| First Author | Schwartz C | Year | 2019 |
| Journal | Allergy | Volume | 74 |
| Issue | 10 | Pages | 1920-1933 |
| PubMed ID | 30937919 | Mgi Jnum | J:346788 |
| Mgi Id | MGI:6756590 | Doi | 10.1111/all.13801 |
| Citation | Schwartz C, et al. (2019) Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1beta. Allergy 74(10):1920-1933 |
| abstractText | 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 (Flg(ft/ft) ) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL-1beta 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. Flg(ft/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 Flg(ft/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 Flg(ft/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-1beta and IL-1R1-signaling. Mechanistically, IL-1beta promoted hyperactivation of IL-1R1-expressing mast cells. Treatment with anti-IL-1beta-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-1beta mediating chronic inflammation in mice with an impaired skin barrier. |
