A Maciejewski-Duval1, C Comarmond2, A Leroyer3, M Zaidan4, A Le Joncour2, A C Desbois2, J P Fouret5, F Koskas6, P Cluzel7, M Garrido1, P Cacoub2, D Saadoun8. 1. Sorbonne 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. 2. Sorbonne 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; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, National Center for Autoimmune and Systemic Rare Disease, National Center for Autoinflammatory Diseases and Amyloidosis, F-75013, Paris, France. 3. Aix-Marseille Université, INSERM, Vascular Research Center of Marseille, UMR-S 1076, Marseille, France. 4. AP-HP, Hôpital Necker-Enfants Malades, Département de Néphrologie, F-75015, Paris, France. 5. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Laboratoire d'anatomopathologie, F-75013, Paris, France. 6. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Chirurgie Vasculaire, UPMC-Paris VI, Paris, France. 7. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département d'Imagerie CardioVasculaire et de Radiologie Interventionnelle, UPMC Paris VI, INSERM-CNRS-LIB, Paris, France. 8. Sorbonne 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; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Département de Médecine Interne et Immunologie Clinique, National Center for Autoimmune and Systemic Rare Disease, National Center for Autoinflammatory Diseases and Amyloidosis, F-75013, Paris, France. Electronic address: david.saadoun@aphp.fr.
Abstract
BACKGROUND: Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.
BACKGROUND:Mammalian target of rapamycin complex 1 (mTORC 1) drives the proinflammatory expansion of T helper (TH) type 1, TH17 cells and controls fibroblast proliferation, typical features of large vessel vasculitis (LVV) pathogenesis. Molecular pathways involved in arterial lesions of LVV are unknown. METHODS: We evaluate mTORC pathway activation in vascular aorta lesions and in T cell homeostasis of patients with LVV. RESULTS: Proliferation of both endothelial cells and vascular smooth-muscle cells was shown in vascular lesions in LVV. The vascular endothelium of proliferating aorta vessels from patients with LVV showed indications of activation of the mTORC1 pathway (S6RP phosphorylation). In cultured vascular endothelial cells, sera from patients with LVV stimulated mTORC1 through the phosphorylation of S6RP. mTORC1 activation was found also in Th1 and Th17 cells both systemically and in inflamed vessels. Patients with LVV exhibited a diminished S6RP phosphorylation in Tregs. Inhibition of mTORC1 pathway with rapamycin, increase Tregs and decrease effector CD4+IFNγ+, CD4+IL17+ and CD4+IL21+ T cells in patients with LVV. CONCLUSIONS: We provided evidence that mTORC1 pathway has a central role in driving T cell inflammation and vascular lesions in LVV. Targeting mTORC pathway may represent a new therapeutic option in patients with LVV.
Authors: Dan Pugh; Maira Karabayas; Neil Basu; Maria C Cid; Ruchika Goel; Carl S Goodyear; Peter C Grayson; Stephen P McAdoo; Justin C Mason; Catherine Owen; Cornelia M Weyand; Taryn Youngstein; Neeraj Dhaun Journal: Nat Rev Dis Primers Date: 2022-01-06 Impact factor: 65.038