SARS-CoV-2 envelope protein induces alveolar hemorrhage and lupus nephritis in systemic lupus erythematosus via binding TLR2 to enhance cell death 9105

Abstract Description The systemic lupus erythematosus (SLE) pathogenesis involves accelerated cell death, releasing autoantigens with immune complexes deposition to induce activity manifesting as alveolar hemorrhage (AH), lupus nephritis (LN), etc. TLR2 is shown to sense SARS-CoV-2-envelope (E), while SLE patients have post-COVID-19 disease flare. Mechanistic evidence of binding between TLR2 and E to induce lupus activity remains to be elucidated. In SLE, there were up-regulated TLR2, iNOS and Nox1 expression in blood mononuclear cells (BMCs), pulmonary and renal tissues with elevated plasma IL-6, IL-8 and IFN-γ levels. In situ cell death were found in the AH lungs and LN kidneys. Molecular docking predicted interaction between TLR2 or TLR4 and E, while co-immunoprecipitation confirmed stronger binding in TLR2 than TLR4. E protein-stimulated BMCs had elevated IL-6, IL-8, IFN-γ, iNOS and Nox1 levels. Increased IL-6, IL-8, IFN-γ, iNOS, Nox1, ROS, p-NF-κB-p65, p-ERK and apoptosis expression in E protein-stimulated RAW264.7 cells were reduced by TLR2 inhibitor or sh-TLR2 transfection. HL-60 cells infected with LV-CoV-2-E, a SARS-CoV-2-E pseudovirus, had enhanced NETosis formation. E protein or LV-CoV-2-E intra-pulmonary infusion enhanced pristane-induced mouse AH by increasing cell death, while AH was reduced by sh-TLR2 co-delivery. LV-CoV-2-E infusion aggravated pristane-induced mouse LN. These data suggest SLE disease flare induced by SARS-CoV-2-E via binding TLR2 to enhance cell death formation. Topic Categories Translational and Interventional Immunology (TI)