학술논문
A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling
Document Type
article
Author
Hackney, Jason A; Shivram, Haridha; Heiden, Jason Vander; 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; Tsitsiklis, Alexandra
Source
iScience. 26(10)
Subject
Language
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.