IL-4 Receptor-Alpha-Dependent Control of Cryptococcus neoformans in the Early Phase of Pulmonary Infection
IL-4 Receptor-Alpha-Dependent Control of Cryptococcus neoformans in the Early Phase of Pulmonary Infection
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DOI：
10.1371/journal.pone.0087341
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发表时间：
2014-01-27
期刊：
影响因子：
3.7
通讯作者：
Alber, Gottfried
中科院分区：
文献类型：
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作者：
Grahnert, Andreas;Richter, Tina;Alber, Gottfried
新型隐球菌是一种机会性真菌病原体，可引起免疫功能低下人群的肺部炎症和脑膜脑炎。此前我们发现，小鼠通过诱导肺白细胞介素（IL）-4Rα依赖性2型免疫反应而死于鼻内感染，而IL-12依赖性1型免疫反应则赋予抵抗力。在此介绍的实验中，IL-4R α(-/-) 小鼠在感染新型隐球菌后出乎意料地显示早期真菌控制能力下降，而野生型小鼠能够控制真菌生长，同时巨噬细胞和树突状细胞招募到感染部位的能力增强。 IL-4R α(-/-) 小鼠肺部巨噬细胞和树突状细胞募集的减少与 CCL2 和 CCL20 趋化因子的肺部表达减少有关。此外，与野生型小鼠相比，IL-4R α(-/-) 小鼠的 IFN-γ 和一氧化氮生成减少。为了直接研究导致 IFN-γ 产生减少的潜在机制，在 IL-4 存在的情况下用新型隐球菌刺激常规树突状细胞，导致 IL-12 产生增加并减少 IL-10 产生。总之，早期 IL-4R α 信号传导在肺隐球菌病中发挥有益作用，这与众所周知的后期 IL-4R α 介导的有害作用形成鲜明对比。
Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4R alpha-dependent type 2 immune responses, whereas IL-12-dependent type 1 responses confer resistance. In the experiments presented here, IL-4R alpha(-/-) mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4R alpha(-/-) mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-gamma and nitric oxide production are diminished in IL-4R alpha(-/-) mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-gamma, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4R alpha signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4R alpha-mediated detrimental effects in the late phase.