Langerinneg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice
Langerinneg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice
复制标题
DOI：
10.1073/pnas.1307569110
复制
发表时间：
2013-06
期刊：
影响因子：
--
通讯作者：
C. Wohn;J. Ober-Blöbaum;Stefan Haak;S. Pantelyushin;C. Cheong;S. Zahner;Sabina Onderwater;Marius Kant-M
中科院分区：
文献类型：
--
作者：
C. Wohn;J. Ober-Blöbaum;Stefan Haak;S. Pantelyushin;C. Cheong;S. Zahner;Sabina Onderwater;Marius Kant-M
牛皮癣是一种病因不明的自体炎症性皮肤病。局部应用含有toll样受体（TLR）7激动剂咪喹莫特（IMQ）的Aldara乳膏可诱导银屑病发作。同样，在小鼠中，IMQ引发的病理变化与银屑病斑块的形成非常相似。主要由树突状细胞（dc）产生的关键细胞因子如IL-23和i型IFN （IFN- i）与牛皮癣有关。尽管浆细胞样树突状细胞（pDCs）是IFNα的主要来源，并被认为引发疾病，但传统的树突状细胞（cdc）似乎维持银屑病病变。cdc在病变形成过程中的作用尚不明确。在这里，我们报道了TLR7信号在CD11c+ dc中的选择性激活足以诱导小鼠牛皮癣样皮肤病。有趣的是，pDCs和IFN-I通路对于局部皮肤炎症的发展都是不可缺少的。选择性TLR7触发Langerin+ dc导致疾病减轻，而它们的消耗不会改变皮肤病变的严重程度。此外，IMQ-painting后，IL-23在体内完全由Langerinneg dc产生。综上所述，tlr7激活的Langerinneg cdc通过il -23介导的先天IL-17/ il -22生成淋巴细胞的激活来触发银屑病斑块的形成，而不依赖于pDCs或IFN-I。这些结果提示通过cdc靶向IL-23的产生来完善当前银屑病的治疗策略。
Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNα and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c+ DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin+ DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerinneg DCs in vivo. In conclusion, TLR7-activated Langerinneg cDCs trigger psoriatic plaque formation via IL-23–mediated activation of innate IL-17/IL-22–producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis.