Influence of tissue stress and -damage on the development of allergic contact dermatitis

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Allergic contact dermatitis (ACD) is a T cell mediated skin disease with increasing prevalence. While the mechanisms resulting in T cell activation are quite well understood, the initial reactions providing a pro-inflammatory milieu in the skin remain unknown. Neither causative treatments for ACD nor validated in vitro assays to safely identify contact sensitizers exist. We have shown that the induction of allergic responses in the murine contact hypersensitivity (CHS) model crucially depends on the induction of an pro-inflammatory cytokine milieu in the skin. Here, activation of innate immune responses via pattern recognition receptors, i.e. the Toll-like receptors 2 and 4, is involved. Production of endogenous ligands for the activation of these receptors is mediated by induction of reactive oxygen species and the degradation of the extracellular matrix component hyaluronic acid. Release of ATP and its activation of the NLRP3 inflammasome are also involved in this setting. Together, these findings indicate that contact sensitizers induce tissue stress and damage as an essential element of the induction of CHS. However, the underlying mechanisms remain unknown so far. In this proposal we will investigate the effect of contact sensitizers and irritants on the induction of tissue stress and damage responses. We hypothesize that contact sensitizers are able to induce the activation of the unfolded protein response (UPR), autophagy, apoptosis and necrosis and that these responses are involved in the essential innate inflammatory response. Our preliminary data shows that the contact sensitizer trinitrochlorobenzene is able to induce the splicing of XBP-1, thus activating an important mediator of the UPR signaling cascade. As it is not known if the signaling pathway activated downstream of the UPR is the same for contact sensitizers and irritants, analysis of these pathways will not only add to our understanding of the mechansims leading to ACD but might also enable a differentiation between sensitizers and irritants in an in vitro setting. Analysis of these pathways might allow us to understand the underlying differences between strong and weak contact sensitizers and interference with these pathways should result in a reduction of inflammation thus abrogating CHS responses. This assumption is strengthened by our preliminary data showing that application of smac mimetica (inhibitors of the IAPs (IAP=inhibitor of apoptosis proteins)) is able to inhibit the CHS response to contact sensitizer treatment. The proposed project will identify potential targets for therapeutic interference as well as provide the basis for the development of urgently needed novel in vitro assays with mechanisitically defined endpoints for contact allergen identification.