Myocardial infarction (MI), an ischemic injury of the myocardium following the obstruction of coronary artery flow, is one of the leading causes of death worldwide and is closely related to inflammation. After MI, various inflammatory mediators released by the ischemic myocardium are involved in tissue repair and related adaptive responses (1–4). The development of necrotic myocardium after MI can be categorized into 3 overlapping stages: the inflammatory stage, the proliferative stage, and the mature stage. During the inflammatory phase, the activated cascades of cytokines, including the Nuclear factor kappa B (NF-kB) system and the complement system, enable the recruitment of neutrophils and macrophages to the infarcted area and clear the necrotic cells. During the proliferation phase, activated macrophages release cytokines and growth factors, such as transforming growth factor (TGF)-β and interleukin (IL)-10, resulting in the formation of highly vascularized granulation tissues. Meanwhile, the expression of pro-inflammatory mediators is inhibited, and fibroblasts and endothelial cells begin to proliferate. The activated myofibroblasts produce extracellular matrix proteins that form extensive microvascular networks. After entering the mature stage, fibroblasts and vascular cells undergo apoptosis, leading to collagen scarring, namely, ventricular remodeling (5, 6). Furthermore, the continuous excessive inflammatory response increases collagen deposition and matrix degradation, thereby aggravating ventricular remodeling and seriously affecting cardiac functions later in life. The inflammatory cascade induced by ischemia–myocardial reperfusion therapy after MI can also damage the myocardial tissue to a certain extent (7). Research evidence suggests that effective inhibition of an excessive inflammatory response after MI can reduce myocardial ischemia injury and improve cardiac function (5, 8). As a newly discovered inflammatory factor, IL-38 has been extensively studied for its anti-inflammatory effects. In our previous study, plasma IL-38 levels were significantly increased in a time-dependent manner in patients with ST-segment elevation MI (9). Animal experiments showed that IL-38 can exhibit an anti-inflammatory effect by regulating macrophage function (10, 11). Therefore, the regulation of the effect of IL-38 on macrophages in myocardial ischemic injury might be considered a new direction for the treatment of MI and the improvement of its prognosis.
Interleukin-38 and Macrophages
IL-38, the 10th member of the IL-1 family, is widely expressed in human organs and tissues such as the placenta, spleen, thymus, and tonsil. It is most abundantly involved in B-cell proliferation in the skin and tonsil, whereas it is present in low levels in the heart and other non-immune organs (12). Close to the genes encoding IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra), the gene encoding IL-38 is located on human chromosome 2Q13-14.1 (13). This cytokine is reported to have 37% (13) and 41% homology with IL-1Ra and 43% homology with IL-36Ra (14, 15). Van de Veerdonk et al. (16) suggested that the biological function of IL-38 is similar to that of IL-36Ra. In other words, it competitively binds to the IL-36 receptor (IL-36R) and inhibits the binding of IL-36 cytokines [IL-1F6 (IL-36α), IL-1F8 (IL-36 β), IL-1F9 (IL-36 γ)] with IL-36R and thereby affects the subsequent activation of NF-κB and Mitogen-activated protein kinase (MAPK), thus exhibiting certain anti-inflammatory effects (16, 17) (Figure 1). Previous studies on the association between IL-38 allele polymorphism and diseases have reported a relationship between IL-38 in compulsive arthritis and psoriatic arthritis (18, 19). Recent studies have reported IL-38 in human coronary atherosclerotic plaques (20). Moreover, polymorphisms in IL-38 are associated with coronary artery disease (21) and C-reactive protein (CRP) concentrations in humans (22). These results suggested that IL-38 may play an important role in coronary artery disease.
Figure 1 Regulation of IL-38 on the IL-36 signaling pathway. IL-38, interleukin-38; IL-36, interleukin-36; IL-36R, interleukin-36 receptor; MAPKs, Mitogen-activated protein kinases; NF-kB, Nuclear factor kappa B.
Macrophages, which are the main cells in inflammation, are functionally divided into classically activated macrophages (M1) associated with inflammatory responses and alternatively activated macrophages (M2) associated with injury repair and regeneration (23). At the onset of the inflammatory phase of MI, M1 macrophages, activated by tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and lipopolysaccharide (LPS), are the major subtypes in the removal of dead cells and extracellular matrix debris (24, 25). In the proliferative stage of MI, M2 macrophages promote the repair and regeneration of damaged heart tissue (26). Notably, recent studies have reported that IL-38 can affect the production and secretion of inflammatory factors related to macrophages, thus playing a relevant role in systemic lupus erythematosus (27), arthritis (28), mandatory spondylitis (29), and cardiovascular diseases (9). Therefore, IL-38 is expected to be a new therapeutic target for ischemic heart injury via the regulation of macrophages.
