EFLA 945 restricts AIM2 inflammasome activation by preventing DNA entry for psoriasis treatment
EFLA 945 restricts AIM2 inflammasome activation by preventing DNA entry for psoriasis treatment
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DOI：
10.1016/j.cyto.2019.154951
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发表时间：
2020-03-01
期刊：
影响因子：
3.8
通讯作者：
Chen, Lih-Chyang
中科院分区：
文献类型：
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作者：
Chung, I-Che;Yuan, Sheng-Ning;Chen, Lih-Chyang
牛皮癣是一种慢性炎症性皮肤病，影响约2%的一般人群。黑色素瘤2（AIM 2）炎性小体的激活对于免疫防御至关重要，但它也可能导致炎症和自身免疫性疾病，包括银屑病。我们目前缺乏一种可用于治疗的AIM 2炎性小体抑制剂。在这里，我们表明EFLA 945，一种安全的红葡萄藤叶提取物产品，可以限制AIM 2炎性小体激活。从机制上讲，EFLA 945阻止DNA进入THP-1衍生的巨噬细胞，从而抑制细胞质DNA依赖性凋亡相关的斑点样蛋白（包含CARD（ASC）寡聚化）、半胱天冬酶-1活化以及白细胞介素（IL）-1 β和IL-18的分泌。EFLA 945的主要植物化学物质白藜芦醇和芍药苷3-O-葡萄糖苷（P3 G）似乎是负责其限制AIM 2依赖性IL-1 β分泌的能力的潜在生物活性化合物。重要的是，在体内小鼠模型中，EFLA 945减弱了局部银屑病皮肤中咪喹莫特（IMQ）诱导的银屑病相关促炎反应，包括半胱天冬酶-1活化、IL-1 β成熟和IL-17产生，并降低了银屑病的严重程度。总之，这些结果表明，安全的天然产品EFLA 945可以通过阻止DNA进入来限制AIM 2炎性小体激活，并可能证明对治疗银屑病有益。
Psoriasis is a chronic inflammatory skin disease that affects about 2% of the general population. Activation of the Absent in Melanoma 2 (AIM2) inflammasome is crucial for immune defense, but it can also cause inflammatory and autoimmune diseases, including psoriasis. We currently lack an AIM2 inflammasome inhibitor that could be used therapeutically. Here, we show that EFLA 945, a safe product of red grape vine leaf extracts, can restrict AIM2 inflammasome activation. Mechanistically, EFLA945 prevents DNA entry into THP-1-derived macrophages, and thereby inhibits cytoplasmic DNA-dependent apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, caspase-1 activation, and the secretion of interleukin (IL)-1 beta and IL-18. The major phytochemicals of EFLA 945, resveratrol and peonidin 3-O-glucoside (P3G), appear to be the potential bioactive compounds responsible for its ability to restrict AIM2-dependent IL-1 beta secretion. Importantly, in an in vivo mouse model, EFLA 945 attenuates imiquimod (IMQ)-induced psoriasis-related pro-inflammatory responses in topical psoriatic skin, including caspase-1 activation, IL-1 beta maturation, and IL-17 production, and decreases the severity of psoriasis. Together, these results demonstrate that the safe natural product, EFLA 945, can restrict the AIM2 inflammasome activation through preventing DNA entry and may prove beneficial for treating psoriasis.