Mast cells drive pathologic vascular lesions in Takayasu arteritis - 05/01/22

Doi : 10.1016/j.jaci.2021.05.003

Alexandre Le Joncour, MD, MSc ^a,^b,^c,^{∗
These authors contributed equally to this work.}, Anne-Claire Desbois, MD, PhD ^a,^b,^c,^{∗
These authors contributed equally to this work.}, Aurélie S. Leroyer, PhD ^d, Edwige Tellier, PhD ^d, Paul Régnier, PhD ^a,^b, Anna Maciejewski-Duval, PhD ^a,^b, Cloé Comarmond, MD, PhD ^a,^b,^c, Stéphane Barete, MD, PhD ^c,^e, Michel Arock, MD, PhD ^f,^g, Patrick Bruneval, MD, PhD ^h, Jean-Marie Launay, MD, PhD ⁱ, Pierre Fouret, MD, PhD ^j, Ulrich Blank, MD, PhD ^k, Michelle Rosenzwajg, MD, PhD ^a,^b,^c, David Klatzmann, MD, PhD ^a,^b,^c, Mohamed Jarraya, MD, PhD ^l, Laurent Chiche, MD, PhD ^m, Fabien Koskas, MD, PhD ^m, Patrice Cacoub, MD, MSc ^a,^b,^c, Gilles Kaplanski, MD, PhD ^d,ⁿ, David Saadoun, MD, PhD ^a,^b,^c,^⁎
^a Department of Immunology-Immunopathology-Immunotherapy, Université Pierre-et-Marie-Curie Université de Paris 06, Unite Mixte de Recherche (UMR)S959, Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Universités, Paris, France
^b Department of Biotherapy, Hôpital Pitié-Salpêtrière, Paris, France
^c Department of Internal Medicine and Clinical Immunology, Centre National de Références Maladies Autoimmunes et Systémiques Rares, Centre National de Références Maladies Autoinflammatoires Rares et Amylose Inflammatoire, Paris, France
^d Centre de Recherche en CardioVasculaire et Nutrition, INSERM U1263, Inrae 1260, Aix-Marseille Université, Marseille, France
^e Department of Dermatology DMU3ID, Unité Fonctionnelle de Dermatologie, Groupe Hospitalier Pitié-Salpêtrière-C. Foix, Paris, France
^f Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, INSERM UMRS1138, Centre de Recherche des Cordeliers, Paris, France
^g Laboratoire d’Hématologie Biologique, Hôpital Pitié-Salpêtrière, Paris, France
^h Laboratoire d’anatomopathologie, Hôpital Européen Georges Pompidou, Paris, France
ⁱ INSERM, UMR-S 942, F-75010, Paris, France
^j Laboratoire d’Anatomopathologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
^k Center of Research on Inflammation, INSERM UMR S1149 and Centre National de la Recherche Scientifique Experimental Research Laboratory 8252, Universite de Paris, Sorbonne Paris Cite, Laboratoire d'Excellence INFLAMEX, Paris, France
^l Banque des Tissus Humains, Hôpital Saint Louis, Paris, France
^m Service de Chirurgie Vasculaire, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique–Hôpitaux de Paris, Paris, France
ⁿ Service de Médecine Interne, Centre Hospitalier Universitaire Conception, Assistance Publique Hôpitaux de Marseille, Marseille, France

^∗Corresponding author: David Saadoun, MD, PhD, Laboratory I3, Immunology, Immunopathology, Immunotherapy, UMR 7211 INSERM U959, Sorbonne University, Hôpital Pitié-Salpétrière, 47-83 Boulevard de l’Hôpital, Paris, France 75013.Laboratory I3Immunology, Immunopathology, ImmunotherapyUMR 7211 INSERM U959Sorbonne UniversityHôpital Pitié-Salpétrière47-83 Boulevard de l’HôpitalParisFrance75013

Abstract

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 α-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.

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Key words : Large vessel vasculitis, mast cell, vascular remodeling, Takayasu

Abbreviations used : α-SMA, HD, HUVEC, IDO, LVV, MC, PDGF, qRT-PCR, TAK

Plan

Gene expression quantification at the mRNA level in aortic tissues and fibroblasts

In vivo permeability assays

In vitro angiogenesis assay

In vitro culture of fibroblasts

Statistics

Results

Increased vessel permeability in TAK is dependent on MCs

MCs support neo-angiogenesis in TAK

MCs support fibrosis in TAK

Discussion

	A.C. Desbois was supported by grant from the Fondation pour la Recherche Médicale. A. Le Joncour was supported by grant from INSERM.
	Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 1

P. 292 - janvier 2022 Retour au numéro

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Mast cells drive pathologic vascular lesions in Takayasu arteritis - 05/01/22

Abstract

Background

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Results

Conclusions

Plan

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