Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk
Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk
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DOI：
10.1172/jci63451
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发表时间：
2012-11-01
影响因子：
15.9
通讯作者：
Kopf, Manfred
中科院分区：
文献类型：
--
作者：
Tortola, Luigi;Rosenwald, Esther;Kopf, Manfred
牛皮癣是一种慢性皮肤炎症性疾病，影响世界上约 2% 的人口。越来越多的证据表明，IL-23/IL-17/IL-22 通路是皮肤免疫病理学发展的关键。然而，人们对角质形成细胞的作用及其在疾病发作时与免疫细胞的相互作用仍知之甚少。在这里，我们发现 IL-36R 缺陷型 (Il36r(-/-)) 小鼠免受咪喹莫特诱导的真皮产生 IL-17 的 γ δ T 细胞增殖和银屑病样皮炎的影响。此外，IL-36R拮抗剂缺陷(Il36rn(-/-))小鼠表现出恶化的病理学。 DC 上的 TLR7 连接诱导 IL-36 介导的与角质形成细胞和真皮间充质细胞的串扰，这对于控制病理性 IL-23/IL-17/IL-22 轴和疾病发展至关重要。值得注意的是，与 Il36r(-/-) 小鼠相比，缺乏 IL-23、IL-17 或 IL-22 的小鼠免受疾病的保护较差，这表明除了诱导病理性 IL-23 轴之外，IL-36 还具有额外的独特活性。此外，虽然IL-1R1的缺失阻止了中性粒细胞浸润，但它并不能防止棘皮症和角化过度，这表明中性粒细胞对于疾病表现来说是可有可无的。这些结果强调了 IL-36 在控制 IL-23/IL-17/IL-22 途径和银屑病皮炎的发展中具有重要且独特的独立于 IL-1 的作用。
Psoriasis is a chronic inflammatory disorder of the skin affecting approximately 2% of the world's population. Accumulating evidence has revealed that the IL-23/IL-17/IL-22 pathway is key for development of skin immunopathology. However, the role of keratinocytes and their crosstalk with immune cells at the onset of disease remains poorly understood. Here, we show that IL-36R-deficient (Il36r(-/-)) mice were protected from imiquimod-induced expansion of dermal IL-17-producing gamma delta T cells and psoriasiform dermatitis. Furthermore, IL-36R antagonist-deficient (Il36rn(-/-)) mice showed exacerbated pathology. TLR7 ligation on DCs induced IL-36-mediated crosstalk with keratinocytes and dermal mesenchymal cells that was crucial for control of the pathological IL-23/IL-17/IL-22 axis and disease development. Notably, mice lacking IL-23, IL-17, or IL-22 were less well protected from disease compared with Il36r(-/-) mice, indicating an additional distinct activity of IL-36 beyond induction of the pathological IL-23 axis. Moreover, while the absence of IL-1R1 prevented neutrophil infiltration, it did not protect from acanthosis and hyperkeratosis, demonstrating that neutrophils are dispensable for disease manifestation. These results highlight a central and unique IL-1-independent role for IL-36 in control of the IL-23/IL-17/IL-22 pathway and development of psoriasiform dermatitis.