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.

Kinome and phosphoproteome reprogramming underlies the aberrant immune responses in critically ill COVID-19 patients

“…Some of the kinase targets, including CK2, JAK2/3, SYK, and TYK2, have been identified in previous studies and reaffirmed in the current one. Importantly, the corresponding kinase inhibitors have shown promise in clinical trials [ 75 – 78 ]. Our study also identified numerous new kinases, such as DNA-PK, PKG1, ROCK1/, PKCδ, and GRK2, providing additional actional targets for the development of immunomodulatory therapies for COVID-19.…”

“…Nevertheless, a recent study has shown that SYK plays a critical role in memory effector T cell activation through macrophages in SARS-CoV-2 mRNA vaccination [ 83 ]. The therapeutic potential of targeting SYK was demonstrated in a recent study showing that the SYK inhibitor fostamatinib mitigated myeloid proinflammatory responses believed to contribute to the immunopathogenesis of severe COVID-19 [ 78 ].…”

Maturing neutrophils of lower density associate with thrombocytopenia in Puumala orthohantavirus-caused hemorrhagic fever with renal syndrome

“…Based on previous observations in other disease contexts, LDGs differ from PMNs by being more immature and showing diminished levels of neutrophil maturity markers CD16 and CD11b (11,(22)(23)(24)(25)(26)(27). To identify the distinct features of PUUV LDGs in contrast to PMNs, we conducted a phenotypic analysis of neutrophils in PBMC and PMN cell fractions during early convalescent PUUV-HFRS focusing on relevant activation and maturation cell surface markers CD11b, CD16, CD33, LOX-1, and HLA-DR.…”

The Functional Roles of MDSCs in Severe COVID-19 Pathogenesis

“…Furthermore, the ability of R406 to impede the production of proinflammatory cytokines raises the question of whether R406 may also impact MDSC development, as pro-inflammatory responses are known to promote MDSC development. Indeed, a separate study demonstrated that R406 could restore myeloid homeostasis by reducing PMN-MDSC levels, increasing levels of monocytes with the HLA-DR hi phenotype, and inhibiting the expression of antiviral genes [ 78 ]. However, more studies will need to be performed to establish the link between SARS-CoV-2 and Syk-signaling, and their interaction with MDSC development and severe disease outcome.…”

“…These effects were successfully abrogated by R406, the active component of fostamatinib, a Syk inhibitor. ( 3 ) Wigerblad et al (2023) [ 78 ] performed a clinical study showing that R406 treatment decreased proinflammatory cytokine production and reduced generation of MDSCs, alongside other beneficial effects such as ameliorated interferon response in severe COVID-19 patients. MDSC: Myeloid-derived suppressor cells.…”