Molecular Imaging of Folate Receptor β-Positive Macrophages during Acute Lung Inflammation
Molecular Imaging of Folate Receptor β-Positive Macrophages during Acute Lung Inflammation
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DOI：
10.1165/rcmb.2014-0289oc
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发表时间：
2015-07-01
影响因子：
6.4
通讯作者：
Blackwell, Timothy S.
中科院分区：
文献类型：
--
作者：
Han, Wei;Zaynagetdinov, Rinat;Blackwell, Timothy S.
鉴定活化的巨噬细胞的标志物的表征可以促进对炎性肺病的理解，并促进用于监测疾病活动的新方法的开发。我们研究了在大肠杆菌LPS诱导的急性炎症过程中，叶酸受体β（FR β）表达是否可用于识别和定量肺中活化的巨噬细胞。我们发现，肺内注射LPS后48小时，肺巨噬细胞中FR β的表达显著增加。用荧光探针（花青5聚乙二醇叶酸酯）进行的体内分子成像显示，胸腔内LPS后48小时荧光信号达到峰值，巨噬细胞耗竭后荧光信号明显减弱。使用流式细胞术，我们鉴定了负责摄取菁5-结合叶酸的细胞为FR β（+）间质巨噬细胞和肺单核细胞，它们共表达与M1促炎巨噬细胞表型相关的标志物。这些发现通过在气道上皮中诱导NF-κ B激活剂的转基因表达产生的第二种急性肺部炎症模型得到证实。使用CC趋化因子受体2缺陷小鼠，我们发现FR β（+）巨噬细胞/单核细胞募集依赖于单核细胞趋化蛋白-1/CC趋化因子受体2途径。总之，我们的研究结果表明，叶酸为基础的分子成像可以作为一种非侵入性的方法来检测经典激活的单核细胞/巨噬细胞招募到肺部急性炎症。
Characterization of markers that identify activated macrophages could advance understanding of inflammatory lung diseases and facilitate development of novel methodologies for monitoring disease activity. We investigated whether folate receptor beta(FR beta) expression could be used to identify and quantify activated macrophages in the lungs during acute inflammation induced by Escherichia coli LPS. We found that FR beta expression was markedly increased in lung macrophages at 48 hours after intratracheal LPS. In vivo molecular imaging with a fluorescent probe (cyanine 5 polyethylene glycol folate) showed that the fluorescence signal over the chest peaked at 48 hours after intratracheal LPS and was markedly attenuated after depletion of macrophages. Using flow cytometry, we identified the cells responsible for uptake of cyanine 5-conjugated folate as FR beta(+) interstitial macrophages and pulmonary monocytes, which coexpressed markers associated with an M1 proinflammatory macrophage phenotype. These findings were confirmed using a second model of acute lung inflammation generated by inducible transgenic expression of an NF-kappa B activator in airway epithelium. Using CC chemokine receptor 2-deficient mice, we found that FR beta(+) macrophage/monocyte recruitment was dependent on the monocyte chemotactic protein-1/CC chemokine receptor 2 pathway. Together, our results demonstrate that folate-based molecular imaging can be used as a noninvasive approach to detect classically activated monocytes/macrophages recruited to the lungs during acute inflammation.