TLR2 sensing of the SARS-CoV-2 envelope protein drives NLRP3-dependent pyroptosis in post-COVID-19 systemic lupus erythematosus 2300032

Abstract

In systemic lupus erythematosus (SLE), accelerated cell death promotes autoantigen release and immune complex formation, leading to visceral deposition and alveolar hemorrhage (AH) and lupus nephritis (LN). Viral infection has been implicated in autoimmunity, and post-COVID-19 disease flares are increasingly reported in SLE. Elevated pro-inflammatory cytokines are observed in SARS-CoV-2—infected individuals and patients with active SLE; however, the mechanistic role of Toll-like receptor 2 (TLR2) sensing of the SARS-CoV-2 envelope (Env) protein in post-COVID-19 SLE flares remains unclear. Peripheral blood, AH lung tissues, and LN kidney tissues were obtained from SLE experiencing post-COVID-19 flares. THP-1 and RAW264.7 cells were stimulated with Env protein, followed by TLR2 inhibition. In vivo, pristane-induced AH or LN mouse models received intratracheal Env pseudovirus infusion in TLR2-deficient mice or in wild-type mice with concomitant sh-TLR2 delivery. Molecular docking predicted TLR2—Env interaction, which was validated by co-immunoprecipitation and solid-phase binding assays. Env stimulation activated NF-κB/MAPK signaling, increased ROS production and pro-inflammatory cytokines in RAW264.7 cells, which were attenuated by TLR2 inhibition or knockdown. In patients with post-COVID-19 SLE flares, plasma IL-1β levels were elevated with increased NLRP3, caspase-1, and N-gasdermin D expression in peripheral blood mononuclear cells, lung, and kidney tissues. Env-induced pyroptosis in THP-1 cells increased LDH and IL-1β release and was suppressed by TLR2 inhibition. In vivo, Env pseudovirus infusion exacerbated pristane-induced alveolar hemorrhage and lupus nephritis via enhanced pyroptosis, whereas TLR2 suppression markedly alleviated disease severity. Together, these findings indicate that TLR2 sensing of the SARS-CoV-2 envelope protein promotes NLRP3-dependent pyroptosis and contributes to post-COVID-19 disease flares in systemic lupus erythematosus. n/a Translational and Interventional Immunology (TI)