Department of Chemical and Biomolecular Engineering, Ohio University, Athens, OH, 45701, United States.
Department of Specialty Medicine, Ohio University, Athens, OH, 45701, United States.
Biochem Biophys Res Commun. 2022 May 21;605:171-176. doi: 10.1016/j.bbrc.2022.03.035. Epub 2022 Mar 16.
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.
严重 COVID-19 的一个关键组成部分是“细胞因子风暴”，即不需要的细胞因子的过度表达。先前的研究表明，SARS-CoV-2 蛋白可诱导巨噬细胞分泌促炎细胞因子；这一过程可能涉及 Toll 样受体 (TLR)。糖原合酶激酶-3 (GSK-3) 已被牵连到 TLR 信号转导中，一种名为 COB-187 的选择性 GSK-3 抑制剂可显著抑制 TLR 配体脂多糖 (LPS) 诱导的细胞因子表达。在本研究中，我们提供了证据表明，SARS-CoV-2 刺突蛋白 (S) 和 S2 亚基 (S2) 通过人巨噬细胞系诱导 CXCL10（一种在严重 COVID-19 中升高的趋化因子）的产生。此外，我们报告说两种临床相关的 GSK-3 抑制剂和 COB-187 可减弱 S 和 S2 蛋白诱导的 CXCL10 产生。综上所述，我们的观察结果为研究 GSK-3 抑制剂作为严重 COVID-19 的潜在治疗方法提供了动力。
