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Conventional Dendritic Cells Impair Recovery After Myocardial Infarction Conventional Dendritic Cells Impair Recovery after Myocardial Infarction Jun Seong Lee, Se-Jin Jeong, Sinai Kim, Lorraine Chalifour, Tae Jin Yun, Mohammad Alam Miah, Bin Li, Abdelilah This information is current as Majdoubi, Antoine Sabourin, Tibor Keler, Jean V. Guimond, of September 28, 2021. Elie Haddad, Eui-Young Choi, Slava Epelman, Jae-Hoon Choi, Jacques Thibodeau, Goo Taeg Oh and Cheolho Cheong J Immunol 2018; 201:1784-1798; Prepublished online 10 Downloaded from August 2018; doi: 10.4049/jimmunol.1800322 http://www.jimmunol.org/content/201/6/1784 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/08/08/jimmunol.180032 Material 2.DCSupplemental References This article cites 76 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/201/6/1784.full#ref-list-1 Why The JI? Submit online. by guest on September 28, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Conventional Dendritic Cells Impair Recovery after Myocardial Infarction Jun Seong Lee,*,†,‡ Se-Jin Jeong,x Sinai Kim,x Lorraine Chalifour,{ Tae Jin Yun,†,‖ Mohammad Alam Miah,*,† Bin Li,*,# Abdelilah Majdoubi,*,‡ Antoine Sabourin,*,‡ Tibor Keler,** Jean V. Guimond,†† Elie Haddad,*,‡‡ Eui-Young Choi,xx Slava Epelman,{{,‖‖,## Jae-Hoon Choi,*** Jacques Thibodeau,*,‡ Goo Taeg Oh,x and Cheolho Cheong*,†,‖,1 Ischemic myocardial injury results in sterile cardiac inflammation that leads to tissue repair, two processes controlled by mono- nuclear phagocytes. Despite global burden of cardiovascular diseases, we do not understand the functional contribution to path- ogenesis of specific cardiac mononuclear phagocyte lineages, in particular dendritic cells. To address this limitation, we used detailed + + lineage tracing and genetic studies to identify bona fide murine and human CD103 conventional dendritic cell (cDC)1s, CD11b Downloaded from cDC2s, and plasmacytoid DCs (pDCs) in the heart of normal mice and immunocompromised NSG mice reconstituted with human CD34+ cells, respectively. After myocardial infarction (MI), the specific depletion of cDCs, but not pDCs, improved cardiac function and prevented adverse cardiac remodeling. Our results showed that fractional shortening measured after MI was not influenced by the absence of pDCs. Interestingly, however, depletion of cDCs significantly improved reduction in fractional shortening. Moreover, fibrosis and cell areas were reduced in infarcted zones. This correlated with reduced numbers of cardiac macrophages, neutrophils, and T cells, indicating a blunted inflammatory response. Accordingly, mRNA levels of proinflamma- http://www.jimmunol.org/ tory cytokines IL-1b and IFN-g were reduced. Collectively, our results demonstrate the unequivocal pathological role of cDCs following MI. The Journal of Immunology, 2018, 201: 1784–1798. yocardial infarction (MI) caused by a thrombotic oc- forces within the myocardium lead to adverse remodeling changes clusion of a coronary artery is the most frequent cause in the remote, uninfarcted myocardial segments (3–5). Ischemic M of cardiac dysfunction and heart failure (1). Ischemia heart disease is the leading cause of death worldwide. Myocardial results in oxygen and nutrient deprivation, leading to car- necrosis after MI triggers immuno-inflammatory reactions that are diomyocyte cell death in the nonperfused territory. This is ac- integral to the healing process but also contribute to left ventric- companied by an intense sterile inflammatory response and a ular (LV) dysfunction (6, 7). Such inflammation results from the by guest on September 28, 2021 gradual collagen-driven scar formation that is required to replace activation of tissue-resident immune cells, which produce pro- the necrotic myocardium (2). Ultimately, altered hemodynamic inflammatory cytokines and chemokines capable of attracting *De´partement de Microbiologie, Infectiologie et Immunologie, Universite´ de Montre´al, Que´be´coise d’Hypertension Arte´rielle – Le Fonds de Recherche du Que´bec - Sante´ J1 Montreal, Quebec H3T 1J4, Canada; †Institut de Recherches Cliniques de Montre´al, Mon- scholarship. treal, Quebec H2W 1R7, Canada; ‡Laboratoire d’Immunologie Mole´culaire, Universite´ de x J.S.L., G.T.O., J.-H.C., and C.C. designed the experiments. J.S.L. executed the ma- Montre´al, Montreal, Quebec H3T 1J4, Canada; Immune and Vascular Cell Network Re- jority of experiments presented. L.C. performed myocardial infarctions. S.