, Borregaard N. Neutrophil extracellular traps - the dark side of neutrophils. J Clin Invest. 2016; 126(5):1612-1620.

[104] DumontBL, NeagoePE, CharlesE, et al. Low density neutrophils and neutrophil extracellular traps (NETs) are new inflammatory players in heart failure. Can J Cardiol. 2024; 28: S0828-282X(24)00281-2.

[105] GrassleS, HuckV, PappelbaumKI, et al. von Willebrand factor directly interacts with DNA from neutrophil extracellular traps. Arterioscler Thromb Vasc Biol. 2014; 34(7):1382-1389.

[106] KolaczkowskaE, JenneCN, SurewaardBGJ, et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat Commun. 2015; 6:6673.

[107] LavoieSS, DumasE, VulesevicB, Neagoe PE, WhiteM, SiroisMG. Synthesis of human neutrophil extracellular traps contributes to angiopoietin-mediated in vitro proinflammatory and proangiogenic activities. J Immunol. 2018; 200(11):3801-3813.

[108] FuchsTA, BrillA, DuerschmiedD, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A. 2010; 107(36):15880-15885.

[109] ThiamHR, WongSL, WagnerDD, Waterman CM. Cellular mechanisms of NETosis. Annu Rev Cell Dev Biol. 2020; 36:191-218.

[110] VafadarnejadE, RizzoG, KrampertL, et al. Dynamics of cardiac neutrophil diversity in murine myocardial infarction. Circ Res. 2020; 127(9): e232-e249.

[111] HorckmansM, RingL, DucheneJ, et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J. 2017; 38(3):187-197.

[112] PapayannopoulosV. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol. 2018; 18(2):134-147.

[113] PhillipsonM, KubesP. The healing power of neutrophils. Trends Immunol. 2019; 40(7):635-647.

[114] QuailDF, AmulicB, AzizM, et al. Neutrophil phenotypes and functions in cancer: a consensus statement. J Exp Med. 2022; 219(6):e20220011.

[115] KaiserR, GoldC, JoppichM, et al. Peripheral priming induces plastic transcriptomic and proteomic responses in circulating neutrophils required for pathogen containment. Sci Adv. 2024; 10(12):eadl1710.

[116] PetersVBM, Matheis F, ErdmannI, et al. Myeloperoxidase induces monocyte migration and activation after acute myocardial infarction. Front Immunol. 2024; 15:1360700.

[117] BaldusS, Heeschen C, MeinertzT, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003; 108(12):1440-1445.

[118] ArataniY. Myeloperoxidase: its role for host defense, inflammation, and neutrophil function. Arch Biochem Biophys. 2018; 640:47-52.

[119] LauD, BaldusS. Myeloperoxidase and its contributory role in inflammatory vascular disease. Pharmacol Ther. 2006; 111(1):16-26.

[120] GuthoffH, HofA, KlinkeA, et al. Protective effects of therapeutic neutrophil depletion and myeloperoxidase inhibition on left ventricular function and remodeling in myocardial infarction. Antioxidants (Basel). 2022; 12(1):33.

[121] MocattaTJ, Pilbrow AP, CameronVA, et al. Plasma concentrations of myeloperoxidase predict mortality after myocardial infarction. J Am Coll Cardiol. 2007; 49(20):1993-2000.

[122] MollenhauerM, Friedrichs K, LangeM, et al. Myeloperoxidase mediates Postischemic Arrhythmogenic ventricular remodeling. Circ Res. 2017; 121(1):56-70.

[123] KargapolovaY, Geißen S, ZhengR, et al. The enzymatic and non-enzymatic function of myeloperoxidase (MPO) in inflammatory communication. Antioxidants (Basel). 2021; 10(4):562.

[124] DaviesMJ, Hawkins CL. The role of myeloperoxidase in biomolecule modification, chronic inflammation, and disease. Antioxid Redox Signal. 2020; 32(13):957-981.

[125] NelanderK, Lagerstrom-Fermer M, AmilonC, et al. Early clinical experience with AZD4831, a novel myeloperoxidase inhibitor, developed for patients with heart failure with preserved ejection fraction. Clin Transl Sci. 2021; 14(3):812-819.

[126] GanLM, Lagerström-Fermér M, EricssonH, et al. Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo-controlled, phase I study in healthy volunteers. Br J Clin Pharmacol. 2019; 85(4):762-770.

[127] KonstamMA, KramerDG, PatelAR, Maron MS, UdelsonJE. Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging. 2011; 4(1):98-108.

[128] PuhlSL, Steffens S. Neutrophils in post-myocardial infarction inflammation: damage vs. Resolution? Front Cardiovasc Med. 2019; 6:25.

[129] AliM, PulliB, CourtiesG, et al. Myeloperoxidase inhibition improves ventricular function and remodeling after experimental myocardial infarction. JACC Basic Transl Sci. 2016; 1(7):633-643.

[130] MaY, Yabluchanskiy A, IyerRP, et al. Temporal neutrophil polarization following myocardial infarction. Cardiovasc Res. 2016; 110(1):51-61.

[131] MihailaAC, Ciortan L, TucureanuMM, SimionescuM, ButoiE. Anti-inflammatory neutrophils reprogram macrophages toward a pro-healing phenotype with increased Efferocytosis capacity. Cells. 2024; 13(3):208.

[132] CartaT, Razzuoli E, FruscioneF, et al. Comparative phenotypic and functional analyses of the effects of IL-10 or TGF-beta on porcine macrophages. Animals (Basel). 2021; 11(4):1098.

[133] MarinkovicG, KoenisDS, de CampL, et al. S100A9 links inflammation and repair in myocardial infarction. Circ Res. 2020; 127(5):664-676.

[134] HeadlandSE, JonesHR, NorlingLV, et al. Neutrophil-derived microvesicles enter cartilage and protect the joint in inflammatory arthritis. Sci Transl Med. 2015; 7(315):315ra190.

[135] SandriS, HebedaCB, BroeringMF, et al. Role of Annexin A1 secreted by neutrophils in melanoma metastasis. Cells. 2023; 12(3):425.

[136] ZifkosK, Bochenek ML, GogirajuR, et al. Endothelial PTP1B deletion promotes VWF exocytosis and venous Thromboinflammation. Circ Res. 2024; 134: e93-e111.

[137] de Paula-SilvaM, Barrios BE, Macció-MarettoL, et al. Role of the protein annexin A1 on the efficacy of anti-TNF treatment in a murine model of acute colitis. Biochem Pharmacol. 2016; 115:104-113.

[138] BoudhraaZ, Rondepierre F, OuchchaneL, et al. Annexin A1 in primary tumors promotes melanoma dissemination. Clin Exp Metastasis. 2014; 31(7):749-760.

[139] BoudhraaZ, MerleC, MazzocutD, et al. Characterization of pro-invasive mechanisms and N-terminal cleavage of ANXA1 in melanoma. Arch Dermatol Res. 2014; 306(10):903-914.

[140] SalehD, JonesRTL, SchrothSL, Thorp EB, FeinsteinMJ. Emerging roles for dendritic cells in heart failure. Biomolecules. 2023; 13(10):1535.

[141] AnzaiA, AnzaiT, NagaiS, et al. Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling. Circulation. 2012; 125(10):1234-1245.

[142] NagaiT, HondaS, SuganoY, et al. Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans. J Am Heart Assoc. 2014; 3(3):e000839.

[143] LeeJH, KimTH, ParkHE, et al. Myosin-primed tolerogenic dendritic cells ameliorate experimental autoimmune myocarditis. Cardiovasc Res. 2014; 101(2):203-210.

[144] DomogallaMP, RostanPV, RakerVK, Steinbrink K. Tolerance through education: how Tolerogenic dendritic cells shape immunity. Front Immunol. 2017; 8:1764.

[145] ChooEH, LeeJH, ParkEH, et al. Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the regulatory T cell and macrophage polarization. Circulation. 2017; 135(15):1444-1457.

[146] LeuschnerF, RauchPJ, UenoT, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012; 209(1):123-137.

[147] NahrendorfM, Swirski FK. Regulating repair: regulatory T cells in myocardial infarction. Circ Res. 2014; 115(1):7-9.

[148] van der BorghtK, ScottCL, NindlV, et al. Myocardial infarction primes autoreactive T cells through activation of dendritic cells. Cell Rep. 2017; 18(12):3005-3017.

[149] FrohlichGM, MeierP, WhiteSK, et al. Myocardial reperfusion injury: looking beyond primary PCI. Eur Heart J. 2013; 34(23):1714-1722.

[150] BurchfieldJS, XieM, HillJA. Pathological ventricular remodeling. Circulation. 2013; 128(4):388-400.

[151] GajarsaJJ, KlonerRA. Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities. Heart Fail Rev. 2011; 16(1):13-21.

[152] MaldonadoRA, von Andrian UH. How tolerogenic dendritic cells induce regulatory T cells. Adv Immunol. 2010; 108:111-165.

[153] GiannoukakisN, Phillips B, FinegoldD, HarnahaJ, TruccoM. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011; 34(9):2026-2032.

[154] LeplinaO, Kurochkina Y, TikhonovaM, ShevelaE, Ostanin A, ChernykhE. Dendritic cells generated in the presence of interferon-alpha and modulated with dexamethasone as a novel tolerogenic vaccine platform. Inflammopharmacology. 2020; 28(1):311-319.

[155] BystromJ, AminK, Bishop-BaileyD. Analysing the eosinophil cationic protein: a clue to the function of the eosinophil granulocyte. Respir Res. 2011; 12(1):10.

