RESUMEN
The presence of congenitally impaired skin barrier followed by atopic dermatitis (AD) is an initial step in the atopic march. The maintenance of acidic pH in the stratum corneum (SC) has been suggested as a therapeutic or preventive strategy for barrier impairment caused by skin inflammation. To determine whether an AD murine model, flaky tail mice, with inherited filaggrin deficiency could develop airway inflammation by repeated topical application followed by nasal inhalation of house dust mite (HDM) antigen (defined as a novel "atopic march animal model"), and whether maintenance of an acidic SC environment by continuous application of acidic cream could interrupt the following atopic march. During the course of HDM treatment, acidic cream (pH2.8) or neutral cream (pH7.4) was applied to flaky tail mice twice daily. Repeated applications and inhalations of HDM to flaky tail mice induced AD skin lesions followed by respiratory allergies. Maintenance of SC acidity inhibited the occurrence of respiratory allergic inflammation as well as AD-like skin lesions. Collectively, a novel atopic march model could be developed by repeated epicutaneous and nasal applications of HDM to flaky tail mice, and that the acidification of SC could prevent the atopic march from AD to respiratory allergy.
Asunto(s)
Dermatitis Atópica/prevención & control , Epidermis/química , Proteínas de Filamentos Intermediarios/genética , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/prevención & control , Crema para la Piel/uso terapéutico , Administración Cutánea , Animales , Antígenos Dermatofagoides/toxicidad , Citocinas/sangre , Dermatitis Atópica/complicaciones , Dermatitis Atópica/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epidermis/metabolismo , Femenino , Proteínas Filagrina , Concentración de Iones de Hidrógeno , Inmunoglobulina E/sangre , Exposición por Inhalación/efectos adversos , Proteínas de Filamentos Intermediarios/deficiencia , Proteínas de la Membrana/metabolismo , Ratones , Precursores de Proteínas/metabolismo , Crema para la Piel/química , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma. OBJECTIVE: We sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency. METHODS: Filaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes. RESULTS: Filaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5-producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects. CONCLUSION: This study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function.
Asunto(s)
Inmunidad Adaptativa , Dermatitis Atópica/complicaciones , Dermatitis Atópica/inmunología , Inmunidad Innata , Neumonía/etiología , Animales , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Proteínas Filagrina , Proteínas de Filamentos Intermediarios/deficiencia , Proteínas de Filamentos Intermediarios/genética , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos/patología , Ratones , Ratones Transgénicos , Mutación , Fenotipo , Neumonía/patología , Piel/inmunología , Piel/metabolismo , Piel/patologíaAsunto(s)
Dermatitis Atópica/patología , Modelos Animales de Enfermedad , Abdomen , Animales , Citocinas/análisis , Dermatitis Atópica/genética , Dermatitis Atópica/fisiopatología , Epidermis/química , Cara , Ratones , Ratones Endogámicos C57BL , Cuello , Pérdida Insensible de Agua , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: Neutralization of stratum corneum (SC) pH, which is induced by a variety of stimuli, such as scratching, use of soap and inflammation, can stimulate activity of serine protease (SPase). Activation of SPase induces production of thymic stromal lymphopoietin (TSLP) through protease-activated receptor-2. Both reduced expression of natural moisturizing factors, which are required for maintenance of SC pH, and the preferential development of atopic dermatitis (AD)-like dermatitis are found in flaky-tail mice (FTM) with a loss-of-function mutation in filaggrin. OBJECTIVE: We examined possible correlations between disturbance of responses to an exogenous stimulus of SC neutralization and the preferential emergence of AD-like dermatitis in FTM. METHODS: FTM and wild-type mice (C57BL/6) were subjected to an SC-neutralization stimulus via application of 1,1,3,3-tetramethylguanidine (TMG). TMG was applied to young mice at a time when FTM had not yet developed significant dermatitis, and we examined their ability to maintain SC acidity and several parameters associated with AD-like dermatitis. RESULTS: The recovery of SC pH after the application of TMG was delayed in FTM, presumably because of unchanged expression of Na(+)/H(+) antiporter 1, which is involved in maintenance of SC acidity. Cutaneous inflammation with elevated SPase activity and serum levels of TSLP, thymus and activation-regulated chemokine and IgE were induced only in TMG-treated FTM. CONCLUSION: Our results suggest that defective maintenance of pH of SC is correlated with emergence and exacerbation of AD-like dermatitis in FTM.
Asunto(s)
Dermatitis Atópica/etiología , Epidermis/química , Animales , Proteínas de Transporte de Catión/metabolismo , Quimiocina CCL17/sangre , Citocinas/sangre , Epidermis/metabolismo , Femenino , Guanidinas , Concentración de Iones de Hidrógeno , Inmunoglobulina E/sangre , Ratones Endogámicos C57BL , Serina Proteasas/metabolismo , Intercambiador 1 de Sodio-Hidrógeno , Intercambiadores de Sodio-Hidrógeno/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
BACKGROUND: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. OBJECTIVE: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. METHODS: A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. RESULTS: The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt(ft) mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6684514, [corrected] in the human MATT gene has a small but significant association with AD. CONCLUSION: In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.