iScience (Oct 2023)
A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling
- 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,
- Wandi S. Zhu
Affiliations
- Jason A. Hackney
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Haridha Shivram
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Jason Vander Heiden
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Chris Overall
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Luz Orozco
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Xia Gao
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Eugene Kim
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Nathan West
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Aditi Qamra
- Hoffman-La Roche Limited, 7070 Mississauga Road, Mississauga, ON L5N 5M8, Canada
- Diana Chang
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Arindam Chakrabarti
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- David F. Choy
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Alexis J. Combes
- University of California San Francisco, San Francisco, CA, USA
- Tristan Courau
- University of California San Francisco, San Francisco, CA, USA
- Gabriela K. Fragiadakis
- University of California San Francisco, San Francisco, CA, USA
- Arjun Arkal Rao
- University of California San Francisco, San Francisco, CA, USA
- Arja Ray
- University of California San Francisco, San Francisco, CA, USA
- Jessica Tsui
- University of California San Francisco, San Francisco, CA, USA
- Kenneth Hu
- University of California San Francisco, San Francisco, CA, USA
- Nicholas F. Kuhn
- University of California San Francisco, San Francisco, CA, USA
- Matthew F. Krummel
- University of California San Francisco, San Francisco, CA, USA
- David J. Erle
- University of California San Francisco, San Francisco, CA, USA
- Kirsten Kangelaris
- University of California San Francisco, San Francisco, CA, USA
- Aartik Sarma
- University of California San Francisco, San Francisco, CA, USA
- Zoe Lyon
- University of California San Francisco, San Francisco, CA, USA
- Carolyn S. Calfee
- University of California San Francisco, San Francisco, CA, USA
- Prescott G. Woodruff
- University of California San Francisco, San Francisco, CA, USA
- Rajani Ghale
- University of California San Francisco, San Francisco, CA, USA
- Eran Mick
- University of California San Francisco, San Francisco, CA, USA
- Ashley Byrne
- University of California San Francisco, San Francisco, CA, USA
- Beth Shoshana Zha
- University of California San Francisco, San Francisco, CA, USA
- Charles Langelier
- University of California San Francisco, San Francisco, CA, USA
- Carolyn M. Hendrickson
- University of California San Francisco, San Francisco, CA, USA
- Monique G.P. van der Wijst
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
- George C. Hartoularos
- University of California San Francisco, San Francisco, CA, USA
- Tianna Grant
- University of California San Francisco, San Francisco, CA, USA
- Raymund Bueno
- University of California San Francisco, San Francisco, CA, USA
- David S. Lee
- University of California San Francisco, San Francisco, CA, USA
- John R. Greenland
- University of California San Francisco, San Francisco, CA, USA
- Yang Sun
- University of California San Francisco, San Francisco, CA, USA
- Richard Perez
- University of California San Francisco, San Francisco, CA, USA
- Anton Ogorodnikov
- University of California San Francisco, San Francisco, CA, USA
- Alyssa Ward
- University of California San Francisco, San Francisco, CA, USA
- Chun Jimmie Ye
- University of California San Francisco, San Francisco, CA, USA
- Thiru Ramalingam
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Jacqueline M. McBride
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Fang Cai
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Anastasia Teterina
- Hoffman-La Roche Limited, 7070 Mississauga Road, Mississauga, ON L5N 5M8, Canada
- Min Bao
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Larry Tsai
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Ivan O. Rosas
- Baylor College of Medicine, 7200 Cambridge St, Houston, TX 77030, USA
- Aviv Regev
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Sharookh B. Kapadia
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Rebecca N. Bauer
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Carrie M. Rosenberger
- Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA; Corresponding author
- 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
- Wandi S. Zhu
- Journal volume & issue
-
Vol. 26,
no. 10
p. 107813
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.
