Immune and ionic mechanisms mediating the effect of dexamethasone in severe COVID-19

Front Immunol. 2023 Mar 24:14:1143350. doi: 10.3389/fimmu.2023.1143350. eCollection 2023.

Abstract

Introduction: Severe COVID-19 is characterized by cytokine storm, an excessive production of proinflammatory cytokines that contributes to acute lung damage and death. Dexamethasone is routinely used to treat severe COVID-19 and has been shown to reduce patient mortality. However, the mechanisms underlying the beneficial effects of dexamethasone are poorly understood.

Methods: We conducted transcriptomic analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild disease, and patients with severe COVID-19 with and without dexamethasone treatment. We then treated healthy donor PBMCs in vitro with dexamethasone and investigated the effects of dexamethasone treatment ion channel abundance (by RT-qPCR and flow cytometry) and function (by electrophysiology, Ca2+ influx measurements and cytokine release) in T cells.

Results: We observed that dexamethasone treatment in severe COVID-19 inhibited pro-inflammatory and immune exhaustion pathways, circulating cytotoxic and Th1 cells, interferon (IFN) signaling, genes involved in cytokine storm, and Ca2+ signaling. Ca2+ influx is regulated by Kv1.3 potassium channels, but their role in COVID-19 pathogenesis remains elusive. Kv1.3 mRNA was increased in PBMCs of severe COVID-19 patients, and was significantly reduced in the dexamethasone-treated group. In agreement with these findings, in vitro treatment of healthy donor PBMCs with dexamethasone reduced Kv1.3 abundance in T cells and CD56dimNK cells. Furthermore, functional studies showed that dexamethasone treatment significantly reduced Kv1.3 activity, Ca2+ influx and IFN-g production in T cells.

Conclusion: Our findings suggest that dexamethasone attenuates inflammatory cytokine release via Kv1.3 suppression, and this mechanism contributes to dexamethasone-mediated immunosuppression in severe COVID-19.

Keywords: COVID-19; cytokine storm; dexamethasone; interferon signaling; ion channels; severe COVID-19; severe COVID-19 immune signaling.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • COVID-19 Drug Treatment
  • COVID-19*
  • Calcium / metabolism
  • Cytokine Release Syndrome / drug therapy
  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Dexamethasone / therapeutic use
  • Humans
  • Leukocytes, Mononuclear / metabolism

Substances

  • Calcium
  • Cytokines
  • Dexamethasone