An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts
Liuliu Yang, Yuling Han, Fabrice Jaffré, Benjamin E. Nilsson-Payant, Yaron Bram, Pengfei Wang, Jiajun Zhu, Tuo Zhang, David Redmond, Sean Houghton, Skyler Uhl, Alain Borczuk, Yaoxing Huang, Chanel Richardson, Vasuretha Chandar, Joshua A. Acklin, Jean K. Lim, Zhengming Chen, Jenny Xiang, David D. Ho, Benjamin R. tenOever, Robert E. Schwartz, Todd Evans, Shuibing Chen
Abstract
Rationale: 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. Objective: 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. Methods and Results: 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. Conclusions: 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.