Physiologic TLR9-CpG-DNA Interaction Is Essential for the Homeostasis of the Intestinal Immune System
Physiologic TLR9-CpG-DNA Interaction Is Essential for the Homeostasis of the Intestinal Immune System
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DOI：
10.1097/01.mib.0000436276.19755.c1
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发表时间：
2014-01-01
影响因子：
4.9
通讯作者：
Obermeier, Florian
中科院分区：
文献类型：
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作者：
Hofmann, Claudia;Dunger, Nadja;Obermeier, Florian
背景：胞嘧啶-鸟苷二核苷酸（Cytosine-guanosine dinucleotide，CpG）基序是细菌DNA的免疫刺激成分，通过Toll样受体9（TLR 9）激活天然免疫。在实验性结肠炎发作前给予CpG寡脱氧核苷酸通过加强调节机制预防肠道炎症研究了生理性CpG/TLR 9相互作用是否对肠道免疫系统的稳态至关重要。方法：采用流式细胞术和蛋白质组分析法对来自BALB/c野生型（wt）或TLR 9（-/-）小鼠的肠系膜淋巴结细胞和固有层单核细胞（LPMC）群体进行了评估。测定细胞因子分泌，并分析核提取物的核因子κ B（NF-B）和cAMP反应元件结合蛋白活性。结果：TLR 9缺陷小鼠肠系膜淋巴结细胞和LPMC的细胞组成和信号蛋白磷酸化水平均发生轻微变化。与wt LPMC相比，来自TLR 9（-/-）小鼠的LPMC显示增加的促炎表型。TLR 9（-/-）小鼠细胞中的NF-B活性增强，而cAMP反应元件结合活性与wt.从TLR 9（-/-）小鼠转移固有层CD 4（+）-富集的T细胞诱导严重的结肠炎，而wt固有层CD 4（+）-富集的T细胞显示减弱的表型。因此，生理性CpG/TLR相互作用对于肠免疫系统的稳态是必不可少的，因为它是诱导反调节抗炎机制所必需的。
Background:Cytosine-guanosine dinucleotide (CpG) motifs are immunostimulatory components of bacterial DNA and activators of innate immunity through Toll-like receptor 9 (TLR9). Administration of CpG oligodeoxynucleotides before the onset of experimental colitis prevents intestinal inflammation by enforcement of regulatory mechanisms. It was investigated whether physiologic CpG/TLR9 interactions are critical for the homeostasis of the intestinal immune system.Methods:Mesenteric lymph node cell and lamina propria mononuclear cell (LPMC) populations from BALB/c wild-type (wt) or TLR9(-/-) mice were assessed by flow cytometry and proteome profiling. Cytokine secretion was determined and nuclear extracts were analyzed for nuclear factor kappa B (NF-B) and cAMP response-element binding protein activity. To assess the colitogenic potential of intestinal T cells, CD4(+)-enriched cells from LPMC of wt or TLR9(-/-) donor mice were injected intraperitoneally in recipient CB-17 SCID mice.Results:TLR9 deficiency was accompanied by slight changes in cellular composition and phosphorylation of signaling proteins of mesenteric lymph node cell and LPMC. LPMC from TLR9(-/-) mice displayed an increased proinflammatory phenotype compared with wt LPMC. NF-B activity in cells from TLR9(-/-) mice was enhanced, whereas cAMP response-element binding activity was reduced compared with wt. Transfer of lamina propria CD4(+)-enriched T cells from TLR9(-/-) mice induced severe colitis, whereas wt lamina propria CD4(+)-enriched T cells displayed an attenuated phenotype.Conclusions:Lack of physiologic CpG/TLR9 interaction impairs the function of the intestinal immune system indicated by enhanced proinflammatory properties. Thus, physiologic CpG/TLR interaction is essential for homeostasis of the intestinal immune system as it is required for the induction of counterregulating anti-inflammatory mechanisms.