Department of Pharmacology, Ribeirão Preto Medical School, and.
Center for Research in Inflammatory Diseases, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirão Preto, Sao Paulo, Brazil.
JCI Insight. 2024 Oct 1;9(21):e171894. doi: 10.1172/jci.insight.171894.
Psoriasis is a chronic and recurrent inflammatory skin disease characterized by abnormal proliferation and differentiation of keratinocytes and activation of immune cells. However, the molecular driver that triggers this immune response in psoriatic skin remains unclear. The inflammation-related gene absent in melanoma 2 (AIM2) was identified as a susceptibility gene/locus associated with psoriasis. In this study, we investigated the role of AIM2 in the pathophysiology of psoriasis. We found elevated levels of mitochondrial DNA in patients with psoriasis, along with high expression of AIM2 in both the human psoriatic epidermis and a mouse model of psoriasis induced by topical imiquimod (IMQ) application. Genetic ablation of AIM2 reduced the development of IMQ-induced psoriasis by decreasing the production of type 3 cytokines (such as IL-17A and IL-23) and infiltration of immune cells into the inflammatory site. Furthermore, we demonstrate that IL-17A induced AIM2 expression in keratinocytes. Finally, the genetic absence of inflammasome components downstream AIM2, ASC, and caspase-1 alleviated IMQ-induced skin inflammation. Collectively, our data show that AIM2 is involved in developing psoriasis through its canonical activation.
银屑病是一种慢性复发性炎症性皮肤病，其特征是角质形成细胞的异常增殖和分化以及免疫细胞的激活。然而，触发银屑病皮肤中这种免疫反应的分子驱动因素仍不清楚。缺失在黑色素瘤 2 中的炎症相关基因（AIM2）被鉴定为与银屑病相关的易感基因/位点。在这项研究中，我们研究了 AIM2 在银屑病发病机制中的作用。我们发现银屑病患者的线粒体 DNA 水平升高，同时人银屑病表皮和咪喹莫特（IMQ）诱导的银屑病小鼠模型中 AIM2 的表达也升高。AIM2 的基因缺失通过减少 3 型细胞因子（如 IL-17A 和 IL-23）的产生和免疫细胞浸润炎症部位，减少了 IMQ 诱导的银屑病的发展。此外，我们证明了 IL-17A 诱导角质形成细胞中 AIM2 的表达。最后，下游 AIM2、ASC 和半胱天冬酶-1 的炎性小体成分的基因缺失减轻了 IMQ 诱导的皮肤炎症。总之，我们的数据表明 AIM2 通过其经典激活参与了银屑病的发生。
