Targeting mechanistic target of rapamycin complex 2 attenuates immunopathology in systemic lupus erythematosus

Area of Science:

• Immunology
• Molecular Biology
• Rheumatology

Background:

• Systemic lupus erythematosus (SLE) is a complex autoimmune disease.
• The role of mechanistic target of rapamycin complex 2 (mTORC2) in SLE pathogenesis is not fully understood.
• Type I interferon (IFN) signaling is implicated in SLE and may regulate mTORC2 activity.

Purpose of the Study:

• To investigate the role of mTORC2 in SLE development.
• To explore the in vivo regulation of mTORC2 by type I IFN signaling in autoimmunity.
• To evaluate mTORC2-targeting therapy for ameliorating lupus-like symptoms in preclinical and clinical models.

Main Methods:

• Induction of lupus-like disease in T-cell-specific Rictor-deficient mice using imiquimod (IMQ).
• Analysis of mTORC2 signaling and immunological phenotypes in type I IFN receptor (IFNAR)-deficient Lpr mice.
• Treatment of MRL/lpr lupus mice and human SLE peripheral blood mononuclear cells (PBMCs) with anti-Rictor antisense oligonucleotide (Rictor-ASO).

Main Results:

• T-cell-specific Rictor deficiency reduced B cell populations, plasma cells, germinal center B cells, and autoantibody production in IMQ-treated mice.
• IFNAR1 deficiency in Lpr mice led to reduced mTORC2 activity in CD4+ T cells, improved glucose metabolism, partially restored T cell trafficking, and decreased systemic inflammation.
• Rictor-ASO treatment improved renal function, pathology, and immunopathology in MRL/lpr mice and significantly reduced immunoglobulin and autoantibody production in human SLE PBMCs.

Conclusions:

• mTORC2 plays a significant role in the development of lupus-like disease.
• Type I IFN signaling influences mTORC2 activity in T cells during autoimmunity.
• Targeting mTORC2 with Rictor-ASO represents a promising therapeutic strategy for SLE.