Role of Interleukin-38 in Myocardial Infarction
MI is one of the cardiovascular events associated with high mortality worldwide. After MI, inflammatory mediators are released from the myocardium as a response to injury, post-injury repair, and adaptation (1–4). Our previous study reported that plasma IL-38 levels in patients with ST-segment elevation MI are positively correlated with CRP, cardiac troponin I (cTNI), and N-terminal pro-brain natriuretic peptide (NT-proBNP) but weakly negatively correlated with left ventricular ejection fraction (9). cTNI has been widely studied as a diagnostic and prognostic marker of the acute coronary syndrome (ACS), and a previous study has reported that patients with ACS with anti-cTNI autoantibodies will eventually trigger severe autoimmune inflammation if mistaken by the immune system for antigens rather than self-protein (30). Thus, cTNI can not only represent the degree of cardiac injury but also predict autoimmune inflammation after Acute myocardial infarction (AMI). Because of its positive correlation with cTNI levels, IL-38 levels may be an indicator of myocardial injury or autoimmunity. Increased serum CRP levels are a nonspecific but sensitive marker of an acute inflammatory response, and high levels of CRP after acute MI can predict infarct expansion, cardiac rupture, and mortality (31, 32). Altogether, plasma IL-38 levels may be a new indicator to determine whether percutaneous coronary intervention is successful or not and can reflect the degree of the anti-inflammatory response in vivo. In addition, Zare Rafie et al. (33) showed that increased serum IL-38 levels were observed 24 h after tissue plasminogen activator treatment in patients with ischemic stroke, and a significant correlation was observed between changes in IL-38 concentration and patients’ prognosis at 3 months. The mechanisms underlying ischemic stroke and MI are blood flow obstruction and subsequent tissue inflammation. These results suggested that changes in serum IL-38 levels may be a new early predictor of the prognosis of ischemic disease.
Interleukin-38 Modulates Macrophage Functions After Myocardial Infarction
After MI, morphological changes occur in the infarcted and non-infarcted areas of the ventricle, which affect the pumping function of the heart and eventually lead to heart failure (34). In this process, inflammation plays an important role in the changes in myocardial tissue structure after MI (35, 36). As key cells involved in inflammation, M1 macrophages mainly secrete TNF-α, IL-1β, and IL-6 to promote inflammation, whereas M2 macrophages mainly secrete IL-10 and TGF-β, which are related to inflammation regression and tissue repair and remodeling (37, 38). Among the inflammatory markers, IL-6 is associated with adverse clinical outcomes as reported in previous clinical trials, whereas increased levels of the anti-inflammatory cytokine IL-10 are associated with more favorable outcomes (39, 40). When MI occurs, the ischemic myocardial tissue rapidly recruits inflammatory monocytes with a high expression of Ly6C and reaches a peak 3 days after MI. The recruited monocytes differentiate into inflammatory macrophages in response to chemokines and inflammatory cytokines (41, 42). Pro-inflammatory M1 macrophages secrete several inflammatory factors such as TNF-α, IL-1 β, and proteases that help clarify dead cells and debris from the infarcted areas. However, the long-term inflammatory response caused by these compounds can lead to extensive damage to the infarcted myocardium, thus affecting subsequent ventricular remodeling (43–45). From 4 to 14 days after MI, macrophages gradually change from inflammatory (M1) to anti-inflammatory or repair (M2). M2 macrophages establish an anti-inflammatory environment by downregulating inflammatory cytokines and upregulating anti-inflammatory cytokines such as IL-10, TGF-β, and vascular endothelial growth factor, and the inflammatory response is gradually replaced by angiogenesis and myofibroblast differentiation (46). Previous studies have reported that IL-38 plays an anti-inflammatory role by binding to the IL-36R and neutralizing the IL-36 inflammatory factor signaling pathway (16). In vitro culture of THP-1 macrophage cell line showed that IL-38 overexpression can effectively reduce the expression of IL-6, TNF-α, IL-23, and IL-10 induced by LPS but did not alter the expression of IL-1β (28). Ge et al. (11) observed that IL-38 promoted the differentiation of macrophages into anti-inflammatory M2 macrophages but prevented the differentiation into pro-inflammatory M1 after exposure to LPS (Figure 2A). IL-38 blocking significantly aggravated the inflammation and increased the differentiation from M2 to M1 macrophages (11). Interestingly, another study reported that dendritic cells (DCs) regulate the expression of inflammatory factors by affecting the infiltration of mononuclear macrophages in the infarcted heart during ventricular remodeling after MI (47).
