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mTOR pathway activation in large vessel vasculitis.

A Maciejewski-Duval1, C Comarmond2, A Leroyer3

  • 1Sorbonne Universités, UPMC Université Paris 06, UMR 7211, Département Hospitalo-Universitaire Inflammation-Immunopathologie-Biotherapie (DHU i2B), F-75005, Paris, France; INSERM, UMR_S 959, F-75013, Paris, France; CNRS, FRE3632, F-75005, Paris, France.

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Summary

The mammalian target of rapamycin complex 1 (mTORC1) pathway drives inflammation and vascular lesions in large vessel vasculitis (LVV). Targeting mTORC1 may offer new therapeutic options for LVV patients.

Keywords:
Giant cell arteritisRapamycinTakayasu arteritisVasculitismTOR

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Area of Science:

  • Immunology
  • Vascular Biology
  • Molecular Medicine

Background:

  • Mammalian target of rapamycin complex 1 (mTORC1) is implicated in T helper cell expansion and fibroblast proliferation, key features in large vessel vasculitis (LVV) pathogenesis.
  • The specific molecular pathways driving arterial lesions in LVV remain largely unknown.

Purpose of the Study:

  • To investigate the activation of the mTORC1 pathway in vascular aorta lesions.
  • To assess the role of mTORC1 in T cell homeostasis within patients diagnosed with LVV.

Main Methods:

  • Analysis of mTORC1 pathway activation (S6RP phosphorylation) in vascular aorta lesions from LVV patients.
  • Evaluation of mTORC1 activation in systemic and inflamed T cells (Th1, Th17, Tregs).
  • Assessment of rapamycin's effect on T cell populations and Tregs in LVV patients.

Main Results:

  • Evidence of mTORC1 pathway activation in the vascular endothelium and smooth-muscle cells of LVV aorta lesions.
  • mTORC1 activation was observed in effector T cells (Th1, Th17) but diminished in regulatory T cells (Tregs) in LVV patients.
  • Rapamycin treatment inhibited mTORC1, increased Tregs, and decreased effector T cells (CD4+IFNγ+, CD4+IL17+, CD4+IL21+) in LVV patients.

Conclusions:

  • The mTORC1 pathway plays a critical role in mediating T cell-driven inflammation and vascular lesions characteristic of LVV.
  • Targeting the mTORC1 pathway presents a potential novel therapeutic strategy for managing patients with large vessel vasculitis.