Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1β

Schwartz C, Moran T, Saunders SP, Kaszlikowska A, Floudas A, Bom J, Nunez G, Iwakura Y, O’Neill L, Irvine AD, McKenzie AN, Ogg G, Walsh PT, Demengeot J, Fallon PG (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Allergy Wiley-Blackwell

DOI: 10.1111/all.13801

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 (Flg ft/ft ) mice develop spontaneous skin inflammation accompanied by an increase in skin ILC2 numbers, IL-1β 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-1β and IL-1R1-signaling. Mechanistically, IL-1β promoted hyperactivation of IL-1R1-expressing mast cells. Treatment with anti-IL-1β-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-1β mediating chronic inflammation in mice with an impaired skin barrier.

Authors with CRIS profile

Christian Schwartz Department of Infection Biology

Involved external institutions

Trinity College Dublin IE Ireland (IE) Temple Street Children's University Hospital / Children's Health Ireland (CHI) IE Ireland (IE) Tokyo University of Science / 東京理科大学 (Tōkyō Rika Daigaku) JP Japan (JP) Instituto Gulbenkian de Ciência PT Portugal (PT) University of Michigan US United States (USA) (US) University of Oxford GB United Kingdom (GB) MRC Laboratory of Molecular Biology DE Germany (DE)

How to cite

APA:

Schwartz, C., Moran, T., Saunders, S.P., Kaszlikowska, A., Floudas, A., Bom, J.,... Fallon, P.G. (2019). Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1β. Allergy. https://dx.doi.org/10.1111/all.13801

MLA:

Schwartz, Christian, et al. "Spontaneous atopic dermatitis in mice with a defective skin barrier is independent of ILC2 and mediated by IL-1β." Allergy (2019).

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