Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.
Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions.
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DOI：
10.1126/scitranslmed.3002001
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发表时间：
2011-05-11
影响因子：
17.1
通讯作者：
Schauber J
中科院分区：
文献类型：
--
作者：
Dombrowski Y;Peric M;Koglin S;Kammerbauer C;Göss C;Anz D;Simanski M;Gläser R;Harder J;Hornung V;Gallo RL;Ruzicka T;Besch R;Schauber J
促炎细胞因子白细胞介素-1β (IL-1β)在包括牛皮癣在内的炎症性皮肤病的发病和病程中起核心作用。IL-1β的转录后激活由炎性小体介导；然而，触发IL-1β加工的机制仍然未知。最近，细胞质DNA已被确定为激活含有DNA传感器AIM2的炎性小体的危险信号。在这项研究中，我们在银屑病病变的角质形成细胞中检测到丰富的细胞质DNA和增加的AIM2表达，而在健康皮肤中则没有。在培养的角质形成细胞中，干扰素γ诱导AIM2，细胞质DNA通过AIM2炎性体触发IL-1β的释放。此外，抗菌抗菌肽LL-37可以与银屑病皮肤中的DNA相互作用，中和角质形成细胞中的胞质DNA，阻断AIM2炎性小体的激活。总之，这些数据表明细胞质DNA是一种重要的疾病相关分子模式，可以触发银屑病AIM2炎性体和IL-1β的激活。此外，cathelicidin LL-37干扰dna感应炎性小体，从而表明该肽具有抗炎功能。因此，我们的数据揭示了AIM2炎性小体、cathelicidin LL-37和银屑病自身炎症之间的联系，为治疗这种慢性皮肤病提供了新的潜在靶点。
The proinflammatory cytokine interleukin-1β (IL-1β) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1β is mediated by inflammasomes; however, the mechanisms triggering IL-1β processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1β via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1β activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.
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影响因子：
3.7
作者：
Peric M;Koglin S;Dombrowski Y;Gross K;Bradac E;Büchau A;Steinmeyer A;Zügel U;Ruzicka T;Schauber J
通讯作者：
Schauber J
影响因子：
30.5
作者：
Buerckstuemmer, Tilmann;Baumann, Christoph;Superti-Furga, Giulio
通讯作者：
Superti-Furga, Giulio
影响因子：
6.5
作者：
Shepherd, J;Little, MC;Nicklin, MJH
通讯作者：
Nicklin, MJH
DOI：
10.1056/nejmoa0807865
发表时间：
2009-06-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Aksentijevich I;Masters SL;Ferguson PJ;Dancey P;Frenkel J;van Royen-Kerkhoff A;Laxer R;Tedgård U;Cowen EW;Pham TH;Booty M;Estes JD;Sandler NG;Plass N;Stone DL;Turner ML;Hill S;Butman JA;Schneider R;Babyn P;El-Shanti HI;Pope E;Barron K;Bing X;Laurence A;Lee CC;Chapelle D;Clarke GI;Ohson K;Nicholson M;Gadina M;Yang B;Korman BD;Gregersen PK;van Hagen PM;Hak AE;Huizing M;Rahman P;Douek DC;Remmers EF;Kastner DL;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
6.5
作者：
Johansen, Claus;Moeller, Kristine;Iversen, Lars
通讯作者：
Iversen, Lars