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Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS-CoV-2 Spike protein #MMPMID34107055
Palasiewicz K; Umar S; Romay B; Zomorrodi RK; Shahrara S
Eur J Immunol 2021[Sep]; 51 (9): 2330-2340 PMID34107055show ga
The molecular mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein was characterized to identify novel therapies. The impact of tofacitinib, IL-6R Ab, or TNFi therapy was determined on Spike protein or LPS/IFN-gamma-induced signaling, inflammation, and metabolic reprogramming in MPhis and/or rheumatoid arthritis (RA) fibroblast-like synoviocyte (FLS). ACE2 frequency was markedly expanded in MPhis compared to T cells and RA FLS. Tofacitinib suppresses Spike protein potentiated STAT1 signaling, whereas this function was unchanged by TNFi. Tofacitinib impairs IL-6/IFN/LPS-induced STAT1 and STAT3 phosphorylation in RA MPhis and FLS. Interestingly, tofacitinib had a broader inhibitory effect on the monokines, glycolytic regulators, or oxidative metabolites compared to IL-6R Ab and TNFi in Spike-protein-activated MPhis. In contrast, all three therapies disrupted IFN-alpha and IFN-beta secretion in response to Spike protein; nonetheless, the IFN-gamma was only curtailed by tofacitinib or IL-6R Ab. While tofacitinib counteracted MPhi metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MPhi and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN-gamma stimulation in MPhis or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MPhi inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID-19 patients.
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Eur+J+Immunol 2021 ; 51 (9): 2330-2340
