Response by Fan et al to Letter Regarding Article, “Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration”

HomeCirculationVol. 140, No. 5Response by Fan et al to Letter Regarding Article, “Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Fan et al to Letter Regarding Article, “Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration” Qin Fan, MD, Ruiyan Zhang, MD, PhD and Xiaoxiang Yan, MD, PhD Qin FanQin Fan Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Search for more papers by this author , Ruiyan ZhangRuiyan Zhang Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Search for more papers by this author and Xiaoxiang YanXiaoxiang Yan Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, People’s Republic of China (Q.F., R.Z., X.F.). Search for more papers by this author Originally published29 Jul 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040944Circulation. 2019;140:e179–e180In Response:We sincerely appreciate the favorable comments and further suggestions raised by Li et al regarding our recent publication, in which we reported the role of macrophage-expressed Dectin-1 in myocardial ischemia/reperfusion injury via mediating immune response and inflammatory cells infiltration.1As Li et al indicated, clarifying the subset-specific and stage-specific functions of monocyte/macrophage is critical to prevent or cure cardiovascular diseases. It has been demonstrated that during homeostasis the adult mouse heart contains 3 macrophage subsets: CCR2– MHC-IIlow, CCR2– MHC-IIhigh, and CCR2+ MHC-IIhigh. CCR2– MHC-IIlow and CCR2– MHC-IIhigh are local resident macrophage subsets that are derived from embryonic origins, maintained by local proliferation, and independent of monocyte input. In contrast, CCR2+ MHC-IIhigh macrophages are derived exclusively from blood monocytes through a CCR2-dependent mechanism. After myocardial ischemia/reperfusion injury or myocardial infarction, the resident macrophages are largely replaced by infiltrating CCR2+ monocytes and CCR2+ monocyte–derived macrophages.2 Indeed, we found that Dectin-1 mediates the migration and infiltration of bone marrow–derived monocytes/macrophages, while hardly influencing the resident macrophages, by classifying different macrophage subsets by using flow cytometry. The upregulated expression of Dectin-1 on these cells may directly mediate their migration from bone marrow, spleen, and blood to the heart and also the polarization, which are independent of resident cardiac macrophages. Although we have not analyzed the expression of MKL1 (megakaryocytic leukemia 1) or reactive oxygen species production after Dectin-1 deficiency, we do plan to conduct similar experiments to further explore the function and underlying mechanism of Dectin-1 in macrophage pathophysiology in the future. The respective relation between Dectin-1 and each kind of macrophage will also be further investigated in detail.In our study, Dectin-1 inhibition did not influence the type and number of immune cells in the heart and blood during stable state, including macrophages, monocytes, and neutrophils. Because Dectin-1 belongs to the C-type lectin family, which is a kind of pattern recognition receptor, its expression and downstream signaling are mainly activated by stimulus including damage-associated molecular patterns after cardiac injury.3 Therefore, it could play a more crucial role in the pathological injury process than in maintaining homeostasis. Furthermore, the baseline echocardiography showed that heart size, structure, and cardiac function were not significantly different between wild-type and dectin-1 knockout mice, supporting that Dectin-1 may not take part in heart development. Nevertheless, how Dectin-1 affects new myocardium formation after cardiac injury remains to be further determined. Furthermore, although we believe that studying the role of Dectin-1 in heart rhythm or cardiac conduction is important and potentially interesting, this is beyond the scope of the current study.4 We will explore its specific functions in future studies. However, Dectin-1 was found to be dispensable for the development of atherosclerosis in one study,5 suggesting that Dectin-1 may mediate cardiac ischemia/reperfusion injury, in particular.In summary, we completely agree that understanding the specific function of macrophage subsets during cardiac injury, and the steady state, as well, will provide novel insights into our understanding of this pathophysiological process and our search for potential therapeutic strategies.DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circReferences1. Fan Q, Tao R, Zhang H, Xie H, Lu L, Wang T, Su M, Hu J, Zhang Q, Chen Q, Iwakura Y, Shen W, Zhang R, Yan X. Dectin-1 contributes to myocardial ischemia/reperfusion injury by regulating macrophage polarization and neutrophil infiltration.Circulation. 2019; 139:663–678. doi: 10.1161/CIRCULATIONAHA.118.036044LinkGoogle Scholar2. Lavine KJ, Pinto AR, Epelman S, Kopecky BJ, Clemente-Casares X, Godwin J, Rosenthal N, Kovacic JC. The macrophage in cardiac homeostasis and disease: JACC Macrophage in CVD Series (Part 4).J Am Coll Cardiol. 2018; 72:2213–2230. doi: 10.1016/j.jacc.2018.08.2149CrossrefMedlineGoogle Scholar3. Brown GD, Willment JA, Whitehead L. C-type lectins in immunity and homeostasis.Nat Rev Immunol. 2018; 18:374–389. doi: 10.1038/s41577-018-0004-8CrossrefMedlineGoogle Scholar4. Hulsmans M, Clauss S, Xiao L, Aguirre AD, King KR, Hanley A, Hucker WJ, Wülfers EM, Seemann G, Courties G, Iwamoto Y, Sun Y, Savol AJ, Sager HB, Lavine KJ, Fishbein GA, Capen DE, Da Silva N, Miquerol L, Wakimoto H, Seidman CE, Seidman JG, Sadreyev RI, Naxerova K, Mitchell RN, Brown D, Libby P, Weissleder R, Swirski FK, Kohl P, Vinegoni C, Milan DJ, Ellinor PT, Nahrendorf M. Macrophages facilitate electrical conduction in the heart.Cell. 2017; 169:510–522.e20. doi: 10.1016/j.cell.2017.03.050CrossrefMedlineGoogle Scholar5. Szilagyi K, Gijbels MJ, van der Velden S, Heinsbroek SE, Kraal G, de Winther MP, van den Berg TK. Dectin-1 deficiency does not affect atherosclerosis development in mice.Atherosclerosis. 2015; 239:318–321. doi: 10.1016/j.atherosclerosis.2015.02.005CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 30, 2019Vol 140, Issue 5 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.040944PMID: 31356136 Originally publishedJuly 29, 2019 PDF download Advertisement