Figure 2 Mechanism of IL-38 in regulating the macrophage function. (A) IL-38 regulates the phenotypic transformation of macrophages. (B) IL-38 inhibits NLRP3 activation. (C) IL-38 binds IL-1RAPL1 to regulate the macrophage function. IL-38, interleukin-38; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-β; NLRP3, NOD-like receptor thermal protein domain-associated protein 3; IL1RAPL1, interleukin-1 receptor accessory protein-like 1 (–); inhibition.
NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, an effective pro-inflammatory mediator of the innate immune system, is also a regulator of various inflammatory diseases such as MI, atherosclerosis, and diabetes (48–51). NLRP3 inflammasome consists of NLRP3 protein, ASC, and caspase 1. Once activated, cytokine precursors (i.e., promoting IL-1β) are converted to a biologically active form and trigger inflammatory responses (52). The NLRP3 inflammasome protein in macrophages cotreated with IL-38 and LPS was downregulated and returned to levels similar to those of control cells that were not treated with LPS (11). IL-38 can significantly inhibit the activation of NLRP3, thus showing a potent anti-inflammatory activity (11) (Figure 2B).
However, recent studies have shown that IL-38 can also exhibit anti-inflammatory effects by binding to interleukin 1 receptor accessory protein-like 1 (IL-1RAPL1) on the surface of LPS-activated macrophages (28, 53). Interestingly, the intact recombinant IL-38 binds to IL-1RAPL1, activates the downstream JNK/AP1 pathway, and increases the production of IL-6 to act as a stimulator (Figure 2C). Conversely, truncated IL-38 reduces JNK/AP1 signaling and restricts Th17 activation by lowering IL-6 and IL-8 levels (53–55). Although most in vitro experiments have reported that IL-38 can regulate the function of macrophages and play an anti-inflammatory role, the specific binding sites of IL-38 on macrophages are not completely known. These results also indicated that IL-38 binding receptors are diverse; hence, how IL-38 acts on macrophages in the myocardium needs to be further studied and discussed.
Regulation of Interleukin-38 in Macrophages Has Therapeutic Potential in Myocardial Ischemia–Reperfusion Injury
Reperfusion therapy for ischemia caused by MI, such as percutaneous coronary intervention and intravenous thrombolytic therapy, can improve myocardial ischemia, limit the MI size in a timely and effective manner, and quickly restore the blood supply to the heart. However, in the process of blood flow restoration of the ischemic myocardium, reperfusion injury may occur because of cellular swelling and myofibrillary contracture, thus resulting in poor prognoses such as local acute inflammatory reaction, and metabolic disorder, apoptosis or necrosis, and even cardiac insufficiency (7, 56, 57). As the main cell of an inflammatory response, macrophages play an important role in this process (58). As mentioned earlier, M1 macrophages, an inflammatory cell, damage cardiac tissues and cells by releasing inflammatory mediators and proteases in the early stage of reperfusion (59). A study has reported that in the myocardium, myocardial ischemia–reperfusion injury is mainly caused by macrophages polarized by Dectin-1 (60). Interestingly, soluble receptors for advanced glycation end products can improve cardiac function after ischemia–reperfusion in mice via IFN-γ production and promote macrophage infiltration and differentiation into the M1 type (61). These results suggested that M1 macrophages not only participate in inflammatory reactions and cause cardiac damage during ischemia–reperfusion but also have a protective effect on the heart during ischemia. On the contrary, M2 macrophages exhibit anti-inflammatory and tissue repair properties by producing high levels of anti-inflammatory cytokines and fibro-progenitors and alleviate myocardial ischemia–reperfusion injury. Our previous study showed that M2 macrophages alternatively activated by Chemerin15 can protect against myocardial ischemia–reperfusion injury in mice by significantly controlling pro-inflammatory cytokines and observably increasing the level of the anti-inflammatory cytokine IL-10 (62). Evidence has indicated that M2 macrophages have a protective effect on the myocardium after ischemia–reperfusion; hence, effectively restricting M1 and promoting differentiation of M2 macrophages may be a therapeutic target for improving myocardial ischemia–reperfusion injury in the future. The aforementioned promotion of IL-38 on M1-to-M2 transformation reflects the potential therapeutic effect of IL-38 on myocardial ischemia–reperfusion injury.
