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A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling.
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 G P; Hartoularos, George C; Grant, Tianna; Bueno, Raymund; Lee, David S; Greenland, John R; Sun, Yang; Perez, Richard; Ogorodnikov, Anton; Ward, Alyssa; Ye, Chun Jimmie; Ramalingam, Thiru; McBride, Jacqueline M; Cai, Fang; Teterina, Anastasia; Bao, Min; Tsai, Larry.
  • Hackney JA; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Shivram H; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Vander Heiden J; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Overall C; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Orozco L; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Gao X; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Kim E; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • West N; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Qamra A; Hoffman-La Roche Limited, 7070 Mississauga Road, Mississauga, ON L5N 5M8, Canada.
  • Chang D; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Chakrabarti A; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Choy DF; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Combes AJ; University of California San Francisco, San Francisco, CA, USA.
  • Courau T; University of California San Francisco, San Francisco, CA, USA.
  • Fragiadakis GK; University of California San Francisco, San Francisco, CA, USA.
  • Rao AA; University of California San Francisco, San Francisco, CA, USA.
  • Ray A; University of California San Francisco, San Francisco, CA, USA.
  • Tsui J; University of California San Francisco, San Francisco, CA, USA.
  • Hu K; University of California San Francisco, San Francisco, CA, USA.
  • Kuhn NF; University of California San Francisco, San Francisco, CA, USA.
  • Krummel MF; University of California San Francisco, San Francisco, CA, USA.
  • Erle DJ; University of California San Francisco, San Francisco, CA, USA.
  • Kangelaris K; University of California San Francisco, San Francisco, CA, USA.
  • Sarma A; University of California San Francisco, San Francisco, CA, USA.
  • Lyon Z; University of California San Francisco, San Francisco, CA, USA.
  • Calfee CS; University of California San Francisco, San Francisco, CA, USA.
  • Woodruff PG; University of California San Francisco, San Francisco, CA, USA.
  • Ghale R; University of California San Francisco, San Francisco, CA, USA.
  • Mick E; University of California San Francisco, San Francisco, CA, USA.
  • Byrne A; University of California San Francisco, San Francisco, CA, USA.
  • Zha BS; University of California San Francisco, San Francisco, CA, USA.
  • Langelier C; University of California San Francisco, San Francisco, CA, USA.
  • Hendrickson CM; University of California San Francisco, San Francisco, CA, USA.
  • van der Wijst MGP; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
  • Hartoularos GC; University of California San Francisco, San Francisco, CA, USA.
  • Grant T; University of California San Francisco, San Francisco, CA, USA.
  • Bueno R; University of California San Francisco, San Francisco, CA, USA.
  • Lee DS; University of California San Francisco, San Francisco, CA, USA.
  • Greenland JR; University of California San Francisco, San Francisco, CA, USA.
  • Sun Y; University of California San Francisco, San Francisco, CA, USA.
  • Perez R; University of California San Francisco, San Francisco, CA, USA.
  • Ogorodnikov A; University of California San Francisco, San Francisco, CA, USA.
  • Ward A; University of California San Francisco, San Francisco, CA, USA.
  • Ye CJ; University of California San Francisco, San Francisco, CA, USA.
  • Ramalingam T; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • McBride JM; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Cai F; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Teterina A; Hoffman-La Roche Limited, 7070 Mississauga Road, Mississauga, ON L5N 5M8, Canada.
  • Bao M; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
  • Tsai L; Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
iScience ; 26(10): 107813, 2023 Oct 20.
Article en En | MEDLINE | ID: mdl-37810211
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.
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Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Idioma: En Año: 2023 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Idioma: En Año: 2023 Tipo del documento: Article