RESUMO
Atopic dermatitis can result from loss of structural proteins in the outermost epidermal layers, leading to a defective epidermal barrier. To test whether this influences tumour formation, we chemically induced tumours in EPI-/- mice, which lack three barrier proteins-Envoplakin, Periplakin, and Involucrin. EPI-/- mice were highly resistant to developing benign tumours when treated with 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The DMBA response was normal, but EPI-/- skin exhibited an exaggerated atopic response to TPA, characterised by abnormal epidermal differentiation, a complex immune infiltrate and elevated serum thymic stromal lymphopoietin (TSLP). The exacerbated TPA response could be normalised by blocking TSLP or the immunoreceptor NKG2D but not CD4+ T cells. We conclude that atopy is protective against skin cancer in our experimental model and that the mechanism involves keratinocytes communicating with cells of the immune system via signalling elements that normally protect against environmental assaults.DOI: http://dx.doi.org/10.7554/eLife.01888.001.
Assuntos
Carcinoma de Células Escamosas/prevenção & controle , Transformação Celular Neoplásica/metabolismo , Dermatite Atópica/metabolismo , Epiderme/metabolismo , Proteínas de Membrana/deficiência , Papiloma/prevenção & controle , Plaquinas/deficiência , Precursores de Proteínas/deficiência , Neoplasias Cutâneas/prevenção & controle , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Comunicação Celular , Diferenciação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Citocinas/sangue , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Epiderme/imunologia , Epiderme/patologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Papiloma/induzido quimicamente , Papiloma/genética , Papiloma/imunologia , Papiloma/metabolismo , Papiloma/patologia , Permeabilidade , Plaquinas/genética , Precursores de Proteínas/genética , Transdução de Sinais , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Acetato de Tetradecanoilforbol , Fatores de Tempo , Linfopoietina do Estroma do TimoRESUMO
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.
