Timed NF-kappaB inhibition in skin reveals dual independent effects on development of HED/EDA and chronic inflammation.
We have shown earlier that inhibiting NF-kappaB 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-kappaB abrogation at different stages of epidermal morphogenesis using a conditional IkappaBalpha transgenic mouse model. We find that blocking NF-kappaB 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-kappaB 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-kappaB in keratinocytes, indicating that an immune cell attractant(s) is directly induced in response to NF-kappaB inhibition. As TNFalpha 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-kappaB inhibition.
Ulvmar
Maria H
MH
Department of Bioscience and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Sur
Inderpreet
I
Mémet
Sylvie
S
Toftgård
Rune
R
D000818:Animals; D000831:Animals, Newborn; D043422:Carboxypeptidases A / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D002908:Chronic Disease; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004476:Ectodermal Dysplasia / Q000276:immunology* / Q000473:pathology; D004817:Epidermis / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007007:Hypohidrosis / Q000276:immunology* / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D052002:NF-kappa B p50 Subunit; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse