Type 2 innate lymphoid cells promote skin inflammation in mice and men, in part by producing IL-5 and IL-13 in response to IL-33

Loss-of-function mutations in the filaggrin gene (FLG), cause the semi-dominant keratinizing disorder, ichthyosis vulgaris1, and convey major genetic risk to atopic dermatitis/eczema, eczema-associated asthma2,3 and other allergic phenotypes5. Several low frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of ~9% in Europe4. Here we report a 1-bp deletion mutation, 5303delA, highly analogous to common human FLG mutations, within the murine flg gene in the spontaneous mouse mutant flaky tail (ft). Importantly, we demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate ft as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.

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Disease conditions associated with pulmonary fibrosis are progressive and have a poor long-term prognosis with irreversible changes in airway architecture leading to marked morbidity and mortalities. Using murine models we demonstrate a role for interleukin (IL)-25 in the generation of pulmonary fibrosis. Mechanistically, we identify IL-13 release from type 2 innate lymphoid cells (ILC2) as sufficient to drive collagen deposition in the lungs of challenged mice and suggest this as a potential mechanism through which IL-25 is acting. Additionally, we demonstrate that in human idiopathic pulmonary fibrosis there is increased pulmonary expression of IL-25 and also observe a population ILC2 in the lungs of idiopathic pulmonary fibrosis patients. Collectively, we present an innate mechanism for the generation of pulmonary fibrosis, via IL-25 and ILC2, that occurs independently of T-cell-mediated antigen-specific immune responses. These results suggest the potential of therapeutically targeting IL-25 and ILC2 for the treatment of human fibrotic diseases.innate response | cytokine | therapy | inflammation