CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels
CCR2-positive monocytes recruited to inflamed lungs downregulate local CCL2 chemokine levels
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DOI：
10.1152/ajplung.00061.2004
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发表时间：
2005-02-01
影响因子：
4.9
通讯作者：
Lohmeyer, J
中科院分区：
文献类型：
--
作者：
Maus, UA;Wellmann, S;Lohmeyer, J
CC趋化因子配体-2（CCL 2）及其受体CCR 2对于炎症条件下的单核细胞运输是必需的。然而，确定炎症肺中响应于CCL 2梯度的肺泡单核细胞积聚的强度和持续时间的机制尚未得到解决。为了确定表达CCR 2的单核细胞在调节肺泡CCL 2水平中的潜在作用，我们比较了白细胞募集动力学和肺泡CCL 2水平在野生型和CCR 2缺陷小鼠中对内毒素攻击的反应。在野生型小鼠中，LPS引起了剂量和时间依赖性的肺泡单核细胞积累，伴随着支气管肺泡灌洗液（BALF）中的低CCL 2水平。相反，LPS处理的CCR 2缺陷小鼠缺乏肺泡单核细胞积聚，这伴随着BALF中相对高的CCL 2水平。类似地，用阻断性抗CCR 2抗体MC 21全身治疗的野生型小鼠完全缺乏LPS诱导的肺泡单核细胞运输，这与BALF中的高CCL 2水平相关。肺内应用抗CCR 2抗体MC 21局部阻断驻留细胞和募集细胞上的CCR 2不影响LPS诱导的肺泡单核细胞运输，但导致BALF CCL 2水平显著增加。相反骨髓移植，LPS治疗的野生型和CCR 2缺陷型小鼠肺泡单核细胞募集和BALF CCL 2水平之间呈严格的负相关关系。此外，新鲜分离的人和小鼠单核细胞能够在体外整合CCL 2。LPS诱导的肺泡单核细胞积聚伴随着肺中CCL 2水平的单核细胞CCR 2依赖性消耗。这种反馈回路可能限制单核细胞募集到发炎肺的强度，并在维持体内平衡中发挥作用。
The CC chemokine ligand-2 (CCL2) and its receptor CCR2 are essential for monocyte trafficking under inflammatory conditions. However, the mechanisms that determine the intensity and duration of alveolar monocyte accumulation in response to CCL2 gradients in inflamed lungs have not been resolved. To determine the potential role of CCR2-expressing monocytes in regulating alveolar CCL2 levels, we compared leukocyte recruitment kinetics and alveolar CCL2 levels in wild-type and CCR2-deficient mice in response to intratracheal LPS challenge. In wild-type mice, LPS elicited a dose- and time-dependent alveolar monocyte accumulation accompanied by low CCL2 levels in bronchoalveolar lavage fluid (BALF). In contrast, LPS-treated CCR2-deficient mice lacked alveolar monocyte accumulation, which was accompanied by relatively high CCL2 levels in BALF. Similarly, wild-type mice that were treated systemically with the blocking anti-CCR2 antibody MC21 completely lacked LPS-induced alveolar monocyte trafficking that was associated with high CCL2 levels in BALF. Intratracheal application of anti-CCR2 antibody MC21 to locally block CCR2 on both resident and recruited cells did not affect LPS-induced alveolar monocyte trafficking but led to significantly increased BALF CCL2 levels. Reciprocally bone marrow-transplanted, LPS-treated wild-type and CCR2-deficient mice showed a strict inverse relationship between alveolar monocyte recruitment and BALF CCL2 levels. In addition, freshly isolated human and mouse monocytes were capable of integrating CCL2 in vitro. LPS-induced alveolar monocyte accumulation is accompanied by monocytic CCR2-dependent consumption of CCL2 levels in the lung. This feedback loop may limit the intensity of monocyte recruitment to inflamed lungs and play a role in the maintenance of homeostasis.