Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a
Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a
复制标题
整合素 CD11b 通过上调 microRNA-146a 负向调节 TLR9 触发的树突状细胞交叉引发
DOI：
10.4049/jimmunol.1102371
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发表时间：
2012-06-01
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Bai, Yi;Qian, Cheng;Cao, Xuetao
树突状细胞(DC)在交叉启动诱导CTL抗感染反应中起关键作用，但DC交叉启动调控的分子机制还需要进一步研究，这可能有助于通过工程修饰来提高DC疫苗的效力。我们以前的研究表明，β2整合素CD11b可以控制TLR触发的NK细胞杀伤和巨噬细胞炎症反应。CD11b在DC中也有大量表达，但目前尚不清楚CD11b是否参与了DC交叉激发对CTL反应的调节。此外，由于microRNAs(MiRNAs)是免疫反应的重要调节因子，目前尚不清楚miRNAs是否受DC中CD11b的调控。在这项研究中，我们发现CD11b缺乏上调了TLR9触发的DC的IL-12p70的产生，而不是TLR4触发的IL-12p70的产生，从而促进了DC对CTL反应的交叉启动。进一步的实验表明，CD11b通过维持晚期核因子-kappaB的激活，选择性地促进TLR9触发的miR-146a在DC中的上调。此外，已知的DC产生IL-12p70的正向调节因子Notch 1被证实是miR-146a的直接靶标。与CD11b缺陷的DC相比，MIR-146a上调和Notch1抑制是TLR9触发的野生型DC产生IL-12p70减少的原因。因此，CD11b及其下游的miR-146a可能通过抑制Notch1的表达和IL-12p70的产生，成为DC交叉启动的新的负性调节因子。我们的数据表明了一种通过整合素和miRNAs调节DC交叉启动的新机制。免疫学杂志，2012,188：5293-5302。
Dendritic cells (DCs) play critical roles in cross-priming to induce the CTL response against infection; however, the molecular mechanisms for the regulation of DC cross-priming need to be investigated further, which may help to improve the potency of DC vaccines through engineering modifications. Our previous studies showed that beta 2 integrin CD11b could control TLR-triggered NK cell cytotoxicity and macrophage inflammatory responses. CD11b is also abundantly expressed in DCs, but it is unknown whether CD11b participates in the regulation of DC cross-priming for the CTL response. Also, because microRNAs (miRNAs) are important regulators of the immune response, it remains unclear whether miRNAs are regulated by CD11b in DCs. In this study, we showed that CD11b deficiency upregulated TLR9-triggered, but not TLR4-triggered, IL-12p70 production in DCs, subsequently promoting DC cross-priming of the CTL response. Further experiments showed that CD11b selectively promoted TLR9-triggered miR-146a upregulation in DCs by sustaining late-phase NF-kappa B activation. Additionally, Notch 1, a known positive regulator of IL-12p70 production in DCs, was confirmed to be directly targeted by miR-146a. miR-146a upregulation and Notch1 repression were determined to be responsible for the reduced IL-12p70 production in TLR9-triggered wild-type DCs compared with that in CD11b-deficient DCs. Therefore, CD11b and downstream miR-146a may be new negative regulators for DC cross-priming by suppressing Notch1 expression and IL-12p70 production. Our data indicate a new mechanism for the regulation of DC cross-priming through integrins and miRNAs. The Journal of Immunology, 2012, 188: 5293-5302.