RESUMEN
We previously observed that aquaporin-3 and aquaporin-10 are upregulated in the epidermis of hand dermatitis patients (Med. Hypotheses, 84, 2015, 498). To address the functional relevance of this upregulation, we overexpressed AQP3/AQP10 in mice using the human K1 promoter. Combining imiquimod with detergent-containing water challenge, a common trigger in hand and other dermatitis, resulted in an increase in acanthosis in mice overexpressing AQP3 or AQP3 and AQP10. Aquaporin overexpression also drove a trend towards greater weight loss in these animals. These data support a role for cutaneous aquaporins in the pathogenesis of dermatitis and as a potential target in their treatment.
Asunto(s)
Acuaporina 3/genética , Acuaporinas/genética , Dermatitis/genética , Epidermis/metabolismo , Pérdida de Peso , Aminoquinolinas , Animales , Acuaporina 3/metabolismo , Acuaporinas/metabolismo , Diferenciación Celular , Dermatitis/etiología , Dermatitis/metabolismo , Detergentes , Proteínas Filagrina , Imiquimod , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/metabolismo , Queratina-10/genética , Queratina-10/metabolismo , Queratinocitos/fisiología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Regulación hacia ArribaRESUMEN
There is competing evidence that plasmacytoid dendritic cells (pDC), the most potent source of IFN-I, may initiate psoriasis. We targeted pDC function using the slc15a4feeble loss-of-function mouse whose pDC are unresponsive to TLR agonists. slc15a4feeble treated with the topical TLR7-agonist imiquimod (IMQ) demonstrated decreased epidermal thickening 24 hours post-treatment which was more pronounced by day 5 as compared to wildtype mice. These findings were specific to the acute IMQ model and not the protracted IL23 model that drives inflammation downstream of TLR activation. Systemically, slc15a4 was required for IMQ-induced weight loss and cutaneous accumulation of CD4+ and Siglec H+, but not CD11b+ cells. Consistent with this phenotype and the function of slc15a4, induction of IFN-I was virtually absent systemically and via cutaneous gene expression. Induction of other inflammatory cytokines (cytokine storm) was modestly blunted in slc15a4feeble except for inflammasome-associated genes consistent with slc15a4 being required for TLR7-mediated (but not inflammasome-mediated) inflammation downstream of IMQ. Surprisingly, only IFN-I gene expression was suppressed within IMQ-treated skin. Other genes including conserved psoriasiform trademark gene expression were augmented in slc15a4feeble versus littermate controls. Taken together, we have identified a role for slc15a4 but not canonical psoriasiform genes in the imiquimod model of psoriasiform dermatitis.