Cannabinoid 1 Receptors in Keratinocytes Modulate Proinflammatory Chemokine Secretion and Attenuate Contact Allergic Inflammation
Cannabinoid 1 Receptors in Keratinocytes Modulate Proinflammatory Chemokine Secretion and Attenuate Contact Allergic Inflammation
复制标题
DOI：
10.4049/jimmunol.1201777
复制
发表时间：
2013-05-15
影响因子：
4.4
通讯作者：
Tueting, Thomas
中科院分区：
文献类型：
--
作者：
Gaffal, Evelyn;Cron, Mira;Tueting, Thomas
表皮角质形成细胞（KCs）和大麻素（CB）受体都参与了过敏性接触性皮炎小鼠模型的炎症反应调控，即对专性致敏剂2,4-二硝基氟苯的接触超敏反应（CHS）反应。在这项研究中，我们研究了CB1受体如何减弱CHS对2,4-二硝基氟苯的反应的细胞和分子机制。我们使用条件基因靶向方法来确定CB1受体对表皮KCs控制CHS反应的相对贡献。为了确定在CHS效应期调节炎症反应的潜在细胞和分子机制，我们使用形态学、分子和免疫学方法对炎症耳组织和原代KC培养物进行了进一步的研究。CB1受体kc特异性缺失的小鼠出现了增加和延长的CHS反应。在CHS的效应期，这些与增强的反应性表皮棘层和炎性KC过度增生有关。体外，与对照组相比，CB1受体缺失的KC原代培养物在ifn - γ刺激后释放的CXCL10和CCL8的量增加。在体内，与对照组相比，CB1受体缺陷KCs接触性变应性耳组织中CXCL10和CCL8的表达增强。进一步的研究证实CCL8是一种由CB1受体调节的促炎趋化因子，可促进免疫细胞向过敏原挑战的皮肤募集。综上所述，这些结果表明CB1受体在体内由KCs功能性表达，并有助于限制促炎趋化因子的分泌，这些趋化因子在CHS的效应期调节T细胞依赖性炎症。
Epidermal keratinocytes (KCs) and cannabinoid (CB) receptors both participate in the regulation of inflammatory responses in a mouse model for allergic contact dermatitis, the contact hypersensitivity (CHS) response to the obligate sensitizer 2,4-dinitrofluorobenzene. In this study, we investigated the cellular and molecular mechanisms how CB1 receptors attenuate CHS responses to 2,4-dinitrofluorobenzene. We used a conditional gene-targeting approach to identify the relative contribution of CB1 receptors on epidermal KCs for the control of CHS responses. To determine the underlying cellular and molecular mechanisms that regulate inflammatory responses in the effector phase of CHS, we performed further investigations on inflamed ear tissue and primary KC cultures using morphologic, molecular, and immunologic methods. Mice with a KC-specific deletion of CB1 receptors developed increased and prolonged CHS responses. These were associated with enhanced reactive epidermal acanthosis and inflammatory KC hyperproliferation in the effector phase of CHS. In vitro, primary cultures of CB1 receptor-deficient KC released increased amounts of CXCL10 and CCL8 after stimulation with IFN-gamma compared with controls. In vivo, contact allergic ear tissue of CB1 receptor-deficient KCs showed enhanced expression of CXCL10 and CCL8 compared with controls. Further investigations established CCL8 as a proinflammatory chemokine regulated by CB1 receptors that promotes immune cell recruitment to allergen-challenged skin. Taken together, these results demonstrate that CB1 receptors are functionally expressed by KCs in vivo and help to limit the secretion of proinflammatory chemokines that regulate T cell-dependent inflammation in the effector phase of CHS.