Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension

作者：Valérie Amsellem, Shariq Abid, Lucie Poupel, Aurélien Parpaleix, Mathieu P. Rodero, Guillaume Gary-Bobo, Mehdi Latiri, J.-L. Dubois-Randé, Larissa Lipskaia, Christophe Combadière, Serge Adnot · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2017 · DOI：10.1165/rcmb.2016-0201oc · 被引用次数：116 · 研究领域：Pulmonary Hypertension Research and Treatments、Chemokine receptors and signaling、ATP Synthase and ATPases Research

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 Ly6Chi and resident Ly6Clo monocyte 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 ...