JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression.
JNK1 negatively controls antifungal innate immunity by suppressing CD23 expression.
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JNK1 通过抑制 CD23 表达负向控制抗真菌先天免疫
DOI：
10.1038/nm.4260
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发表时间：
2017-03
期刊：
影响因子：
82.9
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Zhao X;Guo Y;Jiang C;Chang Q;Zhang S;Luo T;Zhang B;Jia X;Hung MC;Dong C;Lin X
真菌感染是导致免疫功能低下患者死亡的主要原因，由于目前抗真菌药物的毒性和耐药性，迫切需要开发新的抗真菌治疗剂。虽然C型凝集素受体和Toll样受体诱导的信号通路是宿主抗真菌免疫的关键激活剂，但对这些免疫应答的负调控知之甚少。在这里，我们发现JNK1激活抑制小鼠的抗真菌免疫。我们发现JNK1缺陷小鼠在应对白色念珠菌感染时具有显著更高的存活率，并且在造血先天免疫细胞中表达的JNK1对此效应至关重要。JNK1缺陷导致显著更高的诱导CD23，一种新的C型凝集素受体，通过NFATc1介导的调节CD23启动子。阻断CD23上调或CD23依赖性一氧化氮的产生消除了JNK1缺陷小鼠中增强的抗真菌作用。值得注意的是，JNK抑制剂在白色念珠菌感染的小鼠和人细胞中发挥了有效的抗真菌治疗作用，表明JNK1可以成为治疗真菌感染的治疗靶点。
Opportunistic fungal infections are a leading cause of death for immune-compromised patients and there is pressing need to develop new anti-fungal therapeutic agents because of toxicity and resistance to current anti-fungal drugs. Although C-type lectin receptor- and Toll-like receptor-induced signaling pathways are key activators of host anti-fungal immunity, little is known about the negative regulation of these immune responses. Here, we found that JNK1 activation suppresses anti-fungal immunity in mice. We showed that JNK1-deficient mice had significantly higher survival rate in response to Candida albicans infection, and JNK1 expressed in hematopoietic innate immune cells is critical for this effect. JNK1 deficiency leads to significantly higher induction of CD23, a novel C-type lectin receptor, through NFATc1-mediated regulation of the CD23 promoter. Blocking CD23 upregulation or CD23-dependent nitric oxide production eliminated the enhanced anti-fungal effect in JNK1-deficient mice. Notably, JNK inhibitors exerted potent anti-fungal therapeutic effects in Candida albicans-infected mouse and human cells, indicating that JNK1 can be a therapeutic target for treating fungal infection.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
9
作者：
Plato, Anthony;Hardison, Sarah E.;Brown, Gordon D.
通讯作者：
Brown, Gordon D.
影响因子：
5.6
作者：
Romero-Puertas MC;Sandalio LM
通讯作者：
Sandalio LM
影响因子：
30.3
作者：
Ersland K;Wüthrich M;Klein BS
通讯作者：
Klein BS
DOI：
10.1016/j.bbapap.2009.11.002
发表时间：
2010-03-01
影响因子：
3.2
作者：
Bogoyevitch, Marie A.;Ngoei, Kevin R. W.;Ng, Dominic C. H.
通讯作者：
Ng, Dominic C. H.