Rheumatology (Oxford, England) · 2025
Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in systemic lupus erythematosus.
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СтатьяПоддержка NIH: внешняя программаОтозванная публикацияНазвание и аннотация: Перевод в очереди
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Ai Minji, Zhou Xian, Carrer Michele, Jafar-Nejad Paymaan, Li Yanfeng, Gades Naomi, Alexander Mariam, Bautista-Vargas Mario, Duarte-García Alí, Zeng Hu
Аннотация
OBJECTIVE: We aimed to explore the role of mechanistic target of rapamycin complex (mTORC) 2 in SLE development, and the in vivo regulation of mTORC2 by type I IFN signalling in autoimmunity, and to use mTORC2 targeting therapy to ameliorate lupus-like symptoms in an in vivo lupus mouse model and an in vitro co-culture model using human peripheral blood mononuclear cells (PBMCs).
METHOD: We first induced lupus-like disease in T-cell-specific Rictor, a key component of mTORC2-deficient mice, by topical application of imiquimod (IMQ), and monitored disease development. Next, we investigated the changes in mTORC2 signalling and immunological phenotypes in type I IFNAR-deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients' PBMCs using an in vitro T-B co-culture assay.
RESULTS: T-cell-specific Rictor-deficient mice have reduced age-associated B cells, plasma cells and germinal centre 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. Rictor-ASO treatment improved renal function and pathology in MRL/lpr mice, and improved immunopathology. In a human SLE (N = 5) PBMCs derived T-B co-culture assay, RICTOR-ASO significantly reduced the production of immunoglobulin (Ig) and autoantibodies (P < 0.05).
CONCLUSION: Targeting mTORC2 could be a promising therapeutic strategy for SLE.
METHOD: We first induced lupus-like disease in T-cell-specific Rictor, a key component of mTORC2-deficient mice, by topical application of imiquimod (IMQ), and monitored disease development. Next, we investigated the changes in mTORC2 signalling and immunological phenotypes in type I IFNAR-deficient Lpr mice. We then tested the beneficial effects of anti-Rictor antisense oligonucleotide (Rictor-ASO) in a mouse model of lupus: MRL/lpr mice. Finally, we examined the beneficial effects of RICTOR-ASO on SLE patients' PBMCs using an in vitro T-B co-culture assay.
RESULTS: T-cell-specific Rictor-deficient mice have reduced age-associated B cells, plasma cells and germinal centre 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. Rictor-ASO treatment improved renal function and pathology in MRL/lpr mice, and improved immunopathology. In a human SLE (N = 5) PBMCs derived T-B co-culture assay, RICTOR-ASO significantly reduced the production of immunoglobulin (Ig) and autoantibodies (P < 0.05).
CONCLUSION: Targeting mTORC2 could be a promising therapeutic strategy for SLE.