CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment
CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment
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DOI：
10.1038/s41590-019-0377-2
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发表时间：
2019-05-01
影响因子：
30.5
通讯作者：
Lionakis, Michail S.
中科院分区：
文献类型：
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作者：
Drummond, Rebecca A.;Swamydas, Muthulekha;Lionakis, Michail S.
C型凝集素受体-Syk（脾酪氨酸激酶）衔接子CARD 9促进中枢神经系统（CNS）内的保护性抗真菌免疫，因为CARD 9的人类缺陷导致对真菌特异性CNS靶向感染的易感性。CARD 9促进中性粒细胞向真菌感染的CNS的募集，其介导真菌清除。在本研究中，我们调查了宿主和病原体的因素，促进保护中性粒细胞的招聘过程中入侵的中枢神经系统的白色念珠菌。细胞因子IL-1 β通过驱动趋化因子CXCL 1的产生在CNS抗真菌免疫中发挥重要作用，趋化因子CXCL 1募集表达趋化因子受体CXCR 2的中性粒细胞。在小胶质细胞中，由真菌分泌的毒素巨噬细胞溶素以依赖于激酶p38和转录因子c-Fos的方式诱导IL-1 β和CXCL 1的中性粒细胞募集产生。值得注意的是，小胶质细胞依赖于CARD 9产生IL-1 β，通过转录调节IL 1b和炎性小体激活，以及真菌感染的CNS中的CXCL 1。小胶质细胞特异性Card 9缺失损害了IL-1 β和CXCL 1的产生以及中性粒细胞的募集，并增加了CNS中的真菌增殖。因此，宿主-病原体相互作用的复杂网络促进CNS中的抗真菌免疫;这在CARD 9的人类缺陷中受损，这导致CNS的真菌疾病。
The C-type lectin receptor-Syk (spleen tyrosine kinase) adaptor CARD9 facilitates protective antifungal immunity within the central nervous system (CNS), as human deficiency in CARD9 causes susceptibility to fungus-specific, CNS-targeted infection. CARD9 promotes the recruitment of neutrophils to the fungus-infected CNS, which mediates fungal clearance. In the present study we investigated host and pathogen factors that promote protective neutrophil recruitment during invasion of the CNS by Candida albicans. The cytokine IL-1 beta served an essential function in CNS antifungal immunity by driving production of the chemokine CXCL1, which recruited neutrophils expressing the chemokine receptor CXCR2. Neutrophil-recruiting production of IL-1 beta and CXCL1 was induced in microglia by the fungus-secreted toxin Candidalysin, in a manner dependent on the kinase p38 and the transcription factor c-Fos. Notably, microglia relied on CARD9 for production of IL-1 beta, via both transcriptional regulation of Il1b and inflammasome activation, and of CXCL1 in the fungus-infected CNS. Microglia-specific Card9 deletion impaired the production of IL-1 beta and CXCL1 and neutrophil recruitment, and increased fungal proliferation in the CNS. Thus, an intricate network of host-pathogen interactions promotes antifungal immunity in the CNS; this is impaired in human deficiency in CARD9, which leads to fungal disease of the CNS.