tetano
Editor, Senior Moderator
Sci Adv
. 2023 Jan 4;9(1):eade8272.
doi: 10.1126/sciadv.ade8272. Epub 2023 Jan 4.
Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
Gustaf Wigerblad[SUP] 1 [/SUP], Seth A Warner[SUP] 2 [/SUP], Marcos J Ramos-Benitez[SUP] 2 3 4 [/SUP], Lela Kardava[SUP] 5 [/SUP], Xin Tian[SUP] 6 [/SUP], Rui Miao[SUP] 6 [/SUP], Robert Reger[SUP] 7 [/SUP], Mala Chakraborty[SUP] 7 [/SUP], Susan Wong[SUP] 7 [/SUP], Yogendra Kanthi[SUP] 8 [/SUP], Anthony F Suffredini[SUP] 2 [/SUP], Stefania Dell'Orso[SUP] 9 [/SUP], Stephen Brooks[SUP] 10 [/SUP], Christopher King[SUP] 11 [/SUP], Oksana Shlobin[SUP] 11 [/SUP], Steven D Nathan[SUP] 11 [/SUP], Jonathan Cohen[SUP] 12 [/SUP], Susan Moir[SUP] 5 [/SUP], Richard W Childs[SUP] 7 13 [/SUP], Mariana J Kaplan[SUP] 1 [/SUP], Daniel S Chertow[SUP] 2 5 13 [/SUP], Jeffrey R Strich[SUP] 2 13 [/SUP]
Affiliations
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[SUP]+[/SUP]CD33[SUP]-[/SUP]), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR[SUP]-[/SUP]CD33[SUP]+[/SUP]CD11b[SUP]-[/SUP]). 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[SUP]hi[/SUP] 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.
. 2023 Jan 4;9(1):eade8272.
doi: 10.1126/sciadv.ade8272. Epub 2023 Jan 4.
Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19
Gustaf Wigerblad[SUP] 1 [/SUP], Seth A Warner[SUP] 2 [/SUP], Marcos J Ramos-Benitez[SUP] 2 3 4 [/SUP], Lela Kardava[SUP] 5 [/SUP], Xin Tian[SUP] 6 [/SUP], Rui Miao[SUP] 6 [/SUP], Robert Reger[SUP] 7 [/SUP], Mala Chakraborty[SUP] 7 [/SUP], Susan Wong[SUP] 7 [/SUP], Yogendra Kanthi[SUP] 8 [/SUP], Anthony F Suffredini[SUP] 2 [/SUP], Stefania Dell'Orso[SUP] 9 [/SUP], Stephen Brooks[SUP] 10 [/SUP], Christopher King[SUP] 11 [/SUP], Oksana Shlobin[SUP] 11 [/SUP], Steven D Nathan[SUP] 11 [/SUP], Jonathan Cohen[SUP] 12 [/SUP], Susan Moir[SUP] 5 [/SUP], Richard W Childs[SUP] 7 13 [/SUP], Mariana J Kaplan[SUP] 1 [/SUP], Daniel S Chertow[SUP] 2 5 13 [/SUP], Jeffrey R Strich[SUP] 2 13 [/SUP]
Affiliations
- PMID: 36598976
- DOI: 10.1126/sciadv.ade8272
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[SUP]+[/SUP]CD33[SUP]-[/SUP]), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR[SUP]-[/SUP]CD33[SUP]+[/SUP]CD11b[SUP]-[/SUP]). 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[SUP]hi[/SUP] 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.