[156] KhouryP, Grayson PC, KlionAD. Eosinophils in vasculitis: characteristics and roles in pathogenesis. Nat Rev Rheumatol. 2014; 10(8):474-483.

[157] RurikJG, Aghajanian H, EpsteinJA. Immune cells and immunotherapy for cardiac injury and repair. Circ Res. 2021; 128(11):1766-1779.

[158] LiehnEA, Kanzler I, KonschallaS, et al. Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion. Arterioscler Thromb Vasc Biol. 2013; 33(9):2180-2186.

[159] CheungCC, Constantine M, AhmadiA, ShiauC, ChenLYC. Eosinophilic myocarditis. Am J Med Sci. 2017; 354(5):486-492.

[160] VerdoiaM, Schaffer A, CassettiE, et al. Absolute eosinophils count and the extent of coronary artery disease: a single centre cohort study. J Thromb Thrombolysis. 2015; 39(4):459-466.

[161] CikrikciogluMA, SoysalP, DikerdemD, et al. Absolute blood eosinophil count and 1-year mortality risk following hospitalization with acute heart failure. Eur J Emerg Med. 2012; 19(4):257-263.

[162] LiuCL, LiuX, ZhangY, et al. Eosinophils protect mice from angiotensin-II perfusion-induced abdominal aortic aneurysm. Circ Res. 2021; 128(2):188-202.

[163] ZhangY, LiuT, DengZ, et al. Group 2 innate lymphoid cells protect mice from abdominal aortic aneurysm formation via IL5 and eosinophils. Adv Sci (Weinh). 2023; 10(7):e2206958.

[164] BryceK, Vierecke JK. Me versus not me: assimilating to a left ventricular assist device implant. J Heart Lung Transplant. 2024; 43:1249-1251.

[165] AbshireM, Prichard R, CajitaM, DiGiacomoM, Dennison Himmelfarb C. Adaptation and coping in patients living with an LVAD: a metasynthesis. Heart Lung. 2016; 45(5):397-405.

[166] FrantzS, Falcao-Pires I, BalligandJL, et al. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the working group on myocardial function of the ESC. Eur J Heart Fail. 2018; 20(3):445-459.

[167] HanD, WangF, QiaoZ, et al. Neutrophil membrane-camouflaged nanoparticles alleviate inflammation and promote angiogenesis in ischemic myocardial injury. Bioact Mater. 2023; 23:369-382.

[168] KhambhatiJ, EngelsM, Allard-RatickM, SandesaraPB, Quyyumi AA, SperlingL. Immunotherapy for the prevention of atherosclerotic cardiovascular disease: promise and possibilities. Atherosclerosis. 2018; 276:1-9.

[169] ZoccaliC, Mallamaci F. Innate immunity system in patients with cardiovascular and kidney disease. Circ Res. 2023; 132(8):915-932.

[170] LutgensE, AtzlerD, DöringY, DucheneJ, Steffens S, WeberC. Immunotherapy for cardiovascular disease. Eur Heart J. 2019; 40(48):3937-3946.

[171] ZhengWC, ChanW, DartA, Shaw JA. Novel therapeutic targets and emerging treatments for atherosclerotic cardiovascular disease. Eur Heart J Cardiovasc Pharmacother. 2024; 10(1):53-67.

[172] BansalSS, Ismahil MA, GoelM, et al. Activated T lymphocytes are essential drivers of pathological remodeling in ischemic heart failure. Circ Heart Fail. 2017; 10(3):e003688.

[173] IsmahilMA, HamidT, BansalSS, Patel B, KingeryJR, PrabhuSD. Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res. 2014; 114(2):266-282.

[174] KingeryJR, HamidT, LewisRK, et al. Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol. 2017; 112(2):19.

[175] BansalSS, Ismahil MA, GoelM, et al. Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy. Circulation. 2019; 139(2):206-221.

[176] VignaliDA, Collison LW, WorkmanCJ. How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-532.

[177] XiaN, LuY, GuM, et al. A unique population of regulatory T cells in heart potentiates cardiac protection from myocardial infarction. Circulation. 2020; 142(20):1956-1973.

[178] TangTT, YuanJ, ZhuZF, et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol. 2012; 107(1):232.

[179] LiuH, GaoW, YuanJ, et al. Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction. J Mol Cell Cardiol. 2016; 91:123-133.

[180] WangS, YaoY, SongL, et al. ROS-responsive drug-releasing injectable microgels for ameliorating myocardial infarction. Biomaterials. 2024; 307:122534.

[181] SakaguchiS, OnoM, SetoguchiR, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006; 212:8-27.

[182] JosefowiczSZ, LuLF, RudenskyAY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-564.

[183] OhkuraN, Sakaguchi S. Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases. Cell Res. 2020; 30(6):465-474.

