Dexamethasone, but Not Vitamin D or A, Dampens the Inflammatory Neutrophil Response to Protect At-risk COVID-19 Patients

Abstract

Dexamethasone (DEX) was the first drug shown to save lives of critically ill coronavirus disease 2019 (COVID-19) patients suffering from respiratory distress. A hyperactivated state of neutrophils was found in COVID-19 patients compared to non-COVID pneumonia cases. Given the beneficial effects of DEX in COVID-19 patients, we investigated the effects of DEX and of other immunomodulatory drugs vitamin D3 (VD3) and retinoic acid (RA) on neutrophil function. DEX, but not VD3 or RA, significantly inhibited all tested aspects of neutrophil function, e.g., degranulation, intracellular ROS production, CXCL8 release and NETosis. Interestingly, RA displayed the opposite effect by significantly increasing both CXCL8 and NET release by neutrophils. Taken together, these data suggest that the lower COVID-19 mortality in DEX-treated patients may in part be due to the dampening effect of DEX on the inflammatory neutrophil response, which could prevent neutrophil plugs with NETS in the lungs and other inflamed organs of patients.

Targeting Neutrophil Extracellular Trap Formation: Exploring Promising Pharmacological Strategies for the Treatment of Preeclampsia

“…Neutrophils cultured with dexamethasone showed reduced NET formation, after stimulation with PMA [98].…”

“…PE is characterized by a state of systemic inflammation where platelet abnormalities occur. It has been shown that dexamethasone significantly inhibited degranulation, intracellular ROS production, CXCL8 release, and neutrophil NETosis in patients with severe COVID-19 pneumonia [98]. Dexamethasone has been shown to inhibit Staphylococcus aureus-induced NET formation via upregulation of TLR2 and TLR4 receptors [156], this could mean that Dexamethasone induces vital NETs.…”

COVID-19 Therapeutics: An Update on Effective Treatments Against Infection With SARS-CoV-2 Variants

“…Nonetheless, with more information on the pathophysiology of COVID-19, it was hypothesized that the anti-inflammatory properties of corticosteroids may suppress hyperinflammation and modulate the immune-mediated damages following SARS-CoV-2 infection ( 151 ). Dexamethasone (DEX), a glucocorticosteroid used primarily to treat inflammatory and autoimmune diseases, was found to dampen the inflammatory neutrophil response associated with severe COVID-19 in vitro ( 152 ). DEX was examined as treatment in a controlled, randomized, open-label RECOVERY trial ( NCT04381936 ; Table 2 ) ( 153 ).…”

Identification and analysis of chemokine-related and NETosis-related genes in acute pancreatitis to develop a predictive model

“…The pathophysiological role of NETosis in neutrophil infection immunity is not entirely understood, but it is an essential mechanism for neutrophil anti-infection immunity ( Ou et al, 2021 ). Despite the crucial role that NETosis plays in antimicrobial processes, excessive NETosis can lead to severe tissue damage and exacerbation of inflammation ( Hafkamp et al, 2022 ). It is noteworthy that NETosis causes thrombosis, which exacerbates COVID-19, cancer, acute myocardial infarction, and ischemic stroke ( Wang H. et al, 2023 ).…”