Interleukin-38 Ameliorates Malignant Ventricular Remodeling After Myocardial Infarction
Although an early coronary reperfusion strategy can significantly improve survival in patients with MI, reducing the risk of heart failure after MI is essential. The emerging understanding of the role of macrophages in inflammation after MI suggests that these cells are necessary for wound healing and the production of stable scars for ventricular remodeling; however, excess pro-inflammatory macrophages are also harmful (8, 34, 45, 63). Therefore, timely suppression of excessive inflammation after MI is necessary to prevent malignant ventricular remodeling and ensure the optimal formation of a supportive scar in the infarct area. In our previous study, we reported that IL-38 mRNA expression was significantly increased in the boundary region of the infarcted heart in mice and reached a peak at 24 h. Double immunofluorescence experiments on major cells involved in the development of MI showed that IL-38 was mainly expressed in cardiomyocytes and also detected in CD68 macrophages 7 days after MI. Thus, both cardiomyocytes and macrophages can be the sources of IL-38 after MI (10). Combined with the previously observed increase in circulating IL-38 levels in ST-segment elevation MI patients, IL-38 may be implicated in the development of MI (9). The infiltration of CD45+ cells in the infarcted heart of mice treated with recombinant IL-38 on the seventh day was significantly reduced compared with that in the control group. Especially, the macrophages of CD45+CD11b+F4/80+ and CD45+CD11b+F4/80+CD86+ were reduced after IL-38 treatment, whereas the macrophages of CD45+CD11b+F4/80+CD86– were not increased. At the same time, immunohistochemical staining results of mouse hearts showed that CD68+ macrophages in the IL-38 treatment group were significantly reduced compared with those in the control group. These results showed that IL-38 can ameliorate ventricular remodeling after MI by cutting down M1 macrophages to decrease the secretion of pro-inflammatory molecules, rather than increasing the number of M2 macrophages (10, 64). Furthermore, high IL-38 levels in ST-segment elevation MI patients may be an adaptive mechanism to prevent the progression of harmful ventricular remodeling after MI. B-cell lymphoma-2 (Bcl-2) family proteins are upstream regulators of mitochondrial cytochrome C release, and the ratio of Bcl-2-associated X (Bax) to Bcl-2 is an important determiner of cell apoptosis susceptibility (65). IL-38 overexpression in cultured cardiomyocytes reduced the mRNA level of the pro-apoptotic molecule Bax and increased the expression of the anti-apoptotic molecule Bcl-2 (10), suggesting that IL-38 may affect cardiomyocyte apoptosis by regulating the Bcl-2/Bax pathway (Figure 3A).
Figure 3 The mechanisms of IL-38 and ischemic injury and repair after MI. (A) The mechanism of IL-38 on cardiomyocytes during ventricular remodeling. (B) The mechanism of IL-38 on tDCs during ventricular remodeling. MIRI, myocardial ischemia–reperfusion injury; IL-38, interleukin-38; IFN-γ, interferon-γ; tDCs, tolerogenic dendritic cells; Treg cells, regulatory T cells; (+), promoting effect; (-), inhibition.
In addition to acting on cardiomyocytes and macrophages, IL-38 exhibits anti-inflammatory effects by regulating the function of DCs. Anzai et al. (47) reported that the infiltration of M2 macrophages of F4/80+CD206+ was reduced in the DC-deficient MI model, whereas the infiltration of M1 macrophages of F4/80+CD206– was increased. Choo et al. (66) observed the expression of the cell markers of M1 and M2 macrophages in the MI model under tolerogenic dendritic cell (tDC) treatment. They found that the expression of M1 markers (IL-1β, IL-6, IL-12b, and TNF-α mRNA) decreased significantly by day 3. On the contrary, the expression of M2 markers (arginase-1, Mrcl1, Mgl1, and Mgl2) increased by day 5 (66). Moreover, regulatory T (Treg) cells may inhibit inflammation by controlling the secretion of anti-inflammatory factors such as IL-10 and TGF-β (67). Choo et al. (66) reported that tDCs induce the production of myocardium-directed Treg cells, which then orchestrate healing by affecting the polarization of macrophages to initiate repair programs and augmenting new angiogenesis in the infarcted heart. The abundance of Treg cells in mice with MI steered the macrophage differentiation toward the M2 type, thus resulting in favorable ventricular remodeling (Figure 3B). Excessive effective T cells and insufficient recruitment of Treg cells can lead to malignant ventricular remodeling after MI (68). The ability of IL-37-induced DCs to activate naive T cells and induce Treg cells has been reported (69), whereas tolerant DCs induced by IL-38 and TnI show stronger tolerance (10). We found that IL-38 inhibited LPS-induced maturation of DCs, thus resulting in lower expression of cell surface molecules and inflammatory factors than that in LPS-induced DCs that were not treated with IL-38 (10). These results suggested that IL-38 may be involved in ventricular remodeling after MI via the regulation of DCs to Treg cells and macrophage polarization. Therefore, IL-38 has the potential as a protective factor in ameliorating malignant ventricular remodeling after MI.
