miR-146a Is Differentially Expressed by Myeloid Dendritic Cell Subsets and Desensitizes Cells to TLR2-Dependent Activation
miR-146a Is Differentially Expressed by Myeloid Dendritic Cell Subsets and Desensitizes Cells to TLR2-Dependent Activation
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DOI：
10.4049/jimmunol.0903021
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Strobl, Herbert
中科院分区：
文献类型：
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作者：
Jurkin, Jennifer;Schichl, Yvonne M.;Strobl, Herbert
上皮细胞中的朗格汉斯细胞（LCs）和相邻结缔组织中的间质树突状细胞（intdc）代表了两个密切相关的髓源性DC亚群，它们在免疫系统中发挥特殊功能，并且与细胞治疗具有临床相关性。这两个亚群都是由单核细胞承诺的中间体响应组织相关的微环境信号而产生的；然而，髓系DC亚群规范和功能的分子机制仍然不明确。通过微阵列分析，我们鉴定出microRNA (miRNA) miR-146a在人类lc中的组成性表达水平高于intdc。此外，miR-146a水平在单核细胞中较低，在中性粒细胞中检测不到。有趣的是，miR-146a在LC中的组成性高表达是由转录因子PU.1诱导的，以响应tgf - β 1， tgf - β 1是表皮LC分化的关键微环境信号。我们发现miR-146a是单核细胞和DC激活的调节因子，但不是髓细胞/DC亚群分化的调节因子。单核细胞和intdc中的异位miR-146a干扰TLR2下游信号传导和细胞因子的产生，但不影响DC的表型成熟。相反，LCs中miR-146a的沉默增强了tlr2依赖性NF-kappa B信号传导。因此，我们得出结论，高组成性miR-146a水平是由表皮微环境信号诱导的，并且可能使LCs不容易受到体表共生细菌TLR2触发器的不适当激活。中华免疫学杂志，2010,18(4):955- 965。
Langerhans cells (LCs) in epithelia and interstitial dendritic cells (intDCs) in adjacent connective tissues represent two closely related myeloid-derived DC subsets that exert specialized functions in the immune system and are of clinical relevance for cell therapy. Both subsets arise from monocyte-committed intermediates in response to tissue-associated microenvironmental signals; however, molecular mechanisms underlying myeloid DC subset specification and function remain poorly defined. Using microarray profiling, we identified microRNA (miRNA) miR-146a to be constitutively expressed at higher levels in human LCs compared with intDCs. Moreover, miR-146a levels were low in monocytes and nondetectable in neutrophil granulocytes. Interestingly, constitutive high miR-146a expression in LCs is induced by the transcription factor PU.1 in response to TGF-beta 1, a key microenvironmental signal for epidermal LC differentiation. We identified miR-146a as a regulator of monocyte and DC activation but not myeloid/DC subset differentiation. Ectopic miR-146a in monocytes and intDCs interfered with TLR2 downstream signaling and cytokine production, without affecting phenotypic DC maturation. Inversely, silencing of miR-146a in LCs enhanced TLR2-dependent NF-kappa B signaling. We therefore conclude that high constitutive miR-146a levels are induced by microenvironmental signals in the epidermis and might render LCs less susceptible to inappropriate activation by commensal bacterial TLR2 triggers at body surfaces. The Journal of Immunology, 2010, 184: 4955-4965.