@article{3b1e229e23194d1eb0a7416f5fbf1fd2,
title = "The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis",
abstract = "Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae. Hou et al. show that cardiac fibroblasts facilitate infiltrating Ly6Chi and Ly6Clo monocytes to become macrophages. IL-17A trans-signaling through cardiac fibroblasts increases MerTK shedding and promotes a pro-inflammatory and pro-tissue remodeling gene expression profile in Ly6Chi monocyte-derived macrophages. Paradoxically, IL-17A signaling through cardiac fibroblasts can substantially inhibit Ly6Clo monocyte-to-macrophage differentiation.",
keywords = "heart, Ly6C, macrophages, MerTK, monocytes, myocarditis",
author = "Xuezhou Hou and Guobao Chen and William Bracamonte-Baran and Choi, {Hee Sun} and Diny, {Nicola L.} and Jungeun Sung and David Hughes and Taejoon Won and Wood, {Megan Kay} and Talor, {Monica V.} and Hackam, {David Joel} and Karin Klingel and Giovanni Davogustto and Heinrich Taegtmeyer and Isabelle Coppens and Barin, {Jobert G.} and Daniela {\v C}ih{\'a}kov{\'a}",
note = "Funding Information: This work was supported by NIH / NHLBI grants R01HL118183 and R01HL136586 , an American Heart Association (AHA) AWRP Winter 2017 Grant-in-Aid ( 17GRNT33700274 ), AHA 2019 Transformational Project Award 19TPA34910007 , and the Matthew Poyner MVP Memorial Myocarditis Research Fund to D.{\v C}.; the Johns Hopkins Autoimmune Disease Research Center O{\textquoteright}Leary-Wilson Fellowship, the Johns Hopkins Bloomberg School of Public Health Richard J. and Margaret Conn Himelfarb Student Support fund , and a Katherine E. Welsh Fellowship to X.H.; a Myocarditis Foundation Postdoctoral Fellowship ( 90072351 ) to G.C.; an AHA Postdoctoral Fellowship ( 16POST31330012 ) to W.B.-B.; a predoctoral fellowship to H.S.C. ( 16PRE31170040 ) and N.L.D. ( 15PRE25400010 ); as well as AARDA awards to W.B.-B., a Gilead Research Scholar grant and AARDA award to J.G.B., and Deutsche Forschungsgemeinschaft grant KL595/2-3 to K.K. Funding Information: The authors would like to extend their gratitude to Dr. Noel Rose for his kind sponsorship and mentorship, Amgen Inc. (Thousand Oaks, CA) and Dr. J. Kolls (Children's Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA) for IL-17Ra?/? mice, Xiaoling Zhang and Jessica Gucwa at the Johns Hopkins Flow Cytometry Cores, Leonard Marque and Firozeh Dastani at the Johns Hopkins animal resources, Julie Schaub for mouse colony management, Karen Fox-Talbot for human sample immunohistochemistry work, Barbara Smith at the Johns Hopkins SOM microscopy facility, and Haiping Hao and C. Conover Talbot Jr. at the Johns Hopkins Deep Sequencing and Microarray Core Facility. This work was supported by NIH/NHLBI grants R01HL118183 and R01HL136586, an American Heart Association (AHA) AWRP Winter 2017 Grant-in-Aid (17GRNT33700274), AHA 2019 Transformational Project Award 19TPA34910007, and the Matthew Poyner MVP Memorial Myocarditis Research Fund to D.C?.; the Johns Hopkins Autoimmune Disease Research Center O'Leary-Wilson Fellowship, the Johns Hopkins Bloomberg School of Public Health Richard J. and Margaret Conn Himelfarb Student Support fund, and a Katherine E. Welsh Fellowship to X.H.; a Myocarditis Foundation Postdoctoral Fellowship (90072351) to G.C.; an AHA Postdoctoral Fellowship (16POST31330012) to W.B.-B.; a predoctoral fellowship to H.S.C. (16PRE31170040) and N.L.D. (15PRE25400010); as well as AARDA awards to W.B.-B. a Gilead Research Scholar grant and AARDA award to J.G.B. and Deutsche Forschungsgemeinschaft grant KL595/2-3 to K.K. Conceptualization and Methodology, X.H. J.G.B. and D.C.; Software, Validation, Formal Analysis, Data Curation and Visualization, X.H.; Investigation, X.H. G.C. W.B.-B. H.S.C. N.L.D. J.S. T.W. D.H. M.V.T. I.C. and D.C.; Resources, D.J.H. K.K. G.D. and H.T.; Writing ? Original Draft and Writing ? Review & Editing, X.H. M.K.W. and D.C.; Supervision, Project Administration, and Funding Acquisition, D.C. The authors declare no competing interests. Funding Information: The authors would like to extend their gratitude to Dr. Noel Rose for his kind sponsorship and mentorship, Amgen Inc. (Thousand Oaks, CA) and Dr. J. Kolls (Children's Hospital, University of Pittsburgh Medical Center, Pittsburgh, PA) for IL-17Ra−/− mice, Xiaoling Zhang and Jessica Gucwa at the Johns Hopkins Flow Cytometry Cores, Leonard Marque and Firozeh Dastani at the Johns Hopkins animal resources, Julie Schaub for mouse colony management, Karen Fox-Talbot for human sample immunohistochemistry work, Barbara Smith at the Johns Hopkins SOM microscopy facility, and Haiping Hao and C. Conover Talbot Jr. at the Johns Hopkins Deep Sequencing and Microarray Core Facility. This work was supported by NIH/NHLBI grants R01HL118183 and R01HL136586, an American Heart Association (AHA) AWRP Winter 2017 Grant-in-Aid (17GRNT33700274), AHA 2019 Transformational Project Award 19TPA34910007, and the Matthew Poyner MVP Memorial Myocarditis Research Fund to D.{\v C}.; the Johns Hopkins Autoimmune Disease Research Center O'Leary-Wilson Fellowship, the Johns Hopkins Bloomberg School of Public Health Richard J. and Margaret Conn Himelfarb Student Support fund, and a Katherine E. Welsh Fellowship to X.H.; a Myocarditis Foundation Postdoctoral Fellowship (90072351) to G.C.; an AHA Postdoctoral Fellowship (16POST31330012) to W.B.-B.; a predoctoral fellowship to H.S.C. (16PRE31170040) and N.L.D. (15PRE25400010); as well as AARDA awards to W.B.-B. a Gilead Research Scholar grant and AARDA award to J.G.B. and Deutsche Forschungsgemeinschaft grant KL595/2-3 to K.K. Conceptualization and Methodology, X.H. J.G.B. and D.C.; Software, Validation, Formal Analysis, Data Curation and Visualization, X.H.; Investigation, X.H. G.C. W.B.-B. H.S.C. N.L.D. J.S. T.W. D.H. M.V.T. I.C. and D.C.; Resources, D.J.H. K.K. G.D. and H.T.; Writing – Original Draft and Writing – Review & Editing, X.H. M.K.W. and D.C.; Supervision, Project Administration, and Funding Acquisition, D.C. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jul,
day = "2",
doi = "10.1016/j.celrep.2019.06.007",
language = "English (US)",
volume = "28",
pages = "172--189.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}