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

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‐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. 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‐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. 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.