Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation.
Plasmacytoid dendritic cells orchestrate TLR7-mediated innate and adaptive immunity for the initiation of autoimmune inflammation.
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DOI：
10.1038/srep24477
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发表时间：
2016-04-14
影响因子：
4.6
通讯作者：
Sato K
中科院分区：
文献类型：
--
作者：
Takagi H;Arimura K;Uto T;Fukaya T;Nakamura T;Choijookhuu N;Hishikawa Y;Sato K
内体Toll样受体(TLR)介导的病毒核酸(Nas)检测和I型干扰素(IFN-I)的产生是抗病毒防御的关键因素，而对自身Nas的不正确识别和诱导干扰素-I反应与自身免疫有关，如牛皮癣和系统性红斑狼疮。浆细胞样树突状细胞(plmacytoid Dendritic cell，PDCs)是一种通过与胞体TLRs结合而分泌大量干扰素的细胞，主要表达唾液酸结合的Ig样凝集素(Siglec)-H。然而，pDC如何控制内体TLR介导的导致自身免疫的免疫反应仍不清楚。在这里，我们展示了pDC在TLR7介导的自身免疫中的关键作用，使用了Siglec-H表达受损的基因修饰小鼠和选择性消融pDCs。PDCs在诱导全身炎症和TLR7配体触发的效应性T细胞反应中是不可或缺的。PDC通过角质形成细胞的过度增殖、粒细胞和γδT细胞在真皮中的浸润而加重银屑病皮炎。此外，PDCs通过激活炎性单核细胞促进狼疮样疾病中抗自身NA抗体的产生和肾小球肾炎的发生。另一方面，Siglec-H调节TLR7介导的pDC激活。因此，我们的研究结果表明，pDC在TLR7介导的先天免疫和获得性免疫之间为启动干扰素-I相关的自身免疫性炎症提供了重要的联系。
Endosomal toll-like receptor (TLR)-mediated detection of viral nucleic acids (NAs) and production of type I interferon (IFN-I) are key elements of antiviral defense, while inappropriate recognition of self NAs with the induction of IFN-I responses is linked to autoimmunity such as psoriasis and systemic lupus erythematosus. Plasmacytoid dendritic cells (pDCs) are cells specialized in robust IFN-I secretion by the engagement of endosomal TLRs, and predominantly express sialic acid-binding Ig-like lectin (Siglec)-H. However, how pDCs control endosomal TLR-mediated immune responses that cause autoimmunity remains unclear. Here we show a critical role of pDCs in TLR7-mediated autoimmunity using gene-modified mice with impaired expression of Siglec-H and selective ablation of pDCs. pDCs were shown to be indispensable for the induction of systemic inflammation and effector T-cell responses triggered by TLR7 ligand. pDCs aggravated psoriasiform dermatitis mediated through the hyperproliferation of keratinocytes and enhanced dermal infiltration of granulocytes and γδ T cells. Furthermore, pDCs promoted the production of anti-self NA antibodies and glomerulonephritis in lupus-like disease by activating inflammatory monocytes. On the other hand, Siglec-H regulated the TLR7-mediated activation of pDCs. Thus, our findings reveal that pDCs provide an essential link between TLR7-mediated innate and adaptive immunity for the initiation of IFN-I-associated autoimmune inflammation.