Although IL-38 has not been known for a long time, it is actively studied in various inflammatory diseases. In the context of MI, IL-38 may regulate the release of inflammatory factors by regulating the macrophage phenotype (10, 11) and the function of DCs (10, 69) and play a similar function to IL-36Ra by antagonizing the relevant receptors in the IL-36 pathway (16, 70). Thus, it regulates cardiac function and ventricular remodeling after MI, even myocardial injury after ischemia–reperfusion therapy. Most studies have reported that regulating the phenotypic transformation of M1 and M2 macrophages can promote the enhancement of cardiac angiogenesis, improve cardiac function, and reduce the infarct area after MI, thus facilitating a better prognosis (71–73). Therefore, the regulation of macrophages by IL-38 indicates its potential therapeutic value and requires more research. Although several studies have reported the role of IL-38 in autoimmune diseases and inflammation-related diseases, IL-38-related signaling pathways and anti-inflammatory mechanisms are unclear. A series of issues such as the production source of IL-38 in different environments and the main functional cells, the possible different inflammatory effects of different concentrations of IL-38, and whether IL-38 directly acts on macrophages under myocardial ischemia need to be further studied.
ZL, YD, and YP wrote the article. KY and QZ edited the article. YC, RZ, and JY finished the figures. QD, CP, and YZ provided feedback and guidance. All authors contributed to the article and approved the submitted version.
This work was supported by the National Natural Science Foundation of China (grant numbers 82070310, 81770273, 81900400, 81900270, 82100339).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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1. Xia M, Zhang C, Gu J, Chen J, Wang LC, Lu Y, et al. Impact of C-Reactive Protein on Long-Term Mortality in Acute Myocardial Infarction Patients With Diabetes and Those Without. Clin Chim Acta (2018) 480:220–4. doi: 10.1016/j.cca.2018.02.025
2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, et al. Heart Disease and Stroke Statistics–2014 Update: A Report From the American Heart Association. Circulation (2014) 129(3):e28–e292. doi: 10.1161/01.cir.0000441139.02102.80
3. Gupta T, Harikrishnan P, Kolte D, Khera S, Aronow WS, Mujib M, et al. Outcomes of Acute Myocardial Infarction in Patients With Hypertrophic Cardiomyopathy. Am J Med (2015) 128(8):879–87.e1. doi: 10.1016/j.amjmed.2015.02.025
4. Schoenfeld MS, Kassas I, Shah B. Transradial Artery Access in Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction and Cardiogenic Shock. Curr Treat Options Cardiovasc Med (2018) 20(2):11. doi: 10.1007/s11936-018-0607-1
9. Zhong Y, Yu K, Wang X, Wang X, Ji Q, Zeng Q. Elevated Plasma IL-38 Concentrations in Patients With Acute ST-Segment Elevation Myocardial Infarction and Their Dynamics After Reperfusion Treatment. Mediators Inflamm (2015) 2015:490120. doi: 10.1155/2015/490120
11. Ge Y, Chen J, Hu Y, Chen X, Huang M. IL-38 Alleviates Inflammation in Sepsis in Mice by Inhibiting Macrophage Apoptosis and Activation of the NLRP3 Inflammasome. Mediators Inflamm (2021) 2021:6370911. doi: 10.1155/2021/6370911
12. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C. The Interleukin (IL)-1 Cytokine Family–Balance Between Agonists and Antagonists in Inflammatory Diseases. Cytokine (2015) 76(1):25–37. doi: 10.1016/j.cyto.2015.06.017
13. Lin H, Ho AS, Haley-Vicente D, Zhang J, Bernal-Fussell J, Pace AM, et al. Cloning and Characterization of IL-1HY2, a Novel Interleukin-1 Family Member. J Biol Chem (2001) 276(23):20597–602. doi: 10.1074/jbc.M010095200
14. Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, et al. Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family. J Biol Chem (2000) 275(14):10308–14. doi: 10.1074/jbc.275.14.10308
