MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation.
MCPIP1/Regnase-1 Restricts IL-17A- and IL-17C-Dependent Skin Inflammation.
复制标题
DOI：
10.4049/jimmunol.1601551
复制
发表时间：
2017-01-15
期刊：
影响因子：
--
通讯作者：
Gaffen SL
中科院分区：
文献类型：
--
作者：
Monin L;Gudjonsson JE;Childs EE;Amatya N;Xing X;Verma AH;Coleman BM;Garg AV;Killeen M;Mathers A;Ward NL;Gaffen SL
IL-17家族细胞因子IL-17 A和IL-17 C驱动银屑病皮肤炎症的发病机制，并且抗IL-17 A Ab最近被批准用于治疗人银屑病。迄今为止，对抑制IL-17介导的信号传导，特别是IL-17 C的机制知之甚少。在这里，我们表明，核糖核酸内切酶MCPIP 1（也称为Regnase-1）在人类银屑病皮损中显著上调。类似地，MCPIP 1在咪喹莫特（IMQ）驱动的皮肤炎症小鼠模型中过表达。MCPIP 1缺乏的小鼠（Zc 3 h12 a +/−）没有表现出基线皮肤炎症，但在IMQ治疗后表现出恶化的病理学。Zc 3 h12 a +/−小鼠的病理学与IL-17 A和IL-17 C依赖性基因的表达升高以及皮肤中性粒细胞蓄积增加相关。然而，IL-17 A和IL-17 C表达没有改变，这表明Zc 3 h12 a +/-小鼠的炎症增加是由于下游IL-17 R信号传导增强所致。辐射嵌合体表明，非造血细胞中的MCPIP 1负责控制皮肤病理学。此外，给予IMQ的Zc 3 h12 a +/− Il 17 ra −/−小鼠几乎没有表现出疾病。为了确定哪种IL-17 RA配体是必需的，Zc 3 h12 a +/− Il 17 a −/−和Zc 3 h12 a +/− Il 17 c −/−小鼠被给予IMQ;这些小鼠的病理学有所减轻，但没有完全消除，表明MCPIP 1抑制IL-17 A和IL-17 C信号传导。证实了这一假设，Zc 3 h12 a −/−角质形成细胞对IL-17 A和IL-17 C刺激的反应性增加。因此，MCPIP 1是通过IL-17 A和IL-17 C的银屑病皮肤炎症的有效负调节剂。此外，MCPIP 1是第一个描述的IL-17 C信号传导的负调节因子。
The IL-17-family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. To date, little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. Here, we show that the endoribonuclease MCPIP1 (also known as Regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a+/−) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a+/− mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes and also increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a+/− mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in non-hematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a+/−Il17ra−/− mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a+/−Il17a−/− and Zc3h12a+/−Il17c−/− mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits both IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a−/− keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, MCPIP1 is the first described negative regulator of IL-17C signaling.