Evidence for investigating GSK-3 inhibitors as potential therapeutics for severe COVID-19.

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. • Cytokine storms, the overexpression of unneeded cytokines, are a key aspect of severe COVID-19. • CXCL10, a chemokine, has been shown to be elevated in severe COVID-19. • We provide evidence that the SARS-CoV-2 spike protein induces expression of CXCL10 by a human macrophage cell line. • Two clinically relevant GSK-3 inhibitors, and GSK-3 inhibitor COB-187, attenuate spike protein-induced CXCL10 expression. • These findings provide impetus for exploring GSK-3 inhibitors as potential therapeutics for severe COVID-19. [ABSTRACT FROM AUTHOR]