Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in Systemic Lupus Erythematosus

Abstract

AbstractObjectiveWe aim to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in systemic lupus erythematosus (SLE) development, the invivoregulation of mTORC2 by type I interferon (IFN) signaling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in anin vivolupus mouse model and anin vitrococulture model using human PBMCs.MethodWe first induced lupus-like disease in T cell specificRictor, a key component of mTORC2, deficient mice by topical application of imiquimod (IMQ) and monitored disease development. Next, we investigated the changes of mTORC2 signaling and immunological phenotypes in type I IFNAR deficient Lpr mice. We then tested the beneficial effects of anti-Rictorantisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lprmice. Finally, we examined the beneficial effects ofRICTOR-ASO on SLE patients’ PBMCs using anin vitroT-B cell coculture assay.ResultsT cell specificRictordeficient mice have reduced age-associated B cells, plasma cells and germinal center B cells, and less autoantibody production than WT mice following IMQ treatment. IFNAR1 deficient Lpr mice have reduced mTORC2 activity in CD4+T cells accompanied by restored CD4+T cell glucose metabolism, partially recovered T cell trafficking, and reduced systemic inflammation.In vivo Rictor-ASO treatment improves renal function and pathology in MRL/lprmice, along with improved immunopathology. In human SLE (N = 5) PBMCs derived T-B coculture assay,RICTOR-ASO significantly reduce immunoglobulin and autoantibodies production (P < 0.05).ConclusionTargeting mTORC2 could be a promising therapeutic for SLE.