首页> 外文期刊>The journal of immunology >Human Intestinal Lamina Propria CD1c+ Dendritic Cells Display an Activated Phenotype at Steady State and Produce IL-23 in Response to TLR7/8 Stimulation
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Human Intestinal Lamina Propria CD1c+ Dendritic Cells Display an Activated Phenotype at Steady State and Produce IL-23 in Response to TLR7/8 Stimulation

机译:人肠道固有层固有CD1c +树突状细胞在稳态下显示激活的表型,并响应TLR7 / 8刺激产生IL-23。

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Intestinal dendritic cells (DCs) play key roles in mediating tolerance to commensal flora and inflammatory responses against mucosal pathogens. The mechanisms by which intestinal “conditioning” influences human DC responses to microbial stimuli remain poorly understood. Infections with viruses, such as HIV-1, that target mucosal tissue result in intestinal epithelial barrier breakdown and increased translocation of commensal bacteria into the lamina propria (LP). It is unclear whether innate LP DC responses to concurrent viral and bacterial stimuli influence mucosal HIV-1 pathogenesis. In this study, direct ex vivo phenotype and in vitro constitutive cytokine production of CD1c+ DCs in human intestinal LP were compared with those in peripheral blood (PB). To evaluate innate responses to viral and bacterial stimuli, intracellular cytokine production by LP and PB DCs following stimulation with ligands for TLRs 2, 4, 5, and 7/8 was evaluated. At steady state, LP CD1c+ DCs expressed higher levels of activation markers (CD40, CD83, CD86, HLA-DR, and CCR7) than did PB CD1c+ DCs, and higher frequencies of LP CD1c+ DCs constitutively produced IL-6 and -10 and TNF-α. LP DCs had blunted cytokine responses to TLR4 ligand and TLR5 ligand stimulation relative to PB DCs, yet similarly produced IL-10 in response to TLR2 ligand. Only synthetic TLR7/8 ligand, a mimic of viral ssRNA, induced IL-23 production by LP CD1c+ DCs, and this proinflammatory cytokine response was synergistically enhanced following combined TLR7/8 and TLR4 stimulation. These findings highlight a potential mechanism by which viruses like HIV-1 may subvert homeostatic mechanisms and induce inflammation in the intestinal mucosa.
机译:肠道树突状细胞(DC)在介导对共生菌群的耐受性和针对粘膜病原体的炎症反应中起关键作用。肠道“调节”影响人类DC对微生物刺激的反应的机制仍知之甚少。靶向粘膜组织的病毒(如HIV-1)感染会导致肠上皮屏障破坏,共生细菌向固有层(LP)的转运增加。尚不清楚先天的LP DC对病毒和细菌同时刺激的反应是否影响粘膜HIV-1的发病机制。在这项研究中,将人肠道LP和外周血(PB)中CD1c + DC的直接离体表型和体外组成型细胞因子产生进行了比较。为了评估对病毒和细菌刺激的先天反应,评估了用TLR 2、4、5和7/8的配体刺激后LP和PB DC产生的细胞内细胞因子。在稳定状态下,LP CD1c + DCs表达的活化标志物(CD40,CD83,CD86,HLA-DR和CCR7)比PB CD1c + DCs高,而LP CD1c + DCs组成成分产生的IL-6和-10和TNF频率更高-α。相对于PB DC,LP DC对TLR4配体和TLR5配体刺激的细胞因子反应减弱,但同样对TLR2配体产生IL-10。只有合成的TLR7 / 8配体(一种病毒ssRNA的模拟物)诱导了LP CD1c + DC的IL-23产生,并且在组合TLR7 / 8和TLR4刺激后,这种促炎细胞因子反应得到协同增强。这些发现突显了像HIV-1这样的病毒可能破坏体内稳态机制并在肠粘膜中引发炎症的潜在机制。

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