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The role of mTOR signaling pathway in systemic lupus erythematosus and systemic vasculitis
Despina Michailidou1, Yevgeniya Gartshteyn1, Anca D Askanase1
1Division of Rheumatology and Clinical Immunology, Department of Medicine, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, New York, NY, USA.
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.
Insights
The mechanistic target of rapamycin (mTOR) pathway plays a key role in autoimmune diseases like lupus and vasculitis. Inhibiting mTOR could offer a new treatment strategy for these conditions.
Area of Science:
- Immunology
- Cellular Biology
- Molecular Medicine
Background:
- The mechanistic target of rapamycin (mTOR) is a crucial regulator of cell growth, metabolism, and immune cell function.
- The mTOR pathway, comprising mTORC1 and mTORC2 complexes, influences various immune cells and is implicated in autoimmune diseases.
- Dysregulation of mTOR signaling is linked to the pathogenesis of conditions such as cancer, diabetes, and autoimmune disorders.
Purpose of the Study:
- To review the role of the mTOR pathway in the pathogenesis of systemic lupus erythematosus (SLE) and systemic vasculitis.
- To elucidate how mTOR signaling contributes to the immune dysregulation observed in these autoimmune diseases.
- To explore the therapeutic potential of targeting the mTOR pathway for treating SLE and vasculitis.
Main Methods:
- This review synthesizes existing literature on mTOR signaling in the context of SLE and vasculitis.
- It examines the impact of mTOR pathway activation and inhibition on specific immune cell populations and functions.
- The review analyzes findings from studies investigating mTOR activity in patients with active autoimmune disease.
Main Results:
- In SLE, mTOR activation promotes T cell activation, Th17 skewing, B cell proliferation, autoantibody production, and myeloid dendritic cell activation.
- In large vessel vasculitis, mTOR overactivity contributes to endothelial and smooth muscle cell proliferation, T cell polarization, and Treg impairment.
- Conversely, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis shows reduced mTOR activity in neutrophils during active disease phases.
Conclusions:
- The mTOR pathway is differentially involved in the pathogenesis of various autoimmune diseases, with activation promoting SLE and large vessel vasculitis, but reduced activity observed in ANCA-associated vasculitis neutrophils.
- Modulating the mTOR pathway with inhibitors like rapamycin or rapalogues presents a promising therapeutic avenue for SLE and vasculitis.
- Further research is warranted to fully understand the complex role of mTOR in autoimmunity and to optimize mTOR-targeted therapies.
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