Abstract
Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2−/− and Cnr1−/−/Cnr2−/− bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1−/− DCs. In vitro stimulated Cnr2−/− DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2−/− DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2−/− DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.
Highlights
Allergic contact dermatitis (ACD) is an inflammatory skin reaction to subthreshold exposures to low-molecular-weight compounds called haptens [1]
We utilized an in vivo adoptive transfer model to study the effect of cannabinoid receptors 1 (CB1) and/or cannabinoid receptor 2 (CB2) deficiency on the capacity of haptenized dendritic cells (DCs) to sensitize naïve mice for contact hypersensitivity (CHS)
We injected DNFB-haptenized DCs generated from the bone marrow (BM) of Cnr1−/−/Cnr2−/−, Cnr1−/−, Cnr2−/− or wild type (WT) mice into naïve WT recipients
Summary
Allergic contact dermatitis (ACD) is an inflammatory skin reaction to subthreshold exposures to low-molecular-weight compounds called haptens [1]. Skin manifestations such as pruritic skin lesions at sites of allergen exposure often manifest chronically, and they represent a rising global burden on the healthcare system [2,3]. We and others have demonstrated that CB1 and CB2 and their endogenous ligands are involved in skin allergies Genetic deletion of both CB1 and CB2 enhances contact allergic inflammation, with non-redundant roles for each cannabinoid receptor in the allergic response to DNFB [21]. CB2-specific antagonists/inverse agonists have been reported to alleviate chronic inflammation in mice, suggesting that there may be complex CB2-dependent regulation of inflammatory skin immune responses [23,24]. We examined the specific influence of CB1 and CB2 on the capacity of DCs to induce CHS and the specific role of CB2 in DC maturation and migration
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