Timed NF-B inhibition in skin reveals dual independent effects on development of HED/EDA and chronic inflammation

Abstract

We have shown earlier that inhibiting NF-B activity in murine basal keratinocytes leads to hyperproliferation, inflammation, and cancer in a tumor necrosis factor receptor 1 (TNFR1)-dependent manner. We report here the outcomes of NF-B abrogation at different stages of epidermal morphogenesis using a conditional IBα transgenic mouse model. We find that blocking NF-B during embryogenesis mimics the epidermal and glandular defects seen in the human disease hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA), independently of the inflammatory phenotype and TNFR1. The onset of transgene expression after birth correlates with nuclear exclusion of the NF-B p50 subunit, hyperplasia, and development of a chronic inflammation initiated and dominated by macrophages. In this model, macrophages are important producers of the vascular endothelial growth factor A (VEGFA), whose inhibition attenuates the excessive angiogenesis otherwise observed. The inflammatory reaction requires the continuous suppression of NF-B in keratinocytes, indicating that an immune cell attractant(s) is directly induced in response to NF-B inhibition. As TNFα upregulation is a late event in this model, good candidates for such chemoattraction are the monocyte chemotactic proteins 1, 2, and 3 (MCP-1-2-3), which are upregulated in the epidermal compartment concomitantly with the onset of NF-B inhibition. © 2009 The Society for Investigative Dermatology.