Pathogenic Fungus Microsporum canis Activates the NLRP3 Inflammasome
Pathogenic Fungus Microsporum canis Activates the NLRP3 Inflammasome
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病原真菌犬小孢子菌激活 NLRP3 炎症小体
DOI：
10.1128/iai.01097-13
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发表时间：
2014-02-01
影响因子：
3.1
通讯作者：
Meng, Guangxun
中科院分区：
文献类型：
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作者：
Mao, Liming;Zhang, Liping;Meng, Guangxun
犬小孢子菌是一种在世界范围内引起动物和人类头癣的致病性真菌。犬支原体也会在免疫功能低下的患者中引起侵袭性感染。为了对抗病原真菌感染，宿主的先天免疫系统是第一道防线。作为先天免疫的一个重要分支，炎性小体是细胞内的多蛋白复合物，控制caspase-1的激活，caspase-1将促炎细胞因子IL-1β (IL-1β)切割成成熟的形式。为了确定炎症小体是否参与宿主对犬支原体感染的防御，我们用从头癣患者身上分离的犬支原体临床菌株挑战人类单核细胞THP-1细胞和小鼠树突状细胞。我们发现犬支原体感染可触发THP-1细胞和小鼠树突状细胞快速分泌IL-1β。此外，通过使用基因特异性shRNA和竞争性抑制剂，我们确定M. canis诱导的IL-1β分泌依赖于NLRP3。提出的NLRP3炎性小体激活途径，即组织蛋白酶B活性、K+外排和活性氧产生，都是犬支原体触发炎性小体激活所必需的。同时发现Syk、Dectin-1和Card9通过调节IL-1β前转录参与了M. canis诱导的IL-1β分泌。更重要的是，我们的数据显示，在体内，M. canis诱导的IL-1β的产生依赖于NLRP3炎性体。总之，本研究揭示了NLRP3炎症小体在宿主对犬支原体感染的先天免疫应答中发挥关键作用，我们的数据表明，由犬支原体感染引起的疾病可能通过调节炎症小体的激活来控制。
ABSTRACT Microsporum canis is a pathogenic fungus with worldwide distribution that causes tinea capitis in animals and humans. M. canis also causes invasive infection in immunocompromised patients. To defy pathogenic fungal infection, the host innate immune system is the first line of defense. As an important arm of innate immunity, the inflammasomes are intracellular multiprotein complexes that control the activation of caspase-1, which cleaves proinflammatory cytokine pro-interleukin-1β (IL-1β) into its mature form. To determine whether the inflammasome is involved in the host defense against M. canis infection, we challenged human monocytic THP-1 cells and mouse dendritic cells with a clinical strain of M. canis isolated from patients with tinea capitis. We found that M. canis infection triggered rapid secretion of IL-1β from both THP-1 cells and mouse dendritic cells. Moreover, by using gene-specific shRNA and competitive inhibitors, we determined that M. canis-induced IL-1β secretion was dependent on NLRP3. The pathways proposed for NLRP3 inflammasome activation, namely, cathepsin B activity, K+ efflux, and reactive oxygen species production, were all required for the inflammasome activation triggered by M. canis. Meanwhile, Syk, Dectin-1, and Card9 were found to be involved in M. canis-induced IL-1β secretion via regulation of pro-IL-1β transcription. More importantly, our data revealed that M. canis-induced production of IL-1β was dependent on the NLRP3 inflammasome in vivo. Together, this study unveils that the NLRP3 inflammasome exerts a critical role in host innate immune responses against M. canis infection, and our data suggest that diseases that result from M. canis infection might be controlled by regulating the activation of inflammasomes.