Spleen tyrosine kinase inhibition restores neutrophil homeostasis in COVID-19

Abstract

Abstract Spleen tyrosine kinase (SYK) is a novel 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 (LDG) and polymorphonuclear myeloid-derived suppressor cells (HLA-DR–CD33+CD11b−). Additionally, LDG transcriptional profiles were distinct in COVID-19 compared to during autoimmune conditions. Together, these data suggest that SYK inhibition may mitigate proinflammatory neutrophil cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19. This work has been funded in part by the Intramural Research Program of the NIH Clinical Center (NIHCC) including a Research Award for Staff Clinicians (FY2020/FY2021), NHLBI, National Institute of Allergy and Infectious Diseases (NIAID), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAIMS)