Epidermal overexpression of transgenic Δnp63 promotes type 2 immune and myeloid inflammatory responses and hyperplasia via NF-κB activation

ΔNp63 is known to be critical in skin development and cancer; however, how it triggers proliferation and inflammation in vivo remains to be elucidated. Here, we find that induced ΔNp63 expression in skin of transgenic mice (TG) results in a hyperproliferative epidermis coupled with inflammatory infiltrates. In situ, infiltrating cells include CD45⁺ leukocytes, CD19⁺ B lymphocytes, CD3⁺ T lymphocytes, CD4⁺ T helper, CD25⁺/Foxp3⁺ Treg, Ly6B ⁺ neutrophils, S-100⁺ dendritic cells, and macrophages bearing CD11b⁺, F4/80⁺, CD68⁺, and CD206 ⁺ M2 type markers. Transcriptional profiling of TG skin revealed increased gene expression involved in inflammation and immune responses, including Th2/M2 cytokines and chemokines. These genes were co-regulated by ΔNp63 and NF-κB RelA or cRel, and enhanced by TNF-α. Elevated cRel, RelA, and IKKs were observed in TG mouse skin and human squamous carcinomas with ΔNp63 overexpression. Thus, our findings unveil a missing link connecting overexpressed ΔNp63 with aberrant NF-κB activation, pro-inflammatory and type 2 cytokines and chemokines, and host infiltrates during skin inflammation and hyperplasia. Our findings provide a missing link between ΔNp63 overexpression and NF-κB-mediated inflammation, of potential relevance to the pathogenesis of squamous carcinoma. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.