Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium
Attenuation of Intestinal Inflammation in Interleukin-10-Deficient Mice Infected with Citrobacter rodentium
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DOI：
10.1128/iai.00066-14
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发表时间：
2014-05-01
影响因子：
3.1
通讯作者：
Eckmann, Lars
中科院分区：
文献类型：
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作者：
Dann, Sara M.;Le, Christine;Eckmann, Lars
白细胞介素-10（IL-10）减少对微生物感染和自身抗原的免疫应答，并有助于肠道免疫稳态，但IL-10的给药在减轻慢性肠道炎症性疾病方面并不有效，这表明其免疫功能可能是环境依赖性的。为了更广泛地了解IL-10在控制粘膜免疫应答中对感染性挑战的重要性，我们采用了小鼠附着和消除病原体啮齿类柠檬酸杆菌，其主要定植于盲肠和结肠的表面，并引起由Th17和Th1辅助性T细胞驱动的短暂粘膜炎症。感染诱导巨噬细胞和树突状细胞产生IL-10，这削弱了抗菌宿主防御，因为IL-10缺陷小鼠清除感染的速度比野生型对照组快。与此同时，小鼠的急性感染相关性结肠炎较少，并且比对照组更快地解决了它。重要的是，瞬时C.啮齿动物感染保护IL-10缺陷小鼠免于自发性结肠炎的后期发展，所述自发性结肠炎通常在这些小鼠中随着年龄增长而发生。全基因组表达研究表明，IL-10缺乏与促炎途径的下调有关，但与抗炎细胞因子IL-27的表达增加有关。发现IL-27抑制体外Th17，并且在较小程度上抑制独立于IL-10的Th1分化。此外，IL-27的中和导致感染的IL-10缺陷小鼠中更严重的结肠炎。总之，这些发现表明IL-10对于解决C.啮齿动物相关性结肠炎，并进一步表明IL-27可能是控制肠道炎症和Th17和Th1发展的关键因素，通过IL-10非依赖性机制。
Interleukin-10 (IL-10) curtails immune responses to microbial infection and autoantigens and contributes to intestinal immune homeostasis, yet administration of IL-10 has not been effective at attenuating chronic intestinal inflammatory conditions, suggesting that its immune functions may be context dependent. To gain a broader understanding of the importance of IL-10 in controlling mucosal immune responses to infectious challenges, we employed the murine attaching and effacing pathogen Citrobacter rodentium, which colonizes primarily the surfaces of the cecum and colon and causes transient mucosal inflammation driven by Th17 and Th1 T helper cells. Infection induced macrophage and dendritic cell production of IL-10, which diminished antibacterial host defenses, because IL-10-deficient mice cleared infection faster than wild-type controls. In parallel, the mice had less acute infection-associated colitis and resolved it more rapidly than controls. Importantly, transient C. rodentium infection protected IL-10-deficient mice against the later development of spontaneous colitis that normally occurs with aging in these mice. Genome-wide expression studies revealed that IL-10 deficiency was associated with downregulation of proinflammatory pathways but increased expression of the anti-inflammatory cytokine IL-27 in response to infection. IL-27 was found to suppress in vitro Th17 and, to a lesser degree, Th1 differentiation independent of IL-10. Furthermore, neutralization of IL-27 resulted in more severe colitis in infected IL-10-deficient mice. Together, these findings indicate that IL-10 is dispensable for resolving C. rodentium-associated colitis and further suggest that IL-27 may be a critical factor for controlling intestinal inflammation and Th17 and Th1 development by IL-10-independent mechanisms.