Evidence for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19
Davoud Ghazanfari1, Maria Cecilia Courreges2, Lydia Belinski1
1Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, United States.
Abstract:
A key component of severe COVID-19 is a "cytokine storm" i.e., the excessive expression of unneeded cytokines. Previous studies suggest that SARS-CoV-2 proteins can induce macrophages to secrete pro-inflammatory cytokines; a process that may involve Toll-like receptors (TLRs). Glycogen synthase kinase-3 (GSK-3) has been implicated in TLR signal transduction and a selective GSK-3 inhibitor, termed COB-187, dramatically attenuates cytokine expression induced by the TLR ligand lipopolysaccharide (LPS). In the present study, we provide evidence that the SARS-CoV-2 spike protein (S) and the S2 subunit (S2) induce production of CXCL10 (a chemokine elevated in severe COVID-19) by a human macrophage cell line. Further, we report that two clinically relevant GSK-3 inhibitors and COB-187 attenuate S and S2 protein-induced CXCL10 production. Combined, our observations provide impetus for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19.
Insights
Glycogen synthase kinase-3 (GSK-3) inhibitors may treat severe COVID-19 by reducing harmful cytokine storms. This study shows GSK-3 inhibitors block SARS-CoV-2 spike proteins from inducing excessive CXCL10 chemokine production in macrophages.
Area of Science:
- Immunology
- Virology
- Pharmacology
Background:
- Severe COVID-19 is characterized by a cytokine storm, an overproduction of cytokines.
- Toll-like receptors (TLRs) and Glycogen synthase kinase-3 (GSK-3) signaling are implicated in SARS-CoV-2-induced cytokine release.
Purpose of the Study:
- To investigate the role of SARS-CoV-2 spike proteins in inducing pro-inflammatory cytokine production.
- To evaluate the efficacy of GSK-3 inhibitors in mitigating this response.
Main Methods:
- Human macrophage cell line stimulation with SARS-CoV-2 spike protein (S) and S2 subunit.
- Measurement of CXCL10 chemokine production.
- Treatment with selective GSK-3 inhibitors (COB-187 and two clinically relevant compounds).
Main Results:
- SARS-CoV-2 S and S2 proteins induced CXCL10 production in macrophages.
- GSK-3 inhibitors significantly attenuated S and S2-induced CXCL10 production.
- This suggests a role for GSK-3 in the SARS-CoV-2 inflammatory pathway.
Conclusions:
- GSK-3 signaling is involved in SARS-CoV-2 spike protein-mediated cytokine induction.
- GSK-3 inhibitors show therapeutic potential for managing severe COVID-19 cytokine storms.
- Further investigation into GSK-3 inhibitors as COVID-19 therapeutics is warranted.
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