The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis
The role of CC chemokine receptor 6 in host defense in a model of invasive pulmonary aspergillosis
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DOI：
10.1164/rccm.200602-256oc
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发表时间：
2007-06-01
影响因子：
24.7
通讯作者：
Mehrad, Borna
中科院分区：
文献类型：
--
作者：
Phadke, Anagha P.;Akangire, Gangaram;Mehrad, Borna
理由：侵袭性曲霉病是一种严重的真菌感染，影响免疫功能低下患者，特别是中性粒细胞缺陷患者。CCR6是一种β趋化因子受体，介导树突状细胞（dc）和几种淋巴细胞亚群向上皮炎症部位的迁移，但其在感染中的作用尚未得到广泛研究。目的：验证ccr6介导的白细胞募集是侵袭性肺曲霉病神经营养减少宿主有效防御所必需的假设。方法：采用嗜中性粒细胞减少野生型小鼠和CCR6靶向缺失小鼠感染烟曲霉。在体内比较了宿主对感染的反应，并在体外检测了白细胞对真菌的反应。测量结果和主要结果：在感染的情况下，未成熟髓系dc是肺中表达ccr6细胞的主要群体。与野生型动物相比，ccr6缺陷小鼠在感染分生烟曲霉时发生更严重的感染，死亡率更高，肺部真菌负担更重。这与肺中dc的积累减少有关。ccr6缺陷型和野生型dc在分生孢子吞噬、细胞因子反应或体外成熟方面没有差异。然而，在过继性移植实验中，与野生型细胞相比，来自ccr6缺陷供体的dc在感染小鼠肺部的积累较少，并且野生型而非ccr6缺陷供体的dc的转移导致ccr6缺陷受体感染的严重程度减轻。结论：综上所述，这些结果暗示ccr6介导的DC内流进入肺部在侵袭性曲霉病的初始宿主防御中。
Rationale: Invasive aspergillosis is a severe fungal infection afflicting immunocompromised patients, particularly patients with neutrophil defects. CCR6, a beta-chemokine receptor, mediates migration of dendritic cells (DCs) and several lymphocyte subsets to sites of epithelial inflammation, but its role in infections has not been examined extensively.Objectives: To test the hypothesis that CCR6-mediated leukocyte recruitment is necessary for effective host defense in neurtropenic hosts with invasive pulmonary aspergillosis.Methods: Neutropenic wild-type mice and mice with targeted deletion of CCR6 were infected with Aspergillus fumigatus. The host responses to the infection were compared in vivo and leukocyte responses to the fungus were examined in vitro.Measurements and Main Results: In the context of infection, immature myeloid DCs were the major population of CCR6-expressing cells in the lungs. As compared with wild-type animals, CCR6-deficient mice developed a more severe infection when challenged with A. fumigatus conidia, as documented by a higher mortality rate and greater lung fungal burden. This was associated with reduced accumulation of DCs in the lungs. CCR6-deficient and wild-type DCs did not differ in their phagocytosis of conidia, cytokine response, or maturation in vitro. In adoptive transfer experiments, however, DCs from CCR6-deficient donors showed lesser accumulation in the lungs of infected mice as compared with wild-type cells, and transfer of wild-type, but not CCR6-deficient, DCs resulted in attenuated severity of infection in CCR6-deficient recipients.Conclusions: Taken together, these results implicate CCR6-mediated DC influx into the lung in the initial host defense in invasive aspergillosis.