A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

UCSF COMET consortium; 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; Rebecca N. Bauer; Carrie M Rosenberger

doi:10.1016/j.isci.2023.107813

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

UCSF COMET consortium, 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 HuNicholas 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, Rebecca N. Bauer, Carrie M Rosenberger^*

^*Corresponding author voor dit werk

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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-RAGE hi 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.

Originele taal-2	English
Artikelnummer	107813
Aantal pagina's	24
Tijdschrift	Iscience
Volume	26
Nummer van het tijdschrift	10
DOI's	https://doi.org/10.1016/j.isci.2023.107813
Status	Published - 20-okt.-2023

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10.1016/j.isci.2023.107813Licentie: CC BY-NC-ND

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signalingFinal publisher's version, 3,99 MBLicentie: CC BY-NC-ND

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UCSF COMET consortium, Hackney, J. A., Shivram, H., Vander Heiden, J., Overall, C., Orozco, L., Gao, X., Kim, E., West, N., Qamra, A., Chang, D., Chakrabarti, A., Choy, D. F., Combes, A. J., Courau, T., Fragiadakis, G. K., Rao, A. A., Ray, A., Tsui, J., ... Rosenberger, C. M. (2023). A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling. Iscience, 26(10), Artikel 107813. https://doi.org/10.1016/j.isci.2023.107813

@article{6c22f979af2b42f0941eb8b691fb2f95,

title = "A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling",

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-RAGE hi 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. ",

keywords = "Clinical genetics, Immune response, Molecular medicine",

author = "{UCSF COMET consortium} and Hackney, {Jason A.} and Haridha Shivram and {Vander Heiden}, Jason and Chris Overall and Luz Orozco and Xia Gao and Eugene Kim and Nathan West and Aditi Qamra and Diana Chang and Arindam Chakrabarti and Choy, {David F.} and Combes, {Alexis J.} and Tristan Courau and Fragiadakis, {Gabriela K.} and Rao, {Arjun Arkal} and Arja Ray and Jessica Tsui and Kenneth Hu and Kuhn, {Nicholas F.} and Krummel, {Matthew F.} and Erle, {David J.} and Kirsten Kangelaris and Aartik Sarma and Zoe Lyon and Calfee, {Carolyn S.} and Woodruff, {Prescott G.} and Rajani Ghale and Eran Mick and Ashley Byrne and Zha, {Beth Shoshana} and Charles Langelier and Hendrickson, {Carolyn M.} and {van der Wijst}, {Monique G.P.} and Hartoularos, {George C.} and Tianna Grant and Raymund Bueno and Lee, {David S.} and Greenland, {John R.} and Yang Sun and Richard Perez and Anton Ogorodnikov and Alyssa Ward and Ye, {Chun Jimmie} and Yumiko Abe-Jones and Michael Adkisson and Ansel, {K. Mark} and Saurabh Asthana and Alexander Beagle and Bauer, {Rebecca N.} and Rosenberger, {Carrie M}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

day = "20",

doi = "10.1016/j.isci.2023.107813",

language = "English",

volume = "26",

journal = "Iscience",

issn = "2589-0042",

publisher = "Elsevier",

number = "10",

}

UCSF COMET consortium, Hackney, JA, Shivram, H, Vander Heiden, J, Overall, C, Orozco, L, Gao, X, Kim, E, West, N, Qamra, A, Chang, D, Chakrabarti, A, Choy, DF, Combes, AJ, Courau, T, Fragiadakis, GK, Rao, AA, Ray, A, Tsui, J, Hu, K, Kuhn, NF, Krummel, MF, Erle, DJ, Kangelaris, K, Sarma, A, Lyon, Z, Calfee, CS, Woodruff, PG, Ghale, R, Mick, E, Byrne, A, Zha, BS, Langelier, C, Hendrickson, CM, van der Wijst, MGP, Hartoularos, GC, Grant, T, Bueno, R, Lee, DS, Greenland, JR, Sun, Y, Perez, R, Ogorodnikov, A, Ward, A, Ye, CJ, Bauer, RN & Rosenberger, CM 2023, 'A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling', Iscience, vol. 26, nr. 10, 107813. https://doi.org/10.1016/j.isci.2023.107813

TY - JOUR

T1 - A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

AU - UCSF COMET consortium

AU - Hackney, Jason A.

AU - Shivram, Haridha

AU - Vander Heiden, Jason

AU - Overall, Chris

AU - Orozco, Luz

AU - Gao, Xia

AU - Kim, Eugene

AU - West, Nathan

AU - Qamra, Aditi

AU - Chang, Diana

AU - Chakrabarti, Arindam

AU - Choy, David F.

AU - Combes, Alexis J.

AU - Courau, Tristan

AU - Fragiadakis, Gabriela K.

AU - Rao, Arjun Arkal

AU - Ray, Arja

AU - Tsui, Jessica

AU - Hu, Kenneth

AU - Kuhn, Nicholas F.

AU - Krummel, Matthew F.

AU - Erle, David J.

AU - Kangelaris, Kirsten

AU - Sarma, Aartik

AU - Lyon, Zoe

AU - Calfee, Carolyn S.

AU - Woodruff, Prescott G.

AU - Ghale, Rajani

AU - Mick, Eran

AU - Byrne, Ashley

AU - Zha, Beth Shoshana

AU - Langelier, Charles

AU - Hendrickson, Carolyn M.

AU - van der Wijst, Monique G.P.

AU - Hartoularos, George C.

AU - Grant, Tianna

AU - Bueno, Raymund

AU - Lee, David S.

AU - Greenland, John R.

AU - Sun, Yang

AU - Perez, Richard

AU - Ogorodnikov, Anton

AU - Ward, Alyssa

AU - Ye, Chun Jimmie

AU - Abe-Jones, Yumiko

AU - Adkisson, Michael

AU - Ansel, K. Mark

AU - Asthana, Saurabh

AU - Beagle, Alexander

AU - Bauer, Rebecca N.

AU - Rosenberger, Carrie M

PY - 2023/10/20

Y1 - 2023/10/20

N2 - 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-RAGE hi 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.

AB - 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-RAGE hi 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.

KW - Clinical genetics

KW - Immune response

KW - Molecular medicine

UR - http://www.scopus.com/inward/record.url?scp=85172929744&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2023.107813

DO - 10.1016/j.isci.2023.107813

M3 - Article

C2 - 37810211

AN - SCOPUS:85172929744

SN - 2589-0042

VL - 26

JO - Iscience

JF - Iscience

IS - 10

M1 - 107813

ER -

A myeloid program associated with COVID-19 severity is decreased by therapeutic blockade of IL-6 signaling

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