title: Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension.
abstract: Pulmonary artery smooth muscle cell (PA-SMC) proliferation and inflammation are key components of pulmonary arterial hypertension (PAH). Interleukin (IL)-1β binds to IL-1 receptor (R)1, thereby recruiting the molecular adaptor myeloid differentiation primary response protein 88 (MyD88) (involved in IL-1R1 and Toll-like receptor signal transduction) and inducing IL-1, IL-6 and tumour necrosis factor-α synthesis through nuclear factor-κB activation.We investigated the IL-1R1/MyD88 pathway in the pathogenesis of pulmonary hypertension.Marked IL-1R1 and MyD88 expression with predominant PA-SMC immunostaining was found in lungs from patients with idiopathic PAH, mice with hypoxia-induced pulmonary hypertension and SM22-5-HTT(+) mice. Elevations in lung IL-1β, IL-1R1, MyD88 and IL-6 preceded pulmonary hypertension in hypoxic mice. IL-1R1(-/-), MyD88(-/-) and control mice given the IL-1R1 antagonist anakinra were protected similarly against hypoxic pulmonary hypertension and perivascular macrophage recruitment. Anakinra reversed pulmonary hypertension partially in SM22-5-HTT(+) mice and markedly in monocrotaline-treated rats. IL-1β-mediated stimulation of mouse PA-SMC growth was abolished by anakinra and absent in IL-1R1(-/-) and MyD88(-/-) mice. Gene deletion confined to the myeloid lineage (M.lys-Cre MyD88(fl/fl) mice) decreased pulmonary hypertension severity versus controls, suggesting IL-1β-mediated effects on PA-SMCs and macrophages. The growth-promoting effect of media conditioned by M1 or M2 macrophages from M.lys-Cre MyD88(fl/fl) mice was attenuated.Pulmonary vessel remodelling and inflammation during pulmonary hypertension require IL-1R1/MyD88 signalling. Targeting the IL-1β/IL-1R1 pathway may hold promise for treating human PAH.
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Parpaleix
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Amsellem
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Houssaini
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Breau
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Marcos
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sawaki
authors.affiliation: Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Marion
authors.initials: M
authors.lastname: Delcroix
authors.affiliation: Respiratory Division, University Hospitals of Leuven and Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Rozenn
authors.initials: R
authors.lastname: Quarck
authors.affiliation: UMR7355, INEM Centre National de la Recherche Scientifique and Université F-45071 Orleans, Orleans, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Maillard
authors.affiliation: UMR7355, INEM Centre National de la Recherche Scientifique and Université F-45071 Orleans, Orleans, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couillin
authors.affiliation: UMR7355, INEM Centre National de la Recherche Scientifique and Université F-45071 Orleans, Orleans, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, DHU-ATVB, F-94010, Université Paris-Est Créteil (UPEC), Créteil, France serge.adnot@inserm.fr.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D017353:Gene Deletion; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016686:Monocrotaline / Q000737:chemistry; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053573:Receptors, Interleukin-1 Type I / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017077:Culture Media, Conditioned; C508590:IL1R1 protein, human; C583355:IL1R1 protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D053573:Receptors, Interleukin-1 Type I; D016686:Monocrotaline