title: Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension.
abstract: Monocytes/macrophages are major effectors of lung inflammation associated with various forms of pulmonary hypertension (PH). Interactions between the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine systems that guide phagocyte infiltration are incompletely understood. Our objective was to explore the individual and combined actions of CCL2/CCR2 and CX3CL1/CX3CR1 in hypoxia-induced PH in mice; particularly their roles in monocyte trafficking, macrophage polarization, and pulmonary vascular remodeling. The development of hypoxia-induced PH was associated with marked increases in lung levels of CX3CR1, CCR2, and their respective ligands, CX3CL1 and CCL2. Flow cytometry revealed that both inflammatory Ly6Chiand resident Ly6Clomonocyte subsets exhibited sustained increases in blood and a transient peak in lung tissue, and that lung perivascular and alveolar macrophage counts showed sustained elevations. CX3CR1-/-mice were protected against hypoxic PH compared with wild-type mice, whereas CCL2-/-mice and double CX3CR1-/-/CCL2-/-mice exhibited similar PH severity, as did wild-type mice. The protective effects of CX3CR1 deficiency occurred concomitantly with increases in lung monocyte and macrophage counts and with a change from M2 to M1 macrophage polarization that markedly diminished the ability of conditioned media to induce pulmonary artery smooth muscle cell (PA-SMC) proliferation, which was partly dependent on CX3CL1 secretion. Results in mice given the CX3CR1 inhibitor F1 were similar to those in CX3CR1-/-mice. In conclusion, CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment, macrophage polarization, and PA-SMC cell proliferation. Targeting CX3CR1 may hold promise for treating PH.
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Amsellem
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Shariq
authors.initials: S
authors.lastname: Abid
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Poupel
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Parpaleix
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Rodero
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gary-Bobo
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Latiri
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Dubois-Rande
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Combadiere
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Départements Hospitalo Universitaires Ageing Thorax-Vessels-Blood, 94010, Créteil, France; Université Paris-Est Créteil, France; and Sorbonne Universités, Université Pierre et Marie Curie-Université Paris 06, Inserm, UMRS1135, CNRS, Equipes de Recherche Labellisées 8255, Centre d'Immunologie et des Maladies Infectieuses, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000378:metabolism*; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D017353:Gene Deletion; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011651:Pulmonary Artery / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D008024:Ligands; D054390:Receptors, CCR2; D019707:Receptors, Chemokine
keywords: CX3CL1/CX3CR1 and CCL2/CCR2; chemokines; macrophages; monocytes; pulmonary hypertension