1] Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan [2] Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
Division of Molecular and Cellular Immunoscience, Department of Biomolecular Sciences, Saga Medical School, 5-1-1 Nabeshima Saga, Saga 849-8501, Japan.
Nat Commun. 2014 May 7;5:3755. doi: 10.1038/ncomms4755.
A variety of reactive organic compounds, called haptens, can cause allergic contact dermatitis. However, the innate immune mechanisms by which haptens stimulate dendritic cells (DCs) to sensitize T cells remain unclear. Here we show that the coupling of ITAM-Syk-CARD9 signalling to interleukin-1 (IL-1) secretion in DCs is crucial for allergic sensitization to haptens. Both MyD88 and Caspase recruitment domain-containing protein 9 (CARD9) signalling are required for contact hypersensitivity (CHS). Naïve T cells require signals received through IL-1R1-MyD88 for effector differentiation, whereas DCs require CARD9 and spleen tyrosine kinase (Syk) signalling for hapten-induced IL-1α/β secretion and their ability to prime T cells. DC-specific deletion of CARD9, DAP12, Syk or NLRP3, but not MyD88, is sufficient to abolish CHS. All tested haptens, but not irritants, can induce Syk activation, leading to both the CARD9/BCL10-dependent pro-IL-1 synthesis (signal1) and reactive oxygen species-mediated NLRP3 inflammasome activation (signal2), required for IL-1 secretion. These data unveil an innate immune mechanism crucial for allergic contact sensitization to chemical compounds.
多种反应性有机化合物，称为半抗原，可引起过敏性接触性皮炎。然而，半抗原刺激树突状细胞 (DC) 致敏 T 细胞的固有免疫机制仍不清楚。在这里，我们表明 ITAM-Syk-CARD9 信号与白细胞介素-1 (IL-1) 在 DC 中的分泌的偶联对于对半抗原的过敏致敏至关重要。MyD88 和包含衔接蛋白的 Caspase 募集结构域蛋白 9 (CARD9) 信号对于接触超敏反应 (CHS) 都是必需的。幼稚 T 细胞需要通过 IL-1R1-MyD88 接收信号以进行效应物分化，而 DC 需要 CARD9 和脾酪氨酸激酶 (Syk) 信号以诱导半抗原诱导的 IL-1α/β 分泌及其激活 T 细胞的能力。仅特异性敲除 DC 中的 CARD9、DAP12、Syk 或 NLRP3，而不是 MyD88，就足以消除 CHS。所有测试的半抗原，但不是刺激性化合物，都可以诱导 Syk 激活，导致 CARD9/BCL10 依赖性前 IL-1 合成 (信号 1) 和活性氧介导的 NLRP3 炎性小体激活 (信号 2)，这是 IL-1 分泌所必需的。这些数据揭示了一种对于对化学化合物的过敏接触致敏至关重要的固有免疫机制。
