Molecular mechanisms of dexamethasone-mediated modulation of inflammatory and interferon responses in severe COVID-19 patients.

Abstract

Abstract Severe COVID-19 is characterized by cytokine storm, an excessive production of pro-inflammatory cytokines, which results in acute lung damage and death. Dexamethasone (Dex), a corticosteroid administered as a standard of care for severe COVID-19, has been shown to reduce the onset of severe complications in these patients. However, the mechanisms underlying the beneficial effects of Dex are poorly understood. We conducted a transcriptomic analysis (NanoString) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild (no hospitalization) and severe (on ventilator in the ICU) disease. The latter group included patients ± Dex. Treatment of severe COVID-19 patients with Dex inhibited pro-inflammatory pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling and the genes involved in cytokine storm (IL-1, IL-6 and IFN-γ), which were altered in severe vs mild disease. Pro-inflammatory immune cell functions are regulated by calcium signaling, which in turn is under the control of Kv1.3 potassium channels, but their role in the complications associated with COVID-19 remains elusive. RT-qPCR experiments in PBMCs from COVID-19 patient cohorts showed an increase in Kv1.3 expression in severe patients that was significantly reduced by Dex treatment. In agreement with these findings, in vitro treatment with Dex reduced Kv1.3 protein abundance in CD3+, CD4+, CD8+ T cell and CD56dim NK cells in healthy donor (HD) PBMC, while NanoString showed inhibition of pro-inflammatory genes and cytokines. Functional studies showed that Dex significantly reduced Kv1.3 activity and IFN-γ in HD T cells. Thus, our findings suggest that Kv1.3 inhibition contributes to the immunosuppression by Dex. This work was supported by Senior Pilot Grant, University of Cincinnati, Department of Internal Medicine to LC, NIH (R38HL155775 to MC) and Biospecimens and associated data were provided by the Cincinnati COVID-19 Repository at the University of Cincinnati and Cincinnati Children’s Hospital Medical Center.