Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, D-79104 Freiburg, Germany.
J Exp Med. 2010 Nov 22;207(12):2609-19. doi: 10.1084/jem.20092489. Epub 2010 Nov 8.
Sensitization to contact allergens requires activation of the innate immune system by endogenous danger signals. However, the mechanisms through which contact allergens activate innate signaling pathways are incompletely understood. In this study, we demonstrate that mice lacking the adenosine triphosphate (ATP) receptor P2X(7) are resistant to contact hypersensitivity (CHS). P2X(7)-deficient dendritic cells fail to induce sensitization to contact allergens and do not release IL-1β in response to lipopolysaccharide (LPS) and ATP. These defects are restored by pretreatment with LPS and alum in an NLRP3- and ASC-dependent manner. Whereas pretreatment of wild-type mice with P2X(7) antagonists, the ATP-degrading enzyme apyrase or IL-1 receptor antagonist, prevents CHS, IL-1β injection restores CHS in P2X(7)-deficient mice. Thus, P2X(7) is a crucial receptor for extracellular ATP released in skin in response to contact allergens. The lack of P2X(7) triggering prevents IL-1β release, which is an essential step in the sensitization process. Interference with P2X(7) signaling may be a promising strategy for the prevention of allergic contact dermatitis.
致敏原需要通过内源性危险信号激活先天免疫系统。然而，接触致敏原激活先天信号通路的机制尚不完全清楚。在这项研究中，我们证明缺乏三磷酸腺苷（ATP）受体 P2X（7）的小鼠对接触性超敏反应（CHS）具有抗性。缺乏 P2X（7）的树突状细胞不能诱导对接触致敏原的致敏作用，并且对脂多糖（LPS）和 ATP 不释放白细胞介素-1β（IL-1β）。这些缺陷可以通过 LPS 和明矾预处理以 NLRP3 和 ASC 依赖的方式来恢复。虽然野生型小鼠用 P2X（7）拮抗剂、ATP 降解酶 apyrase 或白细胞介素-1 受体拮抗剂预处理可以预防 CHS，但 IL-1β 注射可恢复 P2X（7）缺陷型小鼠的 CHS。因此，P2X（7）是对接触致敏原在皮肤中释放的细胞外 ATP 的关键受体。缺乏 P2X（7）触发可防止 IL-1β 的释放，这是致敏过程中的一个重要步骤。干扰 P2X（7）信号可能是预防过敏性接触性皮炎的一种有前途的策略。
