The IL-13-OVOL1-FLG axis in atopic dermatitis

Abstract

Despite sharing interleukin-4 receptor α (IL-4Rα) in their signaling cascades, IL-4 and IL-13 have different functions in atopic inflammation. IL-13 preferentially participates in the peripheral tissues because tissue-resident group 2 innate lymphoid cells produce IL-13 but not IL-4. In contrast, lymph node T follicular helper cells express IL-4 but not IL-13 to regulate B-cell immunity. The dominant microenvironment of IL-13 is evident in the lesional skin of atopic dermatitis (AD). The IL-13-rich local milieu causes barrier dysfunction by down-regulating the OVOL1-filaggrin (FLG) axis and up-regulating the periostin-IL-24 axis. Genome-wide association studies also point to the crucial involvement of the IL-13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL-13, such as the anti-IL-4Rα antibody dupilumab and the anti-IL-13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL-13 in the pathogenesis of AD.

Keywords: OVOL1; Periostin; atopic dermatitis; filaggrin; interleukin-13.

Figure 1

Simplified pathogenesis of atopic dermatitis. In the lesional skin of atopic dermatitis, T helper type 2 (Th2) cells and innate lymphoid cells (ILCs) produce high amounts of interleukin‐13 (IL‐13). IL‐13 induces OVOL1 inactivation and up‐regulates the periostin–IL‐24 axis, which down‐regulates filaggrin (FLG) and induces subsequent barrier dysfunction. Barrier dysfunction augments the epidermal production of thymic stromal lymphopoietin (TSLP), IL‐25 and IL‐33. These cytokines promote the differentiation of Th2 cells and group 2 ILCs (ILC2) and facilitate their production of IL‐13. IL‐13 also stimulates the sensory nerve and evokes the itch sensation. Itch‐induced scratching further deteriorates barrier dysfunction.