Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile.
Inflammasome activation contributes to interleukin-23 production in response to Clostridium difficile.
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DOI：
10.1128/mbio.02386-14
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发表时间：
2015-01-27
期刊：
影响因子：
6.4
通讯作者：
Petri WA Jr
中科院分区：
文献类型：
--
作者：
Cowardin CA;Kuehne SA;Buonomo EL;Marie CS;Minton NP;Petri WA Jr
艰难梭菌是最常见的医院获得性病原体，在美国每年在超过250，000名患者中引起腹泻相关性腹泻。疾病主要由毒素A和B介导，毒素A和B在宿主细胞中诱导有效的促炎信号传导，并可激活含ASC的炎性体。最近的研究结果表明，宿主对感染的反应强度与疾病的严重程度相关。我们的实验室已经确定了促炎细胞因子白细胞介素-23（IL-23）作为艰难梭菌感染（CDI）过程中的致病介质。然而，艰难梭菌诱导IL-23的机制还不清楚，毒素A和B在该过程中的作用也不清楚。在这里，我们表明毒素A和B单独不足以产生IL-23，但协同增加响应MyD 88依赖性危险信号产生的IL-23的量，包括病原体相关分子模式（PAMP）和宿主衍生的损伤相关分子模式（DAMP）。危险信号还增强了对毒素A和B的应答中IL-1β的分泌，并且随后的IL-1受体信号传导占毒素存在下发生的IL-23增加的大部分。在细胞外K+存在下抑制炎性小体活化同样降低IL-23的产生。最后，我们发现CDI患者血清中的IL-1β增加，这表明这种全身反应可能会影响致病性IL-23的下游产生。危险信号与毒素A和B通过炎性体信号传导的协同作用的鉴定代表了对艰难梭菌诱导的炎症的机制理解中的新发现。艰难梭菌是由于医疗保健相关感染导致死亡的主要原因之一，并且决定疾病严重程度的因素尚未得到很好的理解。艰难梭菌分泌毒素A和B，这会导致炎症和组织损伤，最近的研究结果表明，这种组织损伤中的一些可能是由于不适当的宿主免疫反应。我们已经发现毒素A和B与细菌和宿主来源的危险信号组合，可以诱导促炎细胞因子IL-1β和IL-23的表达。我们的研究结果表明，IL-1β信号转导增强了IL-23的产生，并可能导致CDI期间致病性炎症增加。
Clostridium difficile is the most common hospital-acquired pathogen, causing antibiotic-associated diarrhea in over 250,000 patients annually in the United States. Disease is primarily mediated by toxins A and B, which induce potent proinflammatory signaling in host cells and can activate an ASC-containing inflammasome. Recent findings suggest that the intensity of the host response to infection correlates with disease severity. Our lab has identified the proinflammatory cytokine interleukin-23 (IL-23) as a pathogenic mediator during C. difficile infection (CDI). The mechanisms by which C. difficile induces IL-23, however, are not well understood, and the role of toxins A and B in this process is unclear. Here, we show that toxins A and B alone are not sufficient for IL-23 production but synergistically increase the amount of IL-23 produced in response to MyD88-dependent danger signals, including pathogen-associated molecular patterns (PAMPs) and host-derived damage associated molecular patterns (DAMPs). Danger signals also enhanced the secretion of IL-1β in response to toxins A and B, and subsequent IL-1 receptor signaling accounted for the majority of the increase in IL-23 that occurred in the presence of the toxins. Inhibition of inflammasome activation in the presence of extracellular K+ likewise decreased IL-23 production. Finally, we found that IL-1β was increased in the serum of patients with CDI, suggesting that this systemic response could influence downstream production of pathogenic IL-23. Identification of the synergy of danger signals with toxins A and B via inflammasome signaling represents a novel finding in the mechanistic understanding of C. difficile-induced inflammation. Clostridium difficile is among the leading causes of death due to health care-associated infection, and factors determining disease severity are not well understood. C. difficile secretes toxins A and B, which cause inflammation and tissue damage, and recent findings suggest that some of this tissue damage may be due to an inappropriate host immune response. We have found that toxins A and B, in combination with both bacterium- and host-derived danger signals, can induce expression of the proinflammatory cytokines IL-1β and IL-23. Our results demonstrate that IL-1β signaling enhances IL-23 production and could lead to increased pathogenic inflammation during CDI.