The JAK1/2 Inhibitor Baricitinib Mitigates the Spike-Induced Inflammatory Response of Immune and Endothelial Cells In Vitro

• Published in: Biomedicines 2022-09, Vol.10 (9), p.2324
• Main Authors: Barilli, Amelia, Visigalli, Rossana, Ferrari, Francesca, Recchia Luciani, Giulia, Soli, Maurizio, Dall’Asta, Valeria, Rotoli, Bianca Maria
• Format: Article
• Language: English
• Subjects: Antibodies; baricitinib; Cell activation; Chemokines; Clinical trials; Coronaviruses; COVID-19; Cytokines; Endothelial cells; Endothelium; FDA approval; Gene expression; IL-1β; immune innate cells; Infections; Inflammation; Intercellular adhesion molecule 1; Interleukin 6; Interleukin 8; IP-10 protein; JAK-STAT; Janus kinase; Kinases; Leukocytes (neutrophilic); Macrophages; Monocyte chemoattractant protein 1; Monocytes; Phosphorylation; Proteins; RANTES; Severe acute respiratory syndrome coronavirus 2; Stat1 protein; Stat3 protein; Tumor necrosis factor-α; Vascular cell adhesion molecule 1
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines10092324

The purpose of this study was to examine the effect of the JAK-STAT inhibitor baricitinib on the inflammatory response of human monocyte-derived macrophages (MDM) and endothelial cells upon exposure to the spike S1 protein from SARS-CoV-2. The effect of the drug has been evaluated on the release of cytokines and chemokines from spike-treated MDM, as well as on the activation of endothelial cells (HUVECs) after exposure to conditioned medium collected from spike-activated MDM. Results obtained indicate that, in MDM, baricitinib prevents the S1-dependent phosphorylation of STAT1 and STAT3, along with the induction of IP-10- and MCP-1 secretion; the release of IL-6 and TNFα is also reduced, while all other mediators tested (IL-1β, IL-8, RANTES, MIP-1α and MIP-1β) are not modified. Baricitinib is, instead, poorly effective on endothelial activation when HUVECs are exposed to supernatants from S1-activated macrophages; the induction of VCAM-1, indeed, is not affected by the drug, while that of ICAM-1 is only poorly inhibited. The drug, however, also exerts protective effects on the endothelium by limiting the expression of pro-inflammatory mediators, specifically IL-6, RANTES and IP-10. No effect of baricitinib has been observed on IL-8 synthesis and, consistently, on neutrophils chemiotaxis. Our in vitro findings reveal that the efficacy of baricitinib is limited, with effects mainly focused on the inhibition of the IL-6-mediated inflammatory loop.