CB2R-cAMP-Epac1 pathway orchestrates epithelial-neural-immune interactions in atopic dermatitis

Keratinocytes form the skin's first line of defense, not only serving as a physical barrier but also actively communicating with immune cells and sensory neurons.

This study elucidated the molecular mechanisms by which keratinocytes contribute to barrier dysfunction and neuroimmune activation in atopic dermatitis (AD).

Cannabinoid receptor 2 (CB2R) expression was assessed by RNA sequencing, quantitative reverse transcription PCR (qRT-PCR), RNAscope fluorescence, and Western blot analysis. Pharmacologic activation/inhibition or keratinocyte-specific deletion of CB2R was used to determine its role in AD-associated itch and inflammation. Behavioral assays, immunofluorescence, and qRT-PCR were used to identify downstream signaling components.

CB2R expression was upregulated in the epidermis of MC903-induced AD. CB2R activation alleviated scratching and skin pathology, whereas keratinocyte-specific CB2R deletion exacerbated both. CB2R suppressed adenylate cyclase 3 activity, reducing cAMP levels and downstream Epac1 activation, thereby limiting IL-33 production. This CB2R-cAMP-Epac1-IL-33 axis regulated epidermal hyperplasia, dermal neutrophil infiltration, and chronic itch.

The keratinocyte CB2R-cAMP-Epac1 axis integrates epithelial, neural, and immune signaling to drive AD pathology, representing a potential therapeutic target for chronic itch and skin inflammation.