Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.
Differential activation of airway eosinophils induces IL-13-mediated allergic Th2 pulmonary responses in mice.
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作者：
Jacobsen EA;Doyle AD;Colbert DC;Zellner KR;Protheroe CA;LeSuer WE;Lee NA;Lee JJ
嗜酸性粒细胞是过敏性Th2呼吸道炎症的标志细胞。然而，嗜酸性粒细胞激活和诱导效应功能(如IL-13的表达)在过敏性Th2肺病中的相对重要性仍有待确定。通过建立呼吸道炎症模型，将经细胞因子(GM-−/−、IL-4、IL-33)处理的野生型或细胞因子缺陷型(IL-13-−/−或IL-4-CSF)嗜酸性粒细胞过继转移到嗜酸性粒细胞缺陷受体小鼠体内。对过敏原诱导的肺部改变进行评估。与将未经处理的嗜酸性粒细胞转移到受体嗜酸性粒细胞缺陷小鼠的肺中不会在肺或肺引流淋巴结(LDLN)中引起免疫/炎症变化相反，在转移之前用GM-CSF对血液中的嗜酸性粒细胞进行预处理会引起这些嗜酸性粒细胞向LDLN的转移。反过来，这些LDLN嗜酸性粒细胞诱导树突状细胞和CD4+T细胞聚集到这些相同的LDLN，而不会引起肺部炎症。然而，嗜酸性粒细胞在转移前暴露于GM-CSF、IL-4和IL-33不仅诱导了LDLN中的免疫事件，而且还诱导了变应原介导的气道Th2细胞因子/趋化因子水平的增加，随后CD4+T细胞和交替激活的(M2)巨噬细胞聚集，并诱导了肺组织病理学。值得注意的是，这种过敏性呼吸道炎症依赖于嗜酸性粒细胞来源的IL-13，而嗜酸性粒细胞表达的IL-4没有显著作用。这些数据表明，嗜酸性粒细胞的不同激活是细胞因子暴露的函数，并提示活化细胞的嗜酸性粒细胞特异性IL-13的表达是随后的过敏性Th2肺病理的必要组成部分。
Eosinophils are hallmark cells of allergic Th2 respiratory inflammation. However, the relative importance of eosinophil activation and the induction of effector functions such as the expression of IL-13 to allergic Th2 pulmonary disease remain to be defined. Wild type or cytokine deficient (IL-13−/− or IL-4−/−) eosinophils treated with cytokines (GM-CSF, IL-4, IL-33) were adoptively transferred into eosinophil-deficient recipient mice subjected to allergen provocation using established models of respiratory inflammation. Allergen-induced pulmonary changes were assessed. In contrast to the transfer of untreated blood eosinophils to the lungs of recipient eosinophildeficient mice, which induced no immune/inflammatory changes either in the lung or lung draining lymph nodes (LDLNs), pretreatment of blood eosinophils with GM-CSF prior to transfer elicited trafficking of these eosinophils to LDLNs. In turn, these LDLN eosinophils elicited the accumulation of dendritic cells and CD4+ T cells to these same LDLNs without inducing pulmonary inflammation. However, exposure of eosinophils to GM-CSF, IL-4 and IL-33 prior to transfer induced not only immune events in the LDLN, but also allergen-mediated increases in airway Th2 cytokine/chemokine levels, the subsequent accumulation of CD4+ T cells as well as alternatively activated (M2) macrophages, and the induction of pulmonary histopathologies. Significantly, this allergic respiratory inflammation was dependent on eosinophil-derived IL-13 whereas IL-4 expression by eosinophils had no significant role. The data demonstrate the differential activation of eosinophils as a function of cytokine exposure and suggest that eosinophil-specific IL-13 expression by activated cells is a necessary component of the subsequent allergic Th2 pulmonary pathologies.