Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension
Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension
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DOI：
10.1165/rcmb.2016-0201oc
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发表时间：
2017-05-01
影响因子：
6.4
通讯作者：
Adnot, Serge
中科院分区：
文献类型：
--
作者：
Amsellem, Valerie;Abid, Shariq;Adnot, Serge
单核细胞/巨噬细胞是与各种形式的肺动脉高压（PH）相关的肺部炎症的主要效应物。引导吞噬细胞浸润的CCL 2/CCR 2和CX 3CL 1/CX 3CR 1趋化因子系统之间的相互作用还不完全清楚。我们的目的是探讨CCL 2/CCR 2和CX 3CL 1/CX 3CR 1在缺氧诱导的小鼠PH中的单独和联合作用，特别是它们在单核细胞运输、巨噬细胞极化和肺血管重塑中的作用。缺氧诱导的PH的发展与肺中CX 3CR 1、CCR 2及其各自的配体CX 3CL 1和CCL 2水平的显著增加相关。流式细胞术显示，炎症性Ly 6C（hi）和常驻Ly 6C（lo）单核细胞亚群在血液中表现出持续增加，在肺组织中表现出短暂的峰值，肺血管周围和肺泡巨噬细胞计数显示持续升高。与野生型小鼠相比，CX 3CR（-/-）小鼠可免受缺氧PH的影响，而CCL.2（/）小鼠和双CX 3CR 1（/）/CCL 2（/）小鼠与野生型小鼠表现出相似的PH严重程度。CX 3CR 1缺乏的保护作用伴随着肺单核细胞和巨噬细胞计数的增加，并与从M2到M1的巨噬细胞极化的变化，显着降低了条件培养基诱导肺动脉平滑肌细胞（PA-SMC）增殖的能力，这是部分依赖于CX 3CL 1分泌。给予CX 3CR 1抑制剂F1的小鼠的结果与CX 3CR（-/-）小鼠的结果相似。总之，CX 3CR 1缺陷通过调节单核细胞募集、巨噬细胞极化和PA-SMC细胞增殖来保护缺氧诱导的PH。靶向CX 3CR 1可能有望治疗PH。
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-inducedPHwas associated with marked increases in lung levels of CX3CR1, CCR2, and their respective ligands, CX3CL1 and CCL2. Flow cytometry revealed that both inflammatory Ly6C(hi) and resident Ly6C(lo) 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. CX3CR(-/-) mice were protected against hypoxic PH compared with wild-type mice, whereas CCL.2(/) 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 CX3CR(-/-) 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.