The role of mTOR signaling pathway in systemic lupus erythematosus and systemic vasculitis

Abstract

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular proliferation, metabolism, survival and growth. The mTOR pathway consists of two protein complexes, mTORC1 and mTORC2, which have different sensitivities to rapamycin and cellular functions. mTOR regulates autophagy as well as the function and/or differentiation of many immune cells, including T cells, dendritic cells, natural killer cells, macrophages, neutrophils, and B cells. mTOR signaling is implicated in the pathogenesis of cancer, diabetes and several autoimmune diseases. In this review, we summarize how mTOR pathway may contribute to the pathogenesis of systemic lupus erythematosus (SLE) and systemic vasculitis. In SLE, mTOR activation induces activation of CD4 + T cells, skews differentiation towards Th17 cells resulting in Th17/Treg imbalance, increases production of IL-4 in CD4 - CD8- double-negative (DN) T cells, reduces the number of circulating CD8⁺ memory T cells, promotes B-cell proliferation, increases production of plasmacytes and secretion of autoantibodies, as well as activation of myeloid dendritic cells. In large vessel vasculitis, mTOR overactivity promotes endothelial cell growth, T cell differentiation towards Th1 and Th17 polarization, impairment of Tregs and activation of smooth muscle cell-derived myofibroblasts that contribute to arterial stenosis and ischemia, whereas in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, reduced activity of the mTOR signaling pathway is observed in neutrophils isolated during the active phase of the disease. Targeting mTOR pathway with rapamycin, rapalogues, or other mTOR inhibitors could be efficacious in the treatment of these complex autoimmune diseases.

Keywords: ANCA-associated vasculitis; Giant cell arteritis; Kawasaki disease; Rapamycin; Systemic lupus erythematosus; Takayasu's arteritis; mTOR.