1. A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling
- Author
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Jason A. Hackney, Haridha Shivram, Jason Vander Heiden, Chris Overall, Luz Orozco, Xia Gao, Eugene Kim, Nathan West, Aditi Qamra, Diana Chang, Arindam Chakrabarti, David F. Choy, Alexis J. Combes, Tristan Courau, Gabriela K. Fragiadakis, Arjun Arkal Rao, Arja Ray, Jessica Tsui, Kenneth Hu, Nicholas F. Kuhn, Matthew F. Krummel, David J. Erle, Kirsten Kangelaris, Aartik Sarma, Zoe Lyon, Carolyn S. Calfee, Prescott G. Woodruff, Rajani Ghale, Eran Mick, Ashley Byrne, Beth Shoshana Zha, Charles Langelier, Carolyn M. Hendrickson, Monique G.P. van der Wijst, George C. Hartoularos, Tianna Grant, Raymund Bueno, David S. Lee, John R. Greenland, Yang Sun, Richard Perez, Anton Ogorodnikov, Alyssa Ward, Chun Jimmie Ye, Thiru Ramalingam, Jacqueline M. McBride, Fang Cai, Anastasia Teterina, Min Bao, Larry Tsai, Ivan O. Rosas, Aviv Regev, Sharookh B. Kapadia, Rebecca N. Bauer, Carrie M. Rosenberger, Yumiko Abe-Jones, Michael Adkisson, K. Mark Ansel, Saurabh Asthana, Alexander Beagle, Sharvari Bhide, Cathy Cai, Saharai Caldera, Maria Calvo, Sidney A. Carrillo, Suzanna Chak, Stephanie Christenson, Zachary Collins, Spyros Darmanis, Angela Detweiler, Catherine DeVoe, Walter Eckalbar, Jeremy Giberson, Ana Gonzalez, Gracie Gordon, Paula Hayakawa Serpa, Alejandra Jauregui, Chayse Jones, Serena Ke, Divya Kushnoor, Tasha Lea, Deanna Lee, Aleksandra Leligdowicz, Yale Liu, Salman Mahboob, Lenka Maliskova, Michael Matthay, Elizabeth McCarthy, Priscila Muñoz-Sandoval, Norma Neff, Viet Nguyen, Nishita Nigam, Randy Parada, Maira Phelps, Logan Pierce, Priya Prasad, Sadeed Rashid, Gabriella Reeder, Nicklaus Rodriguez, Bushra Samad, Andrew Schroeder, Cole Shaw, Alan Shen, Austin Sigman, Pratik Sinha, Matthew Spitzer, Sara Sunshine, Kevin Tang, Luz Torres Altamirano, Alexandra Tsitsiklis, Erden Tumurbaatar, Vaibhav Upadhyay, Alexander Whatley, Andrew Willmore, Michael Wilson, Juliane Winkler, Kristine Wong, Kimberly Yee, Michelle Yu, Mingyue Zhou, and Wandi S. Zhu
- Subjects
Clinical genetics ,Molecular medicine ,Immune response ,Science - Abstract
Summary: Altered myeloid inflammation and lymphopenia are hallmarks of severe infections. We identified the upregulated EN-RAGE gene program in airway and blood myeloid cells from patients with acute lung injury from SARS-CoV-2 or other causes across 7 cohorts. This program was associated with greater clinical severity and predicted future mechanical ventilation and death. EN-RAGEhi myeloid cells express features consistent with suppressor cell functionality, including low HLA-DR and high PD-L1. Sustained EN-RAGE program expression in airway and blood myeloid cells correlated with clinical severity and increasing expression of T cell dysfunction markers. IL-6 upregulated many EN-RAGE program genes in monocytes in vitro. IL-6 signaling blockade by tocilizumab in a placebo-controlled clinical trial led to rapid normalization of EN-RAGE and T cell gene expression. This identifies IL-6 as a key driver of myeloid dysregulation associated with worse clinical outcomes in COVID-19 patients and provides insights into shared pathophysiological mechanisms in non-COVID-19 ARDS.
- Published
- 2023
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