Atopic dermatitis is a chronic inflammatory disease characterized by an impaired epidermal barrier function combined with a chronic Th2-type inflammatory response and an intense pruritus. Here we used an experimental mouse model for Th2-type contact hypersensitivity (CHS) to fluorescein isothiocyanate (FITC) to investigate the potential role of cannabinoid 1 receptors (CB1) in the pathophysiology of mouse atopic-like dermatitis. Mice lacking CB1 receptors globally (Cnr1-/- ) or specifically in keratinocytes (KC-Cnr1-/- ) as well as wild-type (WT) control mice were sensitized and challenged with FITC. We examined ear swelling responses, trans-epidermal water loss, Th2 type skin inflammatory responses and serum IgE levels. Both Cnr1-/- and KC-Cnr1-/- showed enhanced CHS responses to FITC and a delayed epidermal barrier repair when compared with WT mice. mRNA levels for IL-4, thymic stromal lymphopoietin (TSLP) and CCL8, as well as eosinophil activity, were significantly increased in inflamed ear tissue of FITC-challenged Cnr1-/- and KC-Cnr1-/- mice. Importantly, CB1 receptor-deficient keratinocytes secreted increased levels of TSLP, a proinflammatory mediator that drives Th2-type skin inflammation in atopic dermatitis, under basal and Th2-type inflammatory conditions. Taken together, our results demonstrate that CB1 receptors in keratinocytes help to maintain epidermal barrier homeostasis and attenuate Th2-type allergic inflammatory responses. Based on our work we propose that enhanced epidermal allergen penetrance cooperates with increased production of TSLP and CCL8 by epidermal keratinocytes for the induction of Type 2 CD4+ T helper cells. Our results place keratinocytes at the cross-roads of outside-in and inside-out pathopyhsiologic mechanisms of atopic dermatitis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.

PMID:

 

24750433

 

[PubMed – as supplied by publisher]