15. Bensen JT, Dawson PA, Mychaleckyj JC, Bowden DW. Identification of a Novel Human Cytokine Gene in the Interleukin Gene Cluster on Chromosome 2q12-14. J Interferon Cytokine Res (2001) 21(11):899–904. doi: 10.1089/107999001753289505
16. van de Veerdonk FL, Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, et al. IL-38 Binds to the IL-36 Receptor and Has Biological Effects on Immune Cells Similar to IL-36 Receptor Antagonist. Proc Natl Acad Sci USA (2012) 109(8):3001–5. doi: 10.1073/pnas.1121534109
18. Chou CT, Timms AE, Wei JC, Tsai WC, Wordsworth BP, Brown MA. Replication of Association of IL1 Gene Complex Members With Ankylosing Spondylitis in Taiwanese Chinese. Ann Rheum Dis (2006) 65(8):1106–9. doi: 10.1136/ard.2005.046847
19. Rahman P, Sun S, Peddle L, Snelgrove T, Melay W, Greenwood C, et al. Association Between the Interleukin-1 Family Gene Cluster and Psoriatic Arthritis. Arthritis Rheumatol (2006) 54(7):2321–5. doi: 10.1002/art.21928
20. Jha HC, Srivastava P, Vardhan H, Singh LC, Bhengraj AR, Prasad J, et al. Chlamydia Pneumoniae Heat Shock Protein 60 Is Associated With Apoptotic Signaling Pathway in Human Atheromatous Plaques of Coronary Artery Disease Patients. J Cardiol (2011) 58(3):216–25. doi: 10.1016/j.jjcc.2011.07.010
21. Sabater-Lleal M, Huang J, Chasman D, Naitza S, Dehghan A, Johnson AD, et al. Multiethnic Meta-Analysis of Genome-Wide Association Studies in >100 000 Subjects Identifies 23 Fibrinogen-Associated Loci But No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease. Circulation (2013) 128(12):1310–24. doi: 10.1161/CIRCULATIONAHA.113.002251
22. Dehghan A, Dupuis J, Barbalic M, Bis JC, Eiriksdottir G, Lu C, et al. Meta-Analysis of Genome-Wide Association Studies in >80 000 Subjects Identifies Multiple Loci for C-Reactive Protein Levels. Circulation (2011) 123(7):731–8. doi: 10.1161/CIRCULATIONAHA.110.948570
23. Zhang Z, Tang J, Cui X, Qin B, Zhang J, Zhang L, et al. New Insights and Novel Therapeutic Potentials for Macrophages in Myocardial Infarction. Inflammation (2021) 44(5):1696–712. doi: 10.1007/s10753-021-01467-2
24. van der Laan AM, Ter Horst EN, Delewi R, Begieneman MP, Krijnen PA, Hirsch A, et al. Monocyte Subset Accumulation in the Human Heart Following Acute Myocardial Infarction and the Role of the Spleen as Monocyte Reservoir. Eur Heart J (2014) 35(6):376–85. doi: 10.1093/eurheartj/eht331
26. Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, et al. Genetic Lineage Tracing Defines Myofibroblast Origin and Function in the Injured Heart. Nat Commun (2016) 7:12260. doi: 10.1038/ncomms12260
27. Chu M, Tam LS, Zhu J, Jiao D, Liu H, Cai Z, et al. In Vivo Anti-Inflammatory Activities of Novel Cytokine IL-38 in Murphy Roths Large (MRL)/lpr Mice. Immunobiology (2017) 222(3):483–93. doi: 10.1016/j.imbio.2016.10.012
28. Boutet MA, Najm A, Bart G, Brion R, Touchais S, Trichet V, et al. IL-38 Overexpression Induces Anti-Inflammatory Effects in Mice Arthritis Models and in Human Macrophages In Vitro. Ann Rheum Dis (2017) 76(7):1304–12. doi: 10.1136/annrheumdis-2016-210630
29. Monnet D, Kadi A, Izac B, Lebrun N, Letourneur F, Zinovieva E, et al. Association Between the IL-1 Family Gene Cluster and Spondyloarthritis. Ann Rheum Dis (2012) 71(6):885–90. doi: 10.1136/annrheumdis-2011-200439
30. Volz HC, Buss SJ, Li J, Goser S, Andrassy M, Ottl R, et al. Autoimmunity Against Cardiac Troponin I in Ischaemia Reperfusion Injury. Eur J Heart Fail (2011) 13(10):1052–9. doi: 10.1093/eurjhf/hfr098
31. Pietila K, Harmoinen A, Hermens W, Simoons ML, Van D, Verstraete M. Serum C-Reactive Protein and Infarct Size in Myocardial Infarct Patients With a Closed Versus an Open Infarct-Related Coronary Artery After Thrombolytic Therapy. Eur Heart J (1993) 14(7):915–9. doi: 10.1093/eurheartj/14.7.915
