A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans.
A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans.
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DOI：
10.1371/journal.ppat.1002379
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Hise AG
中科院分区：
文献类型：
--
作者：
Tomalka J;Ganesan S;Azodi E;Patel K;Majmudar P;Hall BA;Fitzgerald KA;Hise AG
念珠菌属是机会性真菌病原体，其定殖于皮肤和口腔，并且当在允许的条件下过度生长时，引起炎症和疾病。以前，我们确定了NLRP 3炎性体在调节IL-1β产生和抵抗口腔白色念珠菌感染传播中的核心作用。在这里，我们表明，粘膜表达的NLRP 3和NLRC 4诱导念珠菌感染，这些分子的上调受损NLRP 3和NLRC 4缺陷小鼠。此外，我们揭示了NLRC 4炎性体在抗真菌防御中的作用。NLRC 4对于控制粘膜念珠菌感染是重要的，并影响炎症细胞向感染组织的募集，以及防止感染的全身传播。NLRC 4或NLRP 3的缺乏导致口腔中的促炎和抗微生物肽应答严重减弱。使用骨髓嵌合小鼠模型，我们表明，在相反的NLRP 3，限制感染的严重程度时，无论是在造血或基质隔室，NLRC 4起着重要的作用，限制粘膜念珠菌病时，在粘膜基质的水平发挥作用。总的来说，这些研究揭示了NLRP 3和NLRC 4炎性体在针对粘膜念珠菌感染的先天免疫应答中的组织特异性作用。在这篇文章中，我们描述了一组称为“炎性体”的分子的新作用，这些分子处理包括白细胞介素-1-β在内的关键免疫应答蛋白。在以前的工作中，我们和其他人已经表明NLRP 3炎性体在保护免受严重真菌感染方面很重要。我们现在表明，除了NLRP 3炎性小体之外，含有NLRC 4的不同炎性小体在保护免受白色念珠菌感染方面也很重要，并且似乎在口腔和肠道的粘膜衬里中发挥作用，而不是在免疫细胞中。我们的研究解释了真菌感染的粘膜免疫的新机制，并对开发针对真菌感染的新治疗方法具有广泛的意义，真菌感染是疾病和死亡的严重原因，特别是在免疫功能低下的人中。此外，这项研究还可能导致新的方法来识别那些严重真菌感染风险最高的人。
Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β production and resistance to dissemination from oral infection with Candida albicans. Here we show that mucosal expression of NLRP3 and NLRC4 is induced by Candida infection, and up-regulation of these molecules is impaired in NLRP3 and NLRC4 deficient mice. Additionally, we reveal a role for the NLRC4 inflammasome in anti-fungal defenses. NLRC4 is important for control of mucosal Candida infection and impacts inflammatory cell recruitment to infected tissues, as well as protects against systemic dissemination of infection. Deficiency in either NLRC4 or NLRP3 results in severely attenuated pro-inflammatory and antimicrobial peptide responses in the oral cavity. Using bone marrow chimeric mouse models, we show that, in contrast to NLRP3 which limits the severity of infection when present in either the hematopoietic or stromal compartments, NLRC4 plays an important role in limiting mucosal candidiasis when functioning at the level of the mucosal stroma. Collectively, these studies reveal the tissue specific roles of the NLRP3 and NLRC4 inflammasome in innate immune responses against mucosal Candida infection. In this manuscript we describe a new role for a group of molecules termed the “inflammasome” that process key immune response proteins including interleukin-1-β. In previous work, we and others have shown that the NLRP3 inflammasome is important in protecting from severe fungal infections. We now show that, in addition to the NLRP3 inflammasome, a different inflammasome containing NLRC4 is also important in protecting against infection with Candida albicans, and appears to be functioning in the mucosal lining of the mouth and intestines, rather than in immune cells. Our research explains a new mechanism of mucosal immunity to fungal infections and has broad implications for developing new treatments against fungal infections, which are a serious cause of illness and death, particularly in immunocompromised persons. Additionally, this research may also lead to new ways to identify those individuals who are at the highest risk for serious fungal infections.
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影响因子：
30.5
作者：
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通讯作者：
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DOI：
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