title: Proinflammatory Signature of the Dysfunctional Endothelium in Pulmonary Hypertension. Role of the Macrophage Migration Inhibitory Factor/CD74 Complex.
abstract: BACKGROUND
  Inflammation and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). CD74 is a receptor for the proinflammatory cytokine macrophage migration inhibitory factor (MIF). This ligand/receptor complex initiates survival pathways and cell proliferation, and it triggers the synthesis and secretion of major proinflammatory factors and cell adhesion molecules.
  
  
  OBJECTIVE
  We hypothesized that the MIF/CD74 signaling pathway is overexpressed in idiopathic PAH (iPAH) and contributes to a proinflammatory endothelial cell (EC) phenotype.
  
  
  METHODS
  Primary early passage cultures of human ECs isolated from lung tissues obtained from patients with iPAH and controls were examined for their ability to secrete proinflammatory mediators and bind inflammatory cells with or without modulation of the functional activities of the MIF/CD74 complex. In addition, we tested the efficacies of curative treatments with either the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies on the aberrant proinflammatory EC phenotype in vitro and in vivo and on the progression of monocrotaline-induced pulmonary hypertension.
  
  
  RESULTS
  In human lung tissues, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin expressions are markedly up-regulated in the endothelium of distal iPAH pulmonary arteries. Circulating MIF levels are increased in the serum of patients with PAH compared with control subjects, and T-cell lymphocytes represent a source of this overabundance. In addition, CD74 is highly expressed in the endothelium of muscularized pulmonary arterioles and in cultured pulmonary ECs from iPAH, contributing to an exaggerated recruitment of peripheral blood mononuclear cells to pulmonary iPAH ECs. Finally, we found that curative treatments with the MIF antagonist ISO-1 or anti-CD74 neutralizing antibodies partially reversed development of pulmonary hypertension in rats and substantially reduced inflammatory cell infiltration.
  
  
  CONCLUSIONS
  We report here that CD74 and MIF are markedly increased and activated in patients with iPAH, contributing to the abnormal proinflammatory phenotype of pulmonary ECs in iPAH.
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Morane
authors.initials: M
authors.lastname: Le Hiress
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Ly
authors.identifier: http://orcid.org/0000-0003-2336-5099
authors.initials: L
authors.lastname: Tu
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ricard
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Phan
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Thuillet
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.|3 AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, Kremlin-Bicêtre, France; and.
authors.forename: David
authors.identifier: http://orcid.org/0000-0001-5110-9194
authors.initials: D
authors.lastname: Montani
authors.affiliation: 4 Department of Pulmonology, VU University Medical Center/Institute of Cardiovascular Research, Amsterdam, the Netherlands.
authors.forename: Frances
authors.initials: F
authors.lastname: de Man
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.|3 AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, Kremlin-Bicêtre, France; and.
authors.forename: Marc
authors.identifier: http://orcid.org/0000-0003-0703-2892
authors.initials: M
authors.lastname: Humbert
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.|3 AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, Kremlin-Bicêtre, France; and.
authors.forename: Alice
authors.initials: A
authors.lastname: Huertas
authors.affiliation: 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France.|2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France.
authors.forename: Christophe
authors.identifier: http://orcid.org/0000-0002-8545-4452
authors.initials: C
authors.lastname: Guignabert
mesh_terms: D000328:Adult; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019040:E-Selectin / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D065627:Familial Primary Pulmonary Hypertension / Q000276:immunology* / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000276:immunology / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D019040:E-Selectin; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D019010:Vascular Cell Adhesion Molecule-1; C045084:invariant chain; D018799:Intercellular Adhesion Molecule-1
keywords: CD74 signaling pathway; adhesion molecules; endothelial dysfunction; macrophage migration inhibitory factor; pulmonary hypertension