-J.J., S.K., search Center, National Creative Initiatives, Department of Life Sciences, Ewha Womans { and E.-Y.C. did Masson trichrome staining and wheat germ agglutinin staining as University, Seoul 120-750, South Korea; Lady Davis Institute, Division of Experimental ‖ well as echocardiography. T.J.Y. performed phagocytosis assay and marker analysis Medicine, McGill University, Montreal, Quebec H3T 1E2, Canada; Division of Experi- for plasmacytoid dendritic cells. M.A.M. and B.L. prepared mouse and humanized mental Medicine, Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, mouse hearts for FACS. A.M. and A.S. helped analyze flow cytometry data for Canada; #De´partement de Biologie Mole´culaire, Universite´ de Montre´al, Montreal, Quebec identification of dendritic cell subsets. T.K. provided human Flt3L. E.H. and J.V.G. H3T 1J4, Canada; **Celldex Therapeutics, Hampton, NJ 08827; ††Centre de Sante´ et de provided humanized mice. J.S.L., S.E., J.-H.C., G.T.O., J.T., and C.C. interpreted the Services Sociaux Jeanne-Mance, Montreal, Quebec H2T 2R9, Canada; ‡‡Centre Hospitalier xx data. J.S.L., S.E., J.-H.C., G.T.O., and J.T. wrote the manuscript. Universitaire Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada; Gang- nam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Address correspondence and reprint requests to Dr. Jacques Thibodeau or Dr. Goo Korea; {{Peter Munk Cardiac Center, Toronto, Ontario M5G 2N2, Canada; ‖‖Ted Rogers Taeg Oh, Laboratoire d’Immunologie Mole´culaire, De´partement de Microbiologie, Centre for Heart Research, Toronto, Ontario M5G 1X8, Canada; ##Toronto General Hospital Infectiologie et Immunologie, Universite´ de Montre´al, Faculte´ de Me´decine, C.P. Research Institute, University Health Network, Toronto, Ontario M5G 2C4, Canada; and 6128 Succursale Centre-Ville, 2900 Boulevard Edouard Montpetit, Montreal, QC ***Department of Life Science, College of Natural Sciences, Research Institute for Natural H3C 3J7, Canada (J.T.) or National Creative Research Center for Immune and Vas- Sciences, Hanyang University, Seoul 04763, South Korea cular Cell Network, Department of Life Sciences, Ewha Womans University, Seodaemoon-gu, Seoul 120-750, Korea (G.T.O.). E-mail addresses: Jacques. 1Deceased. [email protected] (J.T.) or [email protected] (G.T.O.) ORCIDs: 0000-0001-6675-3265 (J.S.L.); 0000-0002-6375-5334 (S.-J.J.); 0000-0002- The online version of this article contains supplemental material. 5985-7733 (S.K.); 0000-0002-2053-4793 (A.M.); 0000-0003-3732-0190 (E.-Y.C.); 0000-0002-0790-9634 (J.T.). Abbreviations used in this article: BM, bone marrow; cDC, conventional DC; DC, dendritic cell; DN, double-negative; DT, diphtheria toxin; DTR, DT receptor; Flt3L, Received for publication March 5, 2018. Accepted for publication July 6, 2018. Flt3 ligand; hu-mice, humanized mice; LN, lymph node; LV, left ventricular; MF, This work was supported by grants from the Canadian Foundation for Innovation macrophage; MHC II, MHC class II; MI, myocardinal infarction; moDC, monocyte (John R. Evans Leaders Fund to C.C.) and the Canadian Institutes of Health Research DC; pDC, plasmacytoid DC; poly I:C, polyinosinic-polycytidylic acid; pre-cDC, (CIHR) (MOP 125933 to C.C. and J.T., MOP 136802 to J.T., and MOP 133050 to precursor cDC; RA, right atrium; Seg, segment; Treg, regulatory T cell; TTC, tri- C.C.), by Canadian HIV Cure Enterprise Team Grant HIG-133050 (to C.C. and E.H.), phenyltetrazolium chloride; WT, wild type. and by a National Research Foundation of Korea grant funded by the Korean gov- ernment (2012R1A3A2026454 to G.T.O.). J.S.L. was supported by the Fonds de Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 Recherche du Que´bec – Nature et Technologies. J.T. holds the Saputo Research Chair. C.C. was a recipient of a CIHR New Investigator Award and held a Socie´te´ www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800322 The Journal of Immunology 1785 leukocytes from the blood into the region of cardiac injury (8). mouse experiments were performed according to guidelines of the Cana- Various animal and human studies have provided evidence that the dian Council on Animal Care. expansion and/or recruitment of inflammatory leukocytes such as Heart single-cell isolation
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