RESUMO
BACKGROUND: Barrier disruption and the resulting continuous exposure to allergens are presumed to be responsible for the development of atopic dermatitis (AD). However, the mechanism through which skin barrier function is disrupted in patients with AD remains unclear. OBJECTIVES: Taking into account the fact that the TH2 milieu impairs keratinocyte terminal differentiation, we sought to clarify our hypothesis that the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in skin barrier function and can be a therapeutic target for AD. METHODS: We analyzed the mechanism of keratinocyte differentiation using a microarray and small interfering RNA targeting STATs. We studied the effect of the JAK inhibitor JTE-052 on keratinocyte differentiation using the human skin equivalent model and normal human epidermal keratinocytes. We applied topical JAK inhibitor onto NC/Nga mice, dry skin model mice, and human skin grafted to immunocompromised mice. RESULTS: IL-4 and IL-13 downregulated genes involved in keratinocyte differentiation. STAT3 and STAT6 are involved in keratinocyte differentiation and chemokine production by keratinocytes, respectively. Topical application of the JAK inhibitor suppressed STAT3 activation and improved skin barrier function, permitting increases in levels of terminal differentiation proteins, such as filaggrin, and natural moisturizing factors in models of AD and dry skin and in human skin. CONCLUSION: STAT3 signaling is a key element that regulates keratinocyte differentiation. The JAK inhibitor can be a new therapeutic tool for the treatment of disrupted barrier function in patients with AD.
Assuntos
Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Hospedeiro Imunocomprometido , Queratinócitos/efeitos dos fármacos , Fator de Transcrição STAT3/imunologia , Animais , Diferenciação Celular/efeitos dos fármacos , Dermatite Atópica/genética , Dermatite Atópica/patologia , Modelos Animais de Doenças , Proteínas Filagrinas , Regulação da Expressão Gênica , Humanos , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Queratinócitos/imunologia , Queratinócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/imunologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT6/antagonistas & inibidores , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Transdução de Sinais , Transplante de Pele , Pele Artificial , Transplante HeterólogoRESUMO
The BUF/Mna strain of rat is a model of focal and segmental glomerulosclerosis (FSGS) in which a quantitative trait locus (QTL) for proteinuria, Pur1, has been identified. The aim of the present study was to identify candidates for the Pur1 gene. To narrow the Pur1 QTL, we performed fine QTL mapping and single nucleotide polymorphism (SNP) genotyping. To identify candidate genes, sequencing and gene-expression analyses of all genes contained in the narrowed locus were conducted. The narrowed Pur1 region contained 25 genes. Among these genes, only the Arp3 gene was mutated in the BUF/Mna strain; it contained a missense mutation that caused an (L)111(F) substitution. This leucine is conserved across species. Gene-expression analysis failed to identify any other candidate genes for Pur1. Arp3-mediated actin assembly abnormalities were visible in immunohistochemical and electron microscopic examinations of podocytes in old BUF/Mna rats. Taken together, these data suggest that Arp3 is a candidate for the Pur1 gene. This observation is consistent with our growing recognition that abnormal signaling-induced assembly of actin in podocytes leads to the development of FSGS.