[184] CortezJT, Montauti E, ShifrutE, et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature. 2020; 582(7812):416-420.

[185] DelgoboM, Weiß E, AshourDED, et al. Myocardial milieu favors local differentiation of regulatory T cells. Circ Res. 2023; 132(5):565-582.

[186] HofmannU, Beyersdorf N, WeiratherJ, et al. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation. 2012; 125(13):1652-1663.

[187] Blanco-DominguezR, de la Fuente H, RodríguezC, et al. CD69 expression on regulatory T cells protects from immune damage after myocardial infarction. J Clin Invest. 2022; 132(21):e152418.

[188] RieckmannM, Delgobo M, GaalC, et al. Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses. J Clin Invest. 2019; 129(11):4922-4936.

[189] HernandezR, Põder J, LaPorteKM, MalekTR. Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol. 2022; 22(10):614-628.

[190] AbbasAK, TrottaE, R. SimeonovD, Marson A, BluestoneJA. Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018; 3(25):eaat1482.

[191] SpolskiR, LiP, LeonardWJ. Biology and regulation of IL-2: from molecular mechanisms to human therapy. Nat Rev Immunol. 2018; 18(10):648-659.

[192] ApertC, Romagnoli P, van MeerwijkJPM. IL-2 and IL-15 dependent thymic development of Foxp3-expressing regulatory T lymphocytes. Protein Cell. 2018; 9(4):322-332.

[193] WolfD, Gerhardt T, WinkelsH, et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective Apolipoprotein B(100)-reactive CD4(+) T-regulatory cells. Circulation. 2020; 142(13):1279-1293.

[194] TanakaA, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res. 2017; 27(1):109-118.

[195] XiaY, GaoD, WangX, et al. Role of Treg cell subsets in cardiovascular disease pathogenesis and potential therapeutic targets. Front Immunol. 2024; 15:1331609.

[196] WeiratherJ, Hofmann UDW, BeyersdorfN, et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014; 115(1):55-67.

[197] SaigusaR, Winkels H, LeyK. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol. 2020; 17(7):387-401.

[198] SternerRC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021; 11(4):69.

[199] WangZ, WuZ, LiuY, HanW. New development in CAR-T cell therapy. J Hematol Oncol. 2017; 10(1):53.

[200] SermerD, Brentjens R. CAR T-cell therapy: full speed ahead. Hematol Oncol. 2019; 37(Suppl 1):95-100.

[201] FeinsS, KongW, WilliamsEF, Milone MC, FraiettaJA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019; 94(S1): S3-S9.

[202] ZayedMA. Immune modulation of coronary atherosclerosis with anticytokine treatment. Circ Cardiovasc Imaging. 2020; 13(9):e011451.

[203] MorfinoP, AimoA, CastiglioneV, Gálvez-MontónC, EmdinM, Bayes-Genis A. Treatment of cardiac fibrosis: from neuro-hormonal inhibitors to CAR-T cell therapy. Heart Fail Rev. 2023; 28(2):555-569.

[204] LoureiroLR, Hoffmann L, NeuberC, et al. Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment. J Exp Clin Cancer Res. 2023; 42(1):341.

[205] FitzgeraldAA, WeinerLM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020; 39(3):783-803.

[206] CostaA, Kieffer Y, Scholer-DahirelA, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018; 33(3):463-479 e10.

[207] WeberWA, Varasteh Z, FritschleK, MorathV. A Theranostic approach for CAR-T cell therapy. Clin Cancer Res. 2022; 28(24):5241-5243.

[208] XiaoZ, ToddL, HuangL, et al. Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat Commun. 2023; 14(1):5110.

[209] GonzalezA, Schelbert EB, DíezJ, ButlerJ. Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol. 2018; 71(15):1696-1706.

[210] AghajanianH, KimuraT, RurikJG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019; 573(7774):430-433.

[211] RurikJG, Tombácz I, YadegariA, et al. CAR T cells produced in vivo to treat cardiac injury. Science. 2022; 375(6576):91-96.

[212] KaurH, Takefuji M, NgaiCY, et al. Targeted ablation of Periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ Res. 2016; 118(12):1906-1917.

[213] PalaskasNL, AliHJ, KoutroumpakisE, GanatraS, DeswalA. Cardiovascular toxicity of immune therapies for cancer. BMJ. 2024; 385:e075859.

[214] GhoshAK, ChenDH, GuhaA, Mackenzie S, WalkerJM, RoddieC. CAR T cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? JACC CardioOncol. 2020; 2(1):97-109.

[215] LefebvreB, KangY, SmithAM, Frey NV, CarverJR, Scherrer-CrosbieM. Cardiovascular effects of CAR T cell therapy: a retrospective study. JACC CardioOncol. 2020; 2(2):193-203.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.