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Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19

Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improve...

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Autores principales: Wigerblad, Gustaf, Warner, Seth A., Ramos-Benitez, Marcos J., Kardava, Lela, Tian, Xin, Miao, Rui, Reger, Robert, Chakraborty, Mala, Wong, Susan, Kanthi, Yogendra, Suffredini, Anthony F., Dell’Orso, Stefania, Brooks, Stephen, King, Christopher, Shlobin, Oksana, Nathan, Steven D., Cohen, Jonathan, Moir, Susan, Childs, Richard W., Kaplan, Mariana J., Chertow, Daniel S., Strich, Jeffrey R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812373/
https://www.ncbi.nlm.nih.gov/pubmed/36598976
http://dx.doi.org/10.1126/sciadv.ade8272
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author Wigerblad, Gustaf
Warner, Seth A.
Ramos-Benitez, Marcos J.
Kardava, Lela
Tian, Xin
Miao, Rui
Reger, Robert
Chakraborty, Mala
Wong, Susan
Kanthi, Yogendra
Suffredini, Anthony F.
Dell’Orso, Stefania
Brooks, Stephen
King, Christopher
Shlobin, Oksana
Nathan, Steven D.
Cohen, Jonathan
Moir, Susan
Childs, Richard W.
Kaplan, Mariana J.
Chertow, Daniel S.
Strich, Jeffrey R.
author_facet Wigerblad, Gustaf
Warner, Seth A.
Ramos-Benitez, Marcos J.
Kardava, Lela
Tian, Xin
Miao, Rui
Reger, Robert
Chakraborty, Mala
Wong, Susan
Kanthi, Yogendra
Suffredini, Anthony F.
Dell’Orso, Stefania
Brooks, Stephen
King, Christopher
Shlobin, Oksana
Nathan, Steven D.
Cohen, Jonathan
Moir, Susan
Childs, Richard W.
Kaplan, Mariana J.
Chertow, Daniel S.
Strich, Jeffrey R.
author_sort Wigerblad, Gustaf
collection PubMed
description Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10(+)CD33(−)), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR(−)CD33(+)CD11b(−)). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DR(hi) classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.
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spelling pubmed-98123732023-01-10 Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19 Wigerblad, Gustaf Warner, Seth A. Ramos-Benitez, Marcos J. Kardava, Lela Tian, Xin Miao, Rui Reger, Robert Chakraborty, Mala Wong, Susan Kanthi, Yogendra Suffredini, Anthony F. Dell’Orso, Stefania Brooks, Stephen King, Christopher Shlobin, Oksana Nathan, Steven D. Cohen, Jonathan Moir, Susan Childs, Richard W. Kaplan, Mariana J. Chertow, Daniel S. Strich, Jeffrey R. Sci Adv Biomedicine and Life Sciences Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10(+)CD33(−)), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR(−)CD33(+)CD11b(−)). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DR(hi) classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19. American Association for the Advancement of Science 2023-01-04 /pmc/articles/PMC9812373/ /pubmed/36598976 http://dx.doi.org/10.1126/sciadv.ade8272 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Wigerblad, Gustaf
Warner, Seth A.
Ramos-Benitez, Marcos J.
Kardava, Lela
Tian, Xin
Miao, Rui
Reger, Robert
Chakraborty, Mala
Wong, Susan
Kanthi, Yogendra
Suffredini, Anthony F.
Dell’Orso, Stefania
Brooks, Stephen
King, Christopher
Shlobin, Oksana
Nathan, Steven D.
Cohen, Jonathan
Moir, Susan
Childs, Richard W.
Kaplan, Mariana J.
Chertow, Daniel S.
Strich, Jeffrey R.
Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title_full Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title_fullStr Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title_full_unstemmed Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title_short Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
title_sort spleen tyrosine kinase inhibition restores myeloid homeostasis in covid-19
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9812373/
https://www.ncbi.nlm.nih.gov/pubmed/36598976
http://dx.doi.org/10.1126/sciadv.ade8272
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