Morane Le Hiress1,2, Ly Tu1,2, Nicolas Ricard1,2, Carole Phan1,2, Raphaël Thuillet1,2, Elie Fadel1,2, Peter Dorfmüller1,2, David Montani1,2,3, Frances de Man4, Marc Humbert1,2,3, Alice Huertas1,2,3, Christophe Guignabert1,2. 1. 1 INSERM UMR_S 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France. 2. 2 Université Paris-Sud and Université Paris-Saclay, School of Médecine, Kremlin-Bicêtre, France. 3. 3 AP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital de Bicêtre, Kremlin-Bicêtre, France; and. 4. 4 Department of Pulmonology, VU University Medical Center/Institute of Cardiovascular Research, Amsterdam, the Netherlands.
Abstract
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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: Antoine G Sreih; Rana Ezzedine; Lin Leng; Juan Fan; Jie Yao; Duncan Reid; Marta Piecychna; Simon Carette; David Cuthbertson; Paul Dellaripa; Gary S Hoffman; Nader A Khalidi; Curry L Koening; Carol A Langford; Alfred Mahr; Carol A McAlear; Kathleen Maksimowicz-Mckinnon; Paul A Monach; Philip Seo; Ulrich Specks; E William St Clair; John H Stone; Steven R Ytterberg; Jeffrey Edberg; Peter A Merkel; Richard Bucala Journal: Arthritis Rheumatol Date: 2018-10-22 Impact factor: 10.995
Authors: Sébastien Bonnet; Steeve Provencher; Christophe Guignabert; Frédéric Perros; Olivier Boucherat; Ralph Theo Schermuly; Paul M Hassoun; Marlene Rabinovitch; Mark R Nicolls; Marc Humbert Journal: Am J Respir Crit Care Med Date: 2017-03-01 Impact factor: 21.405