Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1ß.
Allergy
; 74(10): 1920-1933, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-30937919
ABSTRACT
BACKGROUND:
Atopic dermatitis (AD) is one of the most common skin diseases with a multifactorial etiology. Mutations leading to loss of skin barrier function are associated with the development of AD with group 2 innate lymphoid cells (ILC2) promoting acute skin inflammation. Filaggrin-mutant (Flgft/ft ) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL-1ß production, and other cytokines recapitulating human AD. Here, we investigated the role of ILC2, effector cytokines, inflammasome activation, and mast cell function on the development of chronic AD-like inflammation in mice.METHODS:
Mice with a frameshift mutation in the filaggrin gene develop spontaneous dermatitis. Flgft/ft mice were crossed to cell- or cytokine-deficient mouse strains, or bred under germ-free conditions. Skin inflammation was scored, and microbiome composition was analyzed. Skin protein expression was measured by multiplex immunoassay. Infiltrating cells were analyzed by flow cytometry.RESULTS:
Wild-type and Flgft/ft mice significantly differ in their microbiome composition. Furthermore, mutant mice do not develop skin inflammation under germ-free conditions. ILC2 deficiency did not ameliorate chronic dermatitis in Flgft/ft mice, which was also independent of IL-4, IL-5, IL-9, IL-13, IL-17A, and IL-22. Inflammation was independent of NLRP3 inflammasome activation but required IL-1ß and IL-1R1-signaling. Mechanistically, IL-1ß promoted hyperactivation of IL-1R1-expressing mast cells. Treatment with anti-IL-1ß-antibody alleviated dermatitis exacerbation, while antibiotic intervention ameliorated dermatitis in neonatal mice but not in adults with established inflammation.CONCLUSIONS:
In summary, we identified a critical role for the microbiome and IL-1ß mediating chronic inflammation in mice with an impaired skin barrier.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos
/
Dermatite Atópica
/
Interleucina-1beta
/
Imunidade Inata
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Allergy
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Irlanda