32. Pietlla KO, Harmoinen AP, Jokiniitty J, Pasternack AI. Serum C-Reactive Protein Concentration in Acute Myocardial Infarction and Its Relationship to Mortality During 24 Months of Follow-Up in Patients Under Thrombolytic Treatment. Eur Heart J (1996) 17(9):1345–9. doi: 10.1093/oxfordjournals.eurheartj.a015068
33. Zare Rafie M, Esmaeilzadeh A, Ghoreishi A, Tahmasebi S, Faghihzadeh E, Elahi R. IL-38 as an Early Predictor of the Ischemic Stroke Prognosis. Cytokine (2021) 146:155626. doi: 10.1016/j.cyto.2021.155626
34. Jenca D, Melenovsky V, Stehlik J, Stanek V, Kettner J, Kautzner J, et al. Heart Failure After Myocardial Infarction: Incidence and Predictors. ESC Heart Fail (2021) 8(1):222–37. doi: 10.1002/ehf2.13144
36. Jung K, Kim P, Leuschner F, Gorbatov R, Kim JK, Ueno T, et al. Endoscopic Time-Lapse Imaging of Immune Cells in Infarcted Mouse Hearts. Circ Res (2013) 112(6):891–9. doi: 10.1161/CIRCRESAHA.111.300484
37. Garg K, Pullen NA, Oskeritzian CA, Ryan JJ, Bowlin GL. Macrophage Functional Polarization (M1/M2) in Response to Varying Fiber and Pore Dimensions of Electrospun Scaffolds. Biomaterials (2013) 34(18):4439–51. doi: 10.1016/j.biomaterials.2013.02.065
39. Heeschen C, Dimmeler S, Hamm CW, Fichtlscherer S, Boersma E, Simoons ML, et al. Serum Level of the Antiinflammatory Cytokine Interleukin-10 Is an Important Prognostic Determinant in Patients With Acute Coronary Syndromes. Circulation (2003) 107(16):2109–14. doi: 10.1161/01.CIR.0000065232.57371.25
40. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship Between Interleukin 6 and Mortality in Patients With Unstable Coronary Artery Disease: Effects of an Early Invasive or Noninvasive Strategy. Jama (2001) 286(17):2107. doi: 10.1001/jama.286.17.2107
41. Wang Z, Huang S, Sheng Y, Peng X, Liu H, Jin N, et al. Topiramate Modulates Post-Infarction Inflammation Primarily by Targeting Monocytes or Macrophages. Cardiovasc Res (2017) 113(5):475–87. doi: 10.1093/cvr/cvx027
43. van Amerongen MJ, Harmsen MC, van Rooijen N, Petersen AH, van Luyn MJ. Macrophage Depletion Impairs Wound Healing and Increases Left Ventricular Remodeling After Myocardial Injury in Mice. Am J Pathol (2007) 170(3):818–29. doi: 10.2353/ajpath.2007.060547
44. Wan E, Yeap XY, Dehn S, Terry R, Novak M, Zhang S, et al. Enhanced Efferocytosis of Apoptotic Cardiomyocytes Through Myeloid-Epithelial-Reproductive Tyrosine Kinase Links Acute Inflammation Resolution to Cardiac Repair After Infarction. Circ Res (2013) 113(8):1004–12. doi: 10.1161/CIRCRESAHA.113.301198
46. Shiraishi M, Shintani Y, Shintani Y, Ishida H, Saba R, Yamaguchi A, et al. Alternatively Activated Macrophages Determine Repair of the Infarcted Adult Murine Heart. J Clin Invest (2016) 126(6):2151–66. doi: 10.1172/JCI85782
47. Anzai A, Anzai T, Nagai S, Maekawa Y, Naito K, Kaneko H, et al. Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling. Circulation (2012) 125(10):1234–45. doi: 10.1161/CIRCULATIONAHA.111.052126
48. van der Heijden T, Kritikou E, Venema W, van Duijn J, van Santbrink PJ, Slutter B, et al. NLRP3 Inflammasome Inhibition by MCC950 Reduces Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice-Brief Report. Arterioscler Thromb Vasc Biol (2017) 37(8):1457–61. doi: 10.1161/ATVBAHA.117.309575
49. van Hout GP, Bosch L, Ellenbroek GH, de Haan JJ, van Solinge WW, Cooper MA, et al. The Selective NLRP3-Inflammasome Inhibitor MCC950 Reduces Infarct Size and Preserves Cardiac Function in a Pig Model of Myocardial Infarction. Eur Heart J (2017) 38(11):828–36. doi: 1093/eurheartj/ehw247
51. Zhai Y, Meng X, Ye T, Xie W, Sun G, Sun X. Inhibiting the NLRP3 Inflammasome Activation With MCC950 Ameliorates Diabetic Encephalopathy in Db/Db Mice. Molecules (2018) 23(3):2–14. doi: 10.3390/molecules23030522
53. Mora J, Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, et al. Interleukin-38 Is Released From Apoptotic Cells to Limit Inflammatory Macrophage Responses. J Mol Cell Biol (2016) 8(5):426–38. doi: 10.1093/jmcb/mjw006
