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

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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.