Epidermal RelA Specifically Restricts Contact Allergen-Induced Inflammation and Apoptosis in Skin

Strong inhibition of NF-κB signaling in the epidermis results in spontaneous skin inflammation in mice and men. As there is evidence for linkage between polymorphisms within the NF-κB signaling pathway and human inflammatory skin phenotypes, we asked whether partial functional inhibition of NF-κB signaling in epidermal keratinocytes can modulate clinically relevant skin inflammation. We therefore mutated rela specifically in the epidermis of mice (RelAE−MUT mice). These mice show no inflammatory phenotype. Induction of contact allergy, but not croton oil-induced irritant dermatitis, resulted in stronger ear swelling and increased epidermal thickness in RelAE−MUT mice. Both contact allergen and croton oil treatment led to increased expression of calgranulins A and B (S100A8/ A9) in RelAE−MUT mice. Epidermal hyperproliferation in RelAE−MUT mice was non-cell autonomous as cultured primary epidermal keratinocytes from RelAE−MUT mice showed reduced proliferation compared with controls. These results demonstrate that epidermal RelA specifically regulates delayed-type hypersensitivity-induced skin inflammation. In addition, we describe here an essential but nonspecific function of RelA in the protection of epidermal keratinocytes from apoptosis. Our study identifies functions of NF-κB signaling in the epidermis and corroborates a specific role of epidermal keratinocytes in the regulation of skin inflammation.