Department of Dermatology and Allergy, Ludwig-Maximilian-University, 80337 Munich, Germany.
Sci Transl Med. 2011 May 11;3(82):82ra38. doi: 10.1126/scitranslmed.3002001.
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.
促炎细胞因子白细胞介素-1β（IL-1β）在炎症性皮肤病（包括银屑病）的发病机制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加工的机制仍不清楚。最近，细胞溶质 DNA 已被确定为一种危险信号，可激活包含 DNA 传感器 AIM2 的炎性小体。在这项研究中，我们在银屑病皮损的角质形成细胞中检测到大量的细胞溶质 DNA 和增加的 AIM2 表达，但在健康皮肤中没有。在培养的角质形成细胞中，干扰素-γ诱导 AIM2，细胞溶质 DNA 通过 AIM2 炎性小体触发 IL-1β的释放。此外，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细胞溶质 DNA 并阻断 AIM2 炎性小体的激活。总之，这些数据表明细胞溶质 DNA 是一种重要的疾病相关分子模式，可触发银屑病中 AIM2 炎性小体和 IL-1β的激活。此外，抗菌肽 LL-37 干扰 DNA 感应炎性小体，从而提示该肽具有抗炎作用。因此，我们的数据揭示了 AIM2 炎性小体、抗菌肽 LL-37 和银屑病自身炎症之间的联系，为这种慢性皮肤病的治疗提供了新的潜在靶点。
