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

BackgroundAtopic 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-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.MethodsMice 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.ResultsWild-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-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.ConclusionsIn summary, we identified a critical role for the microbiome and IL-1β mediating chronic inflammation in mice with an impaired skin barrier.Filaggrin deficiency leads to skin dysbiosis early after birth altering adult immune responses, while mice raised under germ-free conditions remain disease-free. NLR Family Pyrin Domain Containing 3-independent processing of IL-1 in the skin promotes atopic dermatitis (AD)-like ILC2-independent inflammation. IL-1 deficiency or targeting IL-1 by monoclonal antibodies ameliorates dermatitis. IL-1R1-expressing dermal mast cells are key responders to IL-1, acquire a hyperactive phenotype, and promote AD-like inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152008/1/all13801_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152008/2/all13801-sup-0001-Suppinfo.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152008/3/all13801.pd