Mast cells drive pathologic vascular lesions in Takayasu arteritis

Alexandre Le Joncour (1) , Anne-Claire Desbois (1) , Aurélie Leroyer (2) , Edwige Tellier (2) , Paul Régnier , Anna Maciejewski-Duval , Cloé Comarmond , Stéphane Barete , Michel Arock , Patrick Bruneval , Jean-Marie Launay , Pierre Fouret , Ulrich Blank (3) , Michelle Rosenzwajg (4) , David Klatzmann , Mohamed Jarraya , Laurent Chiche (5) , Fabien Koskas , Patrice Cacoub , Gilles Kaplanski (2) , David Saadoun

1 INSERM - Institut National de la Santé et de la Recherche Médicale
2 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
3 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
4 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
5 Imagerie médicale et quantitative

Background: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response. Objectives: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK. Methods: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis. Results: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and a-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD. Conclusions: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis.

Mots clés: Large vessel vasculitis; mast cell; vascular remodeling; Takayasu

Domaines: Sciences du Vivant [q-bio]

Alexandre Le Joncour, Anne-Claire Desbois, Aurélie Leroyer, Edwige Tellier, Paul Régnier, et al.. Mast cells drive pathologic vascular lesions in Takayasu arteritis. Journal of Allergy and Clinical Immunology, 2022, 149 (1), ⟨10.1016/j.jaci.2021.05.003⟩. ⟨hal-03406075⟩