54. Born TL, Smith DE, Garka KE, Renshaw BR, Bertles JS, Sims JE. Identification and Characterization of Two Members of a Novel Class of the Interleukin-1 Receptor (IL-1R) Family. Delineation of a New Class of IL-1R-Related Proteins Based on Signaling. J Biol Chem (2000) 275(39):29946–54. doi: 10.1074/jbc.M004077200
55. Pavlowsky A, Zanchi A, Pallotto M, Giustetto M, Chelly J, Sala C, et al. Neuronal JNK Pathway Activation by IL-1 Is Mediated Through IL1RAPL1, a Protein Required for Development of Cognitive Functions. Commun Integr Biol (2010) 3(3):245–7. doi: 10.4161/cib.3.3.11414
56. Jennings RB, Sommers HM, Smyth GA, Flack HA, Linn H. Myocardial Necrosis Induced by Temporary Occlusion of a Coronary Artery in the Dog. Arch Pathol (1960) 70(1):68. doi: 10.1016/0003-9969(60)90095-9
57. Vincent A, Covinhes A, Barrere C, Gallot L, Thoumala S, Piot C, et al. Acute and Long-Term Cardioprotective Effects of the Traditional Chinese Medicine MLC901 Against Myocardial Ischemia-Reperfusion Injury in Mice. Sci Rep (2017) 7(1):14701. doi: 10.1038/s41598-017-14822-x
58. Vagnozzi RJ, Maillet M, Sargent MA, Khalil H, Johansen AKZ, Schwanekamp JA, et al. An Acute Immune Response Underlies the Benefit of Cardiac Stem Cell Therapy. Nature (2020) 577(7790):405–9. doi: 10.1038/s41586-019-1802-2
60. Fan Q, Tao R, Zhang H, Xie H, Lu L, Wang T, et al. Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration. Circulation (2019) 139(5):663–78. doi: 10.1161/CIRCULATIONAHA.118.036044
61. Zhang X, Cao X, Dang M, Hongxia W, Buxing C, Fenghe D, et al. Soluble Receptor for Advanced Glycation End-Products Enhanced the Production of IFN-γ Through the NF-κb Pathway in Macrophages Recruited by Ischemia/Reperfusion. Int J Mol Med (2019) 43(6):2507–15. doi: 10.3892/ijmm.2019.4152
62. Chang C, Ji Q, Wu B, Yu K, Zeng Q, Xin S, et al. Chemerin15-Ameliorated Cardiac Ischemia-Reperfusion Injury Is Associated With the Induction of Alternatively Activated Macrophages. Mediators Inflamm (2015) 2015:563951. doi: 10.1155/2015/563951
65. Oltval ZN, Milliman CL, Korsmeyer SJ. Bcl-2 Heterodimerizes In Vivo With a Conserved Homolog, Bax, That Accelerates Programed Cell Death. Cell (1993) 74(4):609–19. doi: 10.1016/0092-8674(93)90509-O
66. Choo EH, Lee JH, Park EH, Park HE, Jung NC, Kim TH, et al. Infarcted Myocardium-Primed Dendritic Cells Improve Remodeling and Cardiac Function After Myocardial Infarction by Modulating the Treg and Macrophage Polarization. Circulation (2017) 135(15):CIRCULATIONAHA.116.023106. doi: 10.1161/CIRCULATIONAHA.116.023106
68. Tang TT, Yuan J, Zhu ZF, Zhang WC, Xiao H, Xia N, et al. Regulatory T Cells Ameliorate Cardiac Remodeling After Myocardial Infarction. Basic Res Cardiol (2012) 107(1):232. doi: 10.1007/s00395-011-0232-6
70. Gresnigt MS, Rosler B, Jacobs CW, Becker KL, Joosten LA, van der Meer JW, et al. The IL-36 Receptor Pathway Regulates Aspergillus Fumigatus-Induced Th1 and Th17 Responses. Eur J Immunol (2013) 43(2):416–26. doi: 10.1002/eji.201242711
71. Hasan AS, Luo L, Yan C, Zhang TX, Urata Y, Goto S, et al. Cardiosphere-Derived Cells Facilitate Heart Repair by Modulating M1/M2 Macrophage Polarization and Neutrophil Recruitment. PloS One (2016) 11(10):e0165255. doi: 10.1371/journal.pone.0165255
72. Zhao J, Li X, Hu J, Chen F, Qiao S, Sun X, et al. Mesenchymal Stromal Cell-Derived Exosomes Attenuate Myocardial Ischaemia-Reperfusion Injury Through miR-182-Regulated Macrophage Polarization. Cardiovasc Res (2019) 115(7):1205–16. doi: 10.1093/cvr/cvz040
73. Dai Y, Wang S, Chang S, Ren D, Shali S, Li C, et al. M2 Macrophage-Derived Exosomes Carry microRNA-148a to Alleviate Myocardial Ischemia/Reperfusion Injury via Inhibiting TXNIP and the TLR4/NF-Kappab/NLRP3 Inflammasome Signaling Pathway. J Mol Cell Cardiol (2020) 142:65–79. doi: 10.1016/j.yjmcc.2020.02.007