Recruited Exudative Macrophages Selectively Produce CXCL10 Following Noninfectious Lung Injury
Recruited Exudative Macrophages Selectively Produce CXCL10 Following Noninfectious Lung Injury
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DOI：
10.1165/rcmb.2010-0471oc
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发表时间：
2011-10-01
影响因子：
6.4
通讯作者：
Noble, Paul W.
中科院分区：
文献类型：
--
作者：
Tighe, Robert M.;Liang, Jiurong;Noble, Paul W.
趋化因子CXCL 10及其同源受体CXCR 3是肺纤维化病理生物学的重要介质。巨噬细胞是CXCL 10的已知来源，但由于巨噬细胞亚群的不完全表征，其在肺中的具体来源定义不清楚。我们最近开发了一种新的流式细胞术的方法，区分居民肺泡巨噬细胞从招募渗出性巨噬细胞（ExMacs）感染性肺损伤后。我们假设ExMacs在博莱霉素非感染性肺损伤后存在，并且是CXCL 10的来源。我们发现，ExMac在损伤后被募集到肺中，在第7天达到峰值，然后维持到第28天。在CCR 2缺失小鼠中，ExMac募集显著减少，但未消除。ExMacs，而不是肺泡巨噬细胞，产生CXCL 10，无论是组成性的和刺激后的透明质酸（HA）片段。有趣的是，用LPS刺激ExMac导致CXCL 10的完全抑制。相比之下，ExMacs在用HA和LPS两者刺激后产生TNF-α和CXCL 2/MIP-2（巨噬细胞炎性蛋白-2）。博来霉素后，ExMac存在于CXCR 3缺失小鼠中，但产生最少的CXCL 10。通过给予外源性IFN-γ或IFN-γ与HA克服了这种损害。总的来说，这些数据表明，ExMac在非感染性肺损伤后在肺中被募集和维持，是多种细胞因子的来源，但重要的是，对于抗纤维化CXCL 10的产生是必需的。了解ExMacs对肺损伤和修复的病理生物学的贡献可能会为纤维化肺病带来新的治疗选择。
The chemokine, CXCL10, and its cognate receptor, CXCR3, are important mediators of the pathobiology of lung fibrosis. Macrophages are a known source of CXCL10, but their specific source in the lung is poorly defined due to incomplete characterization of macrophage subpopulations. We recently developed a novel flow cytometric approach that discriminates resident alveolar macrophages from recruited exudative macrophages (ExMacs) after infectious lung injury. We hypothesized that ExMacs are present after noninfectious lung injury with bleomycin, and are a source of CXCL10. We found that ExMacs are recruited to the lung after injury, peaking at Day 7, then maintained through Day 28. ExMac recruitment was significantly reduced, but not abolished, in CCR2 null mice. ExMacs, but not alveolar macrophages, produce CXCL10, both constitutively and after stimulation with hyaluronan (HA) fragments. Interestingly, ExMac stimulation with LPS resulted in complete suppression of CXCL10. In contrast, ExMacs produced TNF-alpha and CXCL2/MIP-2 (Macrophage Inflammatory Protein-2) after stimulation with both HA and LPS. ExMacs were present in CXCR3 null mice after bleomycin, but produced minimal CXCL10. This impairment was overcome by administration of exogenous IFN-gamma or IFN-gamma with HA. Collectively, these data suggest that ExMacs are recruited and maintained in the lung after noninfectious lung injury, are a source of a variety of cytokines, but importantly, are essential for the production of antifibrotic CXCL10. Understanding the contribution of ExMacs to the pathobiology of lung injury and repair could lead to new treatment options for fibrosing lung diseases.