Evidence that IL-4/IL-13-Responsive IGFLs Promote Allergic Skin Inflammation

IGF-Like (IGFL) Family member proteins are a putative cytokine family whose functions are not defined. Here we demonstrate that IGFL1 and IGFL4 are significantly increased in lesional atopic dermatitis (AD) skin and mouse Igfl is significantly increased in an oxazolone (Oxa)-induced model of allergic skin inflammation. In addition, studies with Igfl-deficient mice revealed significant reductions in markers of disease severity. RNA sequencing and qPCR demonstrated reduced Il4, Il13, and other type 2 inflammation-associated transcripts in Oxa treated skin from Igfl-deficient mice. As the Oxa model is Th2 cytokine-dependent, we hypothesized IL-4 and/or IL-13 promote Igfl expression. In support of this, we discovered Il4 precedes Igfl induction in the Oxa model. We then identified mouse keratinocytes as a source of Igfl and found stimulation with IL-4 or IL-13 promoted Igfl expression in these cells, while IFNγ did not. Stimulation of human keratinocytes with IL-4 or IL-13 induced IGFL4. In vivo experiments also demonstrated that Igfl induction is dependent on IL-4Rα in the Oxa model, and AD patients who received dupilumab or tralokinumab treatment showed decreased IGFL4 expression in lesional skin. These data suggest there is a positive feedback loop between IL-4/IL-13 and IGFLs that can promote allergic skin inflammation.