Maus Ulrich A, Wellmann Sandra, Hampl Christine, Kuziel William A, Srivastava Mrigank, Mack Matthias, Everhart M Brett, Blackwell Timothy S, Christman John W, Schlöndorff Detlef, Bohle Rainer M, Seeger Werner, Lohmeyer Jürgen
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Justus-Liebig-University, Klinikstr. 36, Giessen 35392, Germany.
Am J Physiol Lung Cell Mol Physiol. 2005 Feb;288(2):L350-8. doi: 10.1152/ajplung.00061.2004. Epub 2004 Oct 29.
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.
CC趋化因子配体2（CCL2）及其受体CCR2在炎症条件下对单核细胞的迁移至关重要。然而，在炎症肺部中，响应CCL2梯度而决定肺泡单核细胞积聚强度和持续时间的机制尚未明确。为了确定表达CCR2的单核细胞在调节肺泡CCL2水平中的潜在作用，我们比较了野生型和CCR2缺陷型小鼠在气管内注射脂多糖（LPS）刺激后白细胞募集动力学和肺泡CCL2水平。在野生型小鼠中，LPS引发剂量和时间依赖性的肺泡单核细胞积聚，同时支气管肺泡灌洗液（BALF）中的CCL2水平较低。相比之下，LPS处理的CCR2缺陷型小鼠缺乏肺泡单核细胞积聚，同时BALF中的CCL2水平相对较高。同样，用抗CCR2阻断抗体MC21全身处理的野生型小鼠完全缺乏LPS诱导的肺泡单核细胞迁移，这与BALF中高CCL2水平相关。气管内应用抗CCR2抗体MC21以局部阻断驻留细胞和募集细胞上的CCR2，并不影响LPS诱导的肺泡单核细胞迁移，但导致BALF中CCL2水平显著升高。相互进行骨髓移植、LPS处理的野生型和CCR2缺陷型小鼠显示肺泡单核细胞募集与BALF中CCL2水平之间存在严格的反比关系。此外，新鲜分离的人和小鼠单核细胞能够在体外摄取CCL2。LPS诱导的肺泡单核细胞积聚伴随着肺中单核细胞CCR2依赖性CCL2水平的消耗。这种反馈回路可能会限制单核细胞向炎症肺部募集的强度，并在维持体内平衡中发挥作用。
