1. A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling
- Author
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Hackney, Jason A, Shivram, Haridha, Vander Heiden, Jason, Overall, Chris, Orozco, Luz, Gao, Xia, Kim, Eugene, West, Nathan, Qamra, Aditi, Chang, Diana, Chakrabarti, Arindam, Choy, David F, Combes, Alexis J, Courau, Tristan, Fragiadakis, Gabriela K, Rao, Arjun Arkal, Ray, Arja, Tsui, Jessica, Hu, Kenneth, Kuhn, Nicholas F, Krummel, Matthew F, Erle, David J, Kangelaris, Kirsten, Sarma, Aartik, Lyon, Zoe, Calfee, Carolyn S, Woodruff, Prescott G, Ghale, Rajani, Mick, Eran, Byrne, Ashley, Zha, Beth Shoshana, Langelier, Charles, Hendrickson, Carolyn M, van der Wijst, Monique GP, Hartoularos, George C, Grant, Tianna, Bueno, Raymund, Lee, David S, Greenland, John R, Sun, Yang, Perez, Richard, Ogorodnikov, Anton, Ward, Alyssa, Ye, Chun Jimmie, Consortium, UCSF COMET, Abe-Jones, Yumiko, Adkisson, Michael, Ansel, K Mark, Asthana, Saurabh, Beagle, Alexander, Bhide, Sharvari, Cai, Cathy, Caldera, Saharai, Calvo, Maria, Carrillo, Sidney A, Chak, Suzanna, Christenson, Stephanie, Collins, Zachary, Darmanis, Spyros, Detweiler, Angela, DeVoe, Catherine, Eckalbar, Walter, Giberson, Jeremy, Gonzalez, Ana, Gordon, Gracie, Serpa, Paula Hayakawa, Jauregui, Alejandra, Jones, Chayse, Ke, Serena, Kushnoor, Divya, Lea, Tasha, Lee, Deanna, Leligdowicz, Aleksandra, Liu, Yale, Mahboob, Salman, Maliskova, Lenka, Matthay, Michael, McCarthy, Elizabeth, Muñoz-Sandoval, Priscila, Neff, Norma, Nguyen, Viet, Nigam, Nishita, Parada, Randy, Phelps, Maira, Pierce, Logan, Prasad, Priya, Rashid, Sadeed, Reeder, Gabriella, Rodriguez, Nicklaus, Samad, Bushra, Schroeder, Andrew, Shaw, Cole, Shen, Alan, Sigman, Austin, Sinha, Pratik, Spitzer, Matthew, Sunshine, Sara, Tang, Kevin, Altamirano, Luz Torres, and Tsitsiklis, Alexandra
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Emerging Infectious Diseases ,Infectious Diseases ,Clinical Research ,Coronaviruses ,Rare Diseases ,Lung ,Acute Respiratory Distress Syndrome ,2.1 Biological and endogenous factors ,Good Health and Well Being ,UCSF COMET Consortium ,Clinical genetics ,Immune response ,Molecular medicine - Abstract
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