Card9 介导了肠道上皮细胞修复、辅助性 T 细胞 17 反应以及对小鼠细菌感染的控制。
Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice.
机构信息
Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
Gastroenterology. 2013 Sep;145(3):591-601.e3. doi: 10.1053/j.gastro.2013.05.047. Epub 2013 May 31.
BACKGROUND & AIMS: Caspase recruitment domain 9 (CARD9) is an adaptor protein that integrates signals downstream of pattern recognition receptors. CARD9 has been associated with autoinflammatory disorders, and loss-of-function mutations have been associated with chronic mucocutaneous candidiasis, but the role of CARD9 in intestinal inflammation is unknown. We characterized the role of Card9 in mucosal immune responses to intestinal epithelial injury and infection.
METHODS
We induced intestinal inflammation in Card9-null mice by administration of dextran sulfate sodium (DSS) or Citrobacter rodentium. We analyzed body weight, assessed inflammation by histology, and measured levels of cytokines and chemokines using quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Cell populations were compared between wild-type and Card9-null mice by flow cytometry analysis.
RESULTS
Colon tissues and mesenteric lymph nodes of Card9-null mice had reduced levels of interleukin (IL)-6, interferon-γ, and T-helper (Th)17 cytokines after administration of DSS, compared with wild-type mice. IL-17A and IL-22 expression were reduced in the recovery phase after DSS administration, coincident with decreased expression of antimicrobial peptides and the chemokine (C-C motif) ligand 20 (Ccl20). Although Card9-null mice had more intestinal fungi based on 18S analysis, their Th17 responses remained defective even when an antifungal agent was administered throughout DSS exposure. Moreover, Card9-null mice had impaired immune responses to C rodentium, characterized by decreased levels of colonic IL-6, IL-17A, IL-22, and regenerating islet-derived 3 gamma (RegIIIγ), as well as fewer IL-22-producing innate lymphoid cells (ILCs) in colon lamina propria.
CONCLUSIONS
The adaptor protein CARD9 coordinates Th17- and innate lymphoid cell-mediated intestinal immune responses after epithelial injury in mice.
背景与目的
衔接蛋白 Caspase recruitment domain 9（CARD9）是一种整合模式识别受体下游信号的衔接蛋白。CARD9 与自身炎症性疾病相关，功能丧失性突变与慢性黏膜皮肤念珠菌病相关，但 CARD9 在肠道炎症中的作用尚不清楚。我们研究了 CARD9 在肠道上皮损伤和感染后黏膜免疫反应中的作用。
方法
我们通过给予葡聚糖硫酸钠（DSS）或柠檬酸杆菌感染来诱导 CARD9 基因敲除小鼠的肠道炎症。通过组织学评估，测量细胞因子和趋化因子的水平来分析体重、炎症，并使用定量逆转录聚合酶链反应和酶联免疫吸附试验。通过流式细胞术分析比较野生型和 CARD9 基因敲除小鼠之间的细胞群。
结果
与野生型小鼠相比，DSS 处理后 CARD9 基因敲除小鼠的结肠组织和肠系膜淋巴结中的白细胞介素（IL）-6、干扰素-γ和辅助性 T（Th）17 细胞因子水平降低。DSS 处理后恢复阶段的 IL-17A 和 IL-22 表达减少，同时抗菌肽和趋化因子（C-C 基序）配体 20（Ccl20）的表达降低。尽管基于 18S 分析，CARD9 基因敲除小鼠的肠道真菌更多，但即使在整个 DSS 暴露期间给予抗真菌药物，其 Th17 反应仍然存在缺陷。此外，CARD9 基因敲除小鼠对柠檬酸杆菌的免疫反应受损，表现为结肠 IL-6、IL-17A、IL-22 和再生胰岛衍生 3 伽马（RegIIIγ）水平降低，以及结肠固有淋巴样细胞（ILC）中产生 IL-22 的细胞减少。
结论
衔接蛋白 CARD9 协调了小鼠上皮损伤后 Th17 和固有淋巴样细胞介导的肠道免疫反应。
Zotero 插件