The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues.
The Proinflammatory Cytokine IL-36γ Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues.
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DOI：
10.1016/j.celrep.2020.108515
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发表时间：
2020-12-15
期刊：
影响因子：
8.8
通讯作者：
Stacey M
中科院分区：
文献类型：
--
作者：
Macleod T;Ainscough JS;Hesse C;Konzok S;Braun A;Buhl AL;Wenzel J;Bowyer P;Terao Y;Herrick S;Wittmann M;Stacey M
上皮组织代表生物体与其环境之间的重要界面。由于它们不断暴露于有害的病原体、无害的微生物和环境微生物中，它们必须感知并对这些不同类型的微生物做出适当的反应。在这里，我们证明了上皮细胞因子白细胞介素-36 γ（IL-36γ）通过细胞损伤和蛋白水解激活作为致病和无害微生物的全球性屏障。我们发现，细胞内的pro-IL-36γ被真菌和细菌上皮微生物上调;然而，它仅从细胞中释放，随后通过病原体介导的细胞损伤和病原体衍生的蛋白酶加工成其成熟的、有效的促炎形式。这项工作表明，IL-36γ感知病原体诱导的细胞损伤和蛋白水解活性，并且是上皮组织内免疫应答和病理性炎症的关键引发剂。作为一种位于顶端的上皮促炎细胞因子，我们因此提出IL-36γ作为上皮组织内无害微生物和侵入性病原体的初始屏障是至关重要的。上皮病原体诱导IL-36γ的表达和释放几种上皮病原体分泌的蛋白酶激活IL-36γ烟曲霉和化脓性链球菌毒力因子Asp F13和SpeB激活IL-36γ IL-36γ是上皮感染期间病原体衍生的蛋白酶的全局传感器麦克劳德et al.表明上皮细胞因子IL-36γ在上皮屏障处区分病原体和无害的病原体。IL-36γ在微生物攻击后被上皮组织上调，但它仅被破坏性病原微生物释放和激活，因此它启动免疫应答。
Epithelial tissues represent vital interfaces between organisms and their environment. As they are constantly exposed to harmful pathogens, innocuous commensals, and environmental microbes, it is essential they sense and elicit appropriate responses toward these different types of microbes. Here, we demonstrate that the epithelial cytokine interleukin-36γ (IL-36γ) acts as a global discriminator of pathogenic and harmless microbes via cell damage and proteolytic activation. We show that intracellular pro-IL-36γ is upregulated by both fungal and bacterial epithelial microbes; yet, it is only liberated from cells, and subsequently processed to its mature, potent, proinflammatory form, by pathogen-mediated cell damage and pathogen-derived proteases. This work demonstrates that IL-36γ senses pathogen-induced cell damage and proteolytic activity and is a key initiator of immune responses and pathological inflammation within epithelial tissues. As an apically located epithelial proinflammatory cytokine, we therefore propose that IL-36γ is critical as the initial discriminator of harmless microbes and invasive pathogens within epithelial tissues. Epithelial pathogens induce expression and release of IL-36γ Proteases secreted by several epithelial pathogens activate IL-36γ The A. fumigatus and S. pyogenes virulence factors Asp F13 and SpeB activate IL-36γ IL-36γ is a global sensor of pathogen-derived proteases during epithelial infection Macleod et al. demonstrate that the epithelial cytokine IL-36γ discriminates between pathogens and harmless commensals at epithelial barriers. IL-36γ is upregulated by epithelial tissue following microbial challenge, but it is only released and activated by destructive pathogenic microbes, whereupon it initiates an immune response.
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DOI：
10.4049/jimmunol.1301481
发表时间：
2014-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Foster AM;Baliwag J;Chen CS;Guzman AM;Stoll SW;Gudjonsson JE;Ward NL;Johnston A
通讯作者：
Johnston A
影响因子：
4.6
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Macleod T;Doble R;McGonagle D;Wasson CW;Alase A;Stacey M;Wittmann M
通讯作者：
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DOI：
10.4049/jimmunol.1003162
发表时间：
2011-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
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通讯作者：
Gudjonsson JE
影响因子：
4.6
作者：
Boutet, M. -A.;Bart, G.;Blanchard, F.
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Blanchard, F.
DOI：
10.1084/jem.81.6.573
发表时间：
1945-06-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Elliott SD
通讯作者：
Elliott SD