Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis
Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis
复制标题
DOI：
10.1038/mi.2015.67
复制
发表时间：
2016-03-01
影响因子：
8
通讯作者：
Winning, S.
中科院分区：
文献类型：
--
作者：
Flueck, K.;Breves, G.;Winning, S.
树突状细胞（Dendritic cells，DC）是连接先天免疫和适应性免疫的桥梁，有助于维持肠道内环境的稳定。炎症性肠病（IBD）与粘膜免疫反应失调有关。IBD中伴随的缺氧炎症将激活转录因子缺氧诱导因子-1（HIF-1），从而也驱动DC中的基因表达。最近的研究已经描述了上皮HIF-1在IBD小鼠模型中的保护作用。我们在葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中研究了HIF-1在DC功能中的作用。野生型和树突细胞特异性HIF-1 α敲除小鼠用3%DSS处理7天。DCs中HIF-1 α的敲除导致DSS诱导的结肠炎小鼠的体重减轻明显大于对照小鼠。基因敲除小鼠表现出更严重的肠道炎症，促炎细胞因子水平增加，粘蛋白产生增加。树突状细胞HIF-1 α敲除后，调节性T细胞（Tcells）的诱导受损，叉头框P3（Foxp 3）Tcells的数量减少。我们的研究结果表明，在DCs中，HIF-1 α是诱导足够数量的Tcl 3来控制肠道炎症所必需的。
Dendritic cells (DCs) serve as a bridge between innate and adaptive immunity and help to maintain intestinal homeostasis. Inflammatory bowel disease (IBD) is associated with dysregulation of the mucosal immune response. The concomitant hypoxic inflammation in IBD will activate the transcription factor hypoxia-inducible factor-1 (HIF-1) to also drive gene expression in DCs. Recent studies have described a protective role for epithelial HIF-1 in mouse models of IBD. We investigated the role of HIF-1 in DC function in a dextran sodium sulfate (DSS)-induced model of murine colitis. Wild-type and dendritic cell-specific HIF-1 alpha knockout mice were treated with 3% DSS for 7 days. Knockout of HIF-1 alpha in DCs led to a significantly larger loss of body weight in mice with DSS-induced colitis than in control mice. Knockout mice exhibited more severe intestinal inflammation with increased levels of proinflammatory cytokines and enhanced production of mucin. Induction of regulatory T cells (Tregs) was impaired, and the number of forkhead box P3 (Foxp3) Tregs was diminished by dendritic HIF-1 alpha knockout. Our findings demonstrate that in DCs HIF-1 alpha is necessary for the induction of sufficient numbers of Tregs to control intestinal inflammation.