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Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.

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.

SUBMITTER: Wigerblad G

PROVIDER: S-EPMC9812373 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.

Wigerblad Gustaf G Warner Seth A SA Ramos-Benitez Marcos J MJ Kardava Lela L Tian Xin X Miao Rui R Reger Robert R Chakraborty Mala M Wong Susan S Kanthi Yogendra Y Suffredini Anthony F AF Dell'Orso Stefania S Brooks Stephen S King Christopher C Shlobin Oksana O Nathan Steven D SD Cohen Jonathan J Moir Susan S Childs Richard W RW Kaplan Mariana J MJ Chertow Daniel S DS Strich Jeffrey R JR

Science advances 20230104 1

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 demonstrate ...[more]

PMID: 36598976

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Project description:BackgroundRegulation or restoration of therapeutic sensitivity to glucocorticoids is important in patients with steroid-resistant asthma. Spleen tyrosine kinase (Syk) is activated at high levels in asthma patients and mouse models, and small-molecule Syk inhibitors such as R406 show potent anti-inflammatory effects in the treatment of immune inflammatory diseases. Several downstream signaling molecules of Syk are involved in the glucocorticoid response, so we hypothesized that R406 could restore sensitivity to dexamethasone in severe steroid-resistant asthma. Objective: To discover the role of the Syk inhibitor R406 in glucocorticoid resistance in severe asthma. Methods: Steroid-resistant asthma models were induced by exposure of C57BL/6 mice to house dust mite (HDM) and β-glucan and by TNF-α administration to the bronchial epithelial cell line BEAS-2B. We evaluated the role of the Syk inhibitor R406 in dexamethasone (Dex)-insensitive airway inflammation. Pathological alterations and cytokines in the lung tissues and inflammatory cells in BALF were assessed. We examined the effects of Dex or R406 alone and in combination on the phosphorylation of MAPKs, glucocorticoid receptor (GR) and Syk, as well as the transactivation and transrepression induced by Dex in mouse lung tissues and BEAS-2B cells. Results: Exposure to HDM and β-glucan induced steroid-resistant airway inflammation. The Syk inhibitor R406 plus Dex significantly reduced airway inflammation compared with Dex alone. Additionally, TNF-α-induced IL-8 production in BEAS-2B cells was not completely inhibited by Dex, while R406 markedly promoted the anti-inflammatory effect of Dex. Compared with Dex alone, R406 enhanced Dex-mediated inhibition of the phosphorylation of MAPKs and GR-Ser226 induced by allergens or TNF-α in vivo and in vitro. Moreover, R406 also restored the impaired expression and nuclear translocation of GRα induced by TNF-α. Then, the activation of NF-κB and decreased HDAC2 activity in the asthmatic model were further regulated by R406, as well as the expression of GILZ. Conclusions: The Syk inhibitor R406 improves sensitivity to dexamethasone by modulating GR. This study provides a reference for the development of drugs to treat severe steroid-resistant asthma.

Dataset Information

Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.

Publications

Spleen tyrosine kinase inhibition restores myeloid homeostasis in COVID-19.

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