The role of the endocannabinoid system in the regulation of cellular immune responses in the skin

我们发现内源性大麻素系统（ECS）减弱了小鼠半抗原引起的接触超敏反应（CHS）。该实验系统是一种被普遍接受的过敏性接触性皮炎模型，这是一种常见的T细胞介导的皮肤病，对受影响的患者造成相当大的痛苦，并且以职业性接触性皮炎的形式，给社会带来巨大的代价。在上一个资助期间，我们发现了CB1受体在角化细胞（KC）中恢复CHS后表皮完整性和屏障功能的先前未被认识到的生理作用。根据我们的数据，我们假设ECS减少增殖并刺激KC的分化，从而通过CB1受体加速皮肤屏障修复。这导致炎症减少，这是由CB2受体对浸润性免疫细胞的依赖作用补充的。在下一个资助期内，我们将进一步研究所涉及的细胞和分子机制，并将我们的见解转化为针对ECS的新型治疗策略，以减轻过敏性炎症。具体来说，我们将(1)研究为什么缺乏KC上CB1受体的小鼠会表现出增殖增加、异常分化和屏障修复反应延迟；(2)利用组织特异性条件敲除小鼠，分析CB2受体对不同免疫细胞亚群在调节CHS反应中的抗炎作用；(3)制定针对ECS的治疗策略，以增强表皮屏障修复并限制皮肤炎症过程。

We found that the endocannabinoid system (ECS) attenuates contact hypersensitivity (CHS) responses caused by haptens in mice. This experimental system is a generally accepted model for allergic contact dermatitis, a common T cell-mediated skin disease, which causes considerable distress to affected patients and, in the form of occupational contact dermatitis, immense costs for society. During the last funding period we identified a previously unrecognized physiological role of CB1 receptors on keratinocytes (KC) in restoring epidermal integrity and barrier function following CHS. Based on our data we hypothesize that the ECS decreases proliferation and stimulates differentiation of KC, which accelerates skin barrier repair through CB1 receptors. This results in decreased inflammation, which is complemented by CB2 receptor-dependent effects on infiltrating immune cells. In the next funding period we will further investigate the cellular and molecular mechanisms involved and translate our insights into novel treatment strategies targeting the ECS to alleviate allergic inflammation. Specifically, we will (1) investigate why mice lacking CB1 receptors on KC show increased proliferation, aberrant differentiation and a delayed barrier repair response; (2) analyze the anti-inflammatory role of CB2 receptors on different immune cell subpopulations in regulating the CHS response using tissue-specific conditional knockout mice; (3) develop therapeutic strategies targeting the ECS to enhance epidermal barrier repair and limit inflammatory processes in the skin.