Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus
Dectin-1-Dependent Interleukin-22 Contributes to Early Innate Lung Defense against Aspergillus fumigatus
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DOI：
10.1128/iai.05939-11
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发表时间：
2012-01-01
影响因子：
3.1
通讯作者：
Steele, Chad
中科院分区：
文献类型：
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作者：
Gessner, Melissa A.;Werner, Jessica L.;Steele, Chad
我们之前报道过，缺乏β -葡聚糖受体Dectin-1的小鼠在肺中白细胞介素23 （IL-23）和IL-17A产生较低的情况下，对烟曲霉肺部感染的易感性增加，并报道了IL-17A在肺防御中的作用。由于IL-23也被认为控制IL-22的产生，我们研究了Dectin-1在IL-22产生中的作用，以及IL-22在天然宿主防御烟熏假单胞菌中的作用。在这里，我们发现dectin -1缺陷小鼠在烟曲霉攻击后早期肺部IL-22水平显着降低。体外培养的酶促肺消化细胞进一步证明了dectin -1依赖性IL-22的产生。另外发现IL-22的产生与IL-1 β、IL-6或IL-18无关，但需要IL-23。重组IL-23的加入增加了野生型（WT）肺细胞中IL-22的产生，并恢复了dectin -1缺失小鼠肺细胞中IL-22的产生。WT小鼠肺中IL-22的体内中和导致烟曲霉肺清除率受损。此外，在IL-1 β、肿瘤坏死因子α (tnf - α)、CCL3/MIP-1 α和CCL4/MIP-1 β生成受损、中性粒细胞募集减少、IL-17A生成完整的情况下，IL-22缺失的小鼠在烟曲霉攻击后也表现出更高的肺部真菌负荷。我们进一步表明，从烟曲霉感染的dectin -1缺陷和il -22缺陷小鼠中收集的肺灌洗液在体外对烟曲霉的抗真菌活性均受到损害。尽管我们观察到脂连蛋白2的产生依赖于Dectin-1和IL-22，但脂连蛋白2缺乏的小鼠并未表现出烟曲霉清除能力受损。此外，无论是dectin -1缺陷小鼠还是il -22缺陷小鼠，肺S100a8、S100a9和Reg3g mRNA的表达均未降低。总之，我们的研究结果表明，早期对烟曲霉的先天性肺防御是由dectin -1依赖性IL-22的产生介导的。
We have previously reported that mice deficient in the beta-glucan receptor Dectin-1 displayed increased susceptibility to Aspergillus fumigatus lung infection in the presence of lower interleukin 23 (IL-23) and IL-17A production in the lungs and have reported a role for IL-17A in lung defense. As IL-23 is also thought to control the production of IL-22, we examined the role of Dectin-1 in IL-22 production, as well as the role of IL-22 in innate host defense against A. fumigatus. Here, we show that Dectin-1-deficient mice demonstrated significantly reduced levels of IL-22 in the lungs early after A. fumigatus challenge. Culturing cells from enzymatic lung digests ex vivo further demonstrated Dectin-1-dependent IL-22 production. IL-22 production was additionally found to be independent of IL-1 beta, IL-6, or IL-18 but required IL-23. The addition of recombinant IL-23 augmented IL-22 production in wild-type (WT) lung cells and rescued IL-22 production by lung cells from Dectin-1-deficient mice. In vivo neutralization of IL-22 in the lungs of WT mice resulted in impaired A. fumigatus lung clearance. Moreover, mice deficient in IL-22 also demonstrated a higher lung fungal burden after A. fumigatus challenge in the presence of impaired IL-1 beta, tumor necrosis factor alpha (TNF-alpha), CCL3/MIP-1 alpha, and CCL4/MIP-1 beta production and lower neutrophil recruitment, yet intact IL-17A production. We further show that lung lavage fluid collected from both A. fumigatus-challenged Dectin-1-deficient and IL-22-deficient mice had compromised anti-fungal activity against A. fumigatus in vitro. Although lipocalin 2 production was observed to be Dectin-1 and IL-22 dependent, lipocalin 2-deficient mice did not demonstrate impaired A. fumigatus clearance. Moreover, lung S100a8, S100a9, and Reg3g mRNA expression was not lower in either Dectin-1-deficient or IL-22-deficient mice. Collectively, our results indicate that early innate lung defense against A. fumigatus is mediated by Dectin-1-dependent IL-22 production.