An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts
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- Liuliu Yang
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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- Yuling Han
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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- Fabrice Jaffré
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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- Benjamin E. Nilsson-Payant
- Department of Microbiology (B.E.N.-P., S.U., J.K.L., B.R.t.), Icahn School of Medicine at Mount Sinai, New York, NY.
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- Yaron Bram
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.B., C.R., V.C., R.E.S.), Weill Cornell Medicine, New York, NY.
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- Pengfei Wang
- Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY (P.W., Y. Huang, D.D.H.).
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- Jiajun Zhu
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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- Tuo Zhang
- Genomics Resources Core Facility (T.Z., J.X.), Weill Cornell Medicine, New York, NY.
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- David Redmond
- Division of Regenerative Medicine, Ansary Stem Cell Institute (D.R., S.H.), Weill Cornell Medicine, New York, NY.
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- Sean Houghton
- Division of Regenerative Medicine, Ansary Stem Cell Institute (D.R., S.H.), Weill Cornell Medicine, New York, NY.
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- Skyler Uhl
- Department of Microbiology (B.E.N.-P., S.U., J.K.L., B.R.t.), Icahn School of Medicine at Mount Sinai, New York, NY.
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- Alain Borczuk
- Department of Pathology and Laboratory Medicine (A.B.), Weill Cornell Medicine, New York, NY.
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- Yaoxing Huang
- Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY (P.W., Y. Huang, D.D.H.).
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- Chanel Richardson
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.B., C.R., V.C., R.E.S.), Weill Cornell Medicine, New York, NY.
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- Vasuretha Chandar
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.B., C.R., V.C., R.E.S.), Weill Cornell Medicine, New York, NY.
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- Joshua A. Acklin
- Graduate School of Biomedical Sciences (J.A.A.), Icahn School of Medicine at Mount Sinai, New York, NY.
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- Jean K. Lim
- Department of Microbiology (B.E.N.-P., S.U., J.K.L., B.R.t.), Icahn School of Medicine at Mount Sinai, New York, NY.
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- Zhengming Chen
- Department of Population Health Sciences (Z.C.), Weill Cornell Medicine, New York, NY.
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- Jenny Xiang
- Genomics Resources Core Facility (T.Z., J.X.), Weill Cornell Medicine, New York, NY.
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- David D. Ho
- Aaron Diamond AIDS Research Center, Columbia University Irving Medical Center, New York, NY (P.W., Y. Huang, D.D.H.).
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- Benjamin R. tenOever
- Department of Microbiology (B.E.N.-P., S.U., J.K.L., B.R.t.), Icahn School of Medicine at Mount Sinai, New York, NY.
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- Robert E. Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine (Y.B., C.R., V.C., R.E.S.), Weill Cornell Medicine, New York, NY.
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- Todd Evans
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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- Shuibing Chen
- Department of Surgery (L.Y., Y. Han, F.J., J.Z., T.E., S.C.), Weill Cornell Medicine, New York, NY.
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説明
<jats:sec> <jats:title>Rationale:</jats:title> <jats:p>While respiratory failure is a frequent and clinically significant outcome of coronavirus disease 2019 (COVID-19), cardiac complications are a common feature in hospitalized COVID-19 patients and are associated with worse patient outcomes. The cause of cardiac injury in COVID-19 patients is not yet known. Case reports of COVID-19 autopsy heart samples have demonstrated abnormal inflammatory infiltration of macrophages in heart tissues.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>Generate an immunocardiac coculture platform to model macrophage-mediated hyperinflammation in COVID-19 hearts and screen for drugs that can block the macrophage-mediated inflammation.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results:</jats:title> <jats:p>We systematically compared autopsy samples from non–COVID-19 donors and COVID-19 patients using RNA sequencing and immunohistochemistry. We observed strikingly increased expression levels of CCL2 (C-C motif chemokine ligand 2) and macrophage infiltration in heart tissues of COVID-19 patients. We generated an immunocardiac coculture platform containing human pluripotent stem cell–derived cardiomyocytes and macrophages. We found that macrophages induce increased reactive oxygen species and apoptosis in cardiomyocytes by secreting IL (interleukin)-6 and TNF-α (tumor necrosis factor alpha) after Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. Using this immunocardiac coculture platform, we performed a high content screen and identified ranolazine and tofacitinib as compounds that protect cardiomyocytes from macrophage-induced cardiotoxicity.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>We established an immuno-host coculture system to study macrophage-induced host cell damage following SARS-CoV-2 infection and identified Food and Drug Administration–approved drug candidates that alleviate the macrophage-mediated hyperinflammation and cellular injury.</jats:p> </jats:sec>
収録刊行物
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- Circulation Research
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Circulation Research 129 (1), 33-46, 2021-06-25
Ovid Technologies (Wolters Kluwer Health)