Tofacitinib therapy intercepts macrophage metabolic reprogramming instigated by SARS‐CoV‐2 Spike protein. Issue 9 (24th June 2021)

• Record Type: Journal Article
• Authors: Palasiewicz, Karol; Umar, Sadiq; Romay, Bianca; Zomorrodi, Ryan K.; Shahrara, Shiva
• Is Part Of: European journal of immunology. Volume 51:Issue 9(2021)
• Page Start: 2330
• Page End: 2340
• Publication Date: 2021-06-24
• Subjects: Macrophages -- Osteoclasts -- RA FLS -- Spike protein -- Tofacitinib; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202049159
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: 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‐γ‐induced signaling, inflammation, and metabolic reprogramming in MΦs and/or rheumatoid arthritis (RA) fibroblast‐like synoviocyte (FLS). ACE2 frequency was markedly expanded in MΦs 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 MΦs 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 MΦs. In contrast, all three therapies disrupted IFN‐α and IFN‐β secretion in response to Spike protein; nonetheless, the IFN‐γ was only curtailed by tofacitinib or IL‐6R Ab. While tofacitinib counteracted MΦ metabolic rewiring instigated by Spike protein, it was inconsequential on the glycolysis expansion mediated via HK2 and/or LDHA in the activated RA MΦ and FLS. Nevertheless, the potentiated inflammatory response and the diminished oxidative phosphorylation modulated by Spike protein and/or LPS/IFN‐γ stimulation in MΦs or RA FLS were reversed by tofacitinib. In conclusion, tofacitinib suppresses MΦ inflammation and immunometabolism triggered by Spike protein and may provide a promising strategy for COVID‐19 patients. Abstract : Tofacitinib has both overlapping and distinct characteristics in cells treated with Spike protein or danger signals. The mutual effect of tofacitinib on MΦ activation syndrome (MAS) in response to Spike protein or danger signal is its ability to counteract inflammation and potentiate oxidative phosphorylation. Tofacitinib distinctly reverses Spike‐protein‐induced metabolic reprogramming by restraining glycolytic intermediates.