title: Mice deficient in involucrin, envoplakin, and periplakin have a defective epidermal barrier.
abstract: The cornified envelope is assembled from transglutaminase cross-linked proteins and lipids in the outermost epidermal layers and is essential for skin barrier function. Involucrin, envoplakin, and periplakin form the protein scaffold on which the envelope assembles. To examine their combined function, we generated mice deficient in all three genes. The triple knockouts have delayed embryonic barrier formation and postnatal hyperkeratosis (abnormal accumulation of cornified cells) resulting from impaired desquamation. Cornified envelopes form but are ultrastructurally abnormal, with reduced lipid content and decreased mechanical integrity. Expression of proteases is reduced and the protease inhibitor, serpina1b, is highly upregulated, resulting in defective filaggrin processing and delayed degradation of desmoglein 1 and corneodesmosin. There is infiltration of CD4+ T cells and a reduction in resident gammadelta+ T cells, reminiscent of atopic dermatitis. Thus, combined loss of the cornified envelope proteins not only impairs the epidermal barrier, but also changes the composition of T cell subpopulations in the skin.
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, England, UK.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sevilla
authors.forename: Rachida
authors.initials: R
authors.lastname: Nachat
authors.forename: Karen R
authors.initials: KR
authors.lastname: Groot
authors.forename: John F
authors.initials: JF
authors.lastname: Klement
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Philippe
authors.initials: P
authors.lastname: Djian
authors.forename: Arto
authors.initials: A
authors.lastname: Määttä
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D004817:Epidermis / Q000002:abnormalities* / Q000378:metabolism* / Q000648:ultrastructure; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D010447:Peptide Hydrolases / Q000378:metabolism; D051179:Plakins / Q000172:deficiency / Q000235:genetics*; D011480:Protease Inhibitors / Q000378:metabolism; D011498:Protein Precursors / Q000172:deficiency / Q000235:genetics*
chemical_list: D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D051179:Plakins; C110037:Ppl protein, mouse; D011480:Protease Inhibitors; D011498:Protein Precursors; C100754:envoplakin; C032253:involucrin; D010447:Peptide Hydrolases