Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19

Gustaf Wigerblad; Seth A Warner; Marcos J Ramos-Benitez; Lela Kardava; Xin Tian; Rui Miao; Robert Reger; Mala Chakraborty; Susan Wong; Yogendra Kanthi; Anthony F Suffredini; Stefania Dell'Orso; Stephen Brooks; Christopher King; Oksana Shlobin; Steven D Nathan; Jonathan Cohen; Susan Moir; Richard W Childs; Mariana J Kaplan; Daniel S Chertow; Jeffrey R Strich

doi:10.1126/sciadv.ade8272

Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19

Sci Adv. 2023 Jan 4;9(1):eade8272. doi: 10.1126/sciadv.ade8272. Epub 2023 Jan 4.

Authors

Gustaf Wigerblad¹, Seth A Warner², Marcos J Ramos-Benitez^{2

3

4}, Lela Kardava⁵, Xin Tian⁶, Rui Miao⁶, Robert Reger⁷, Mala Chakraborty⁷, Susan Wong⁷, Yogendra Kanthi⁸, Anthony F Suffredini², Stefania Dell'Orso⁹, Stephen Brooks¹⁰, Christopher King¹¹, Oksana Shlobin¹¹, Steven D Nathan¹¹, Jonathan Cohen¹², Susan Moir⁵, Richard W Childs^{7

13}, Mariana J Kaplan¹, Daniel S Chertow^{2

5

13}, Jeffrey R Strich^{2

13}

Affiliations

¹ Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD, USA.
² Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
³ Postdoctoral Research Associate Training Program, National Institute of General Medical Sciences, Bethesda, MD, USA.
⁴ Ponce Health Science University and Ponce Research Institute, Department of Basic Sciences, School of Medicine, Ponce, Puerto Rico, USA.
⁵ Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD, USA.
⁶ Office of Biostatistics Research, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
⁷ Laboratory of Transplantation Immunotherapy, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
⁸ Laboratory of Vascular Thrombosis and Inflammation, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
⁹ Genomic Technology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
¹⁰ Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
¹¹ Advanced Lung Disease and Lung Transplant Program, Inova Fairfax Hospital, Falls Church, VA, USA.
¹² Adventist Healthcare Shady Grove Medical Center, Rockville, MD, USA.
¹³ United States Public Health Service Commissioned Corps, Rockville, MD, USA.

Abstract

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.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase II

MeSH terms

COVID-19*
HLA-DR Antigens
Homeostasis
Humans
Oxazines / pharmacology
Oxazines / therapeutic use
Syk Kinase

Substances

Syk Kinase
Oxazines
HLA-DR Antigens