IL-4/IL-13 Axis

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are hallmark type 2 cytokines produced by Th2 lymphocytes, innate lymphoid cells type 2 (ILC2s), mast cells, basophils, and eosinophils. Epithelial barrier disruption and the resulting release of alarmins including TSLP, IL-33, and IL-25 initiates the type 2 inflammatory cascade by activating ILC2s and promoting Th2 differentiation. IL-4 signals through the type I receptor complex (IL-4Ralpha/gammac) on T-cells, driving Th2 polarisation and IgE class-switching in B-cells. Both IL-4 and IL-13 signal through the type II receptor complex (IL-4Ralpha/IL-13Ralpha1), expressed on non-haematopoietic cells including keratinocytes, airway epithelium, and smooth muscle.

In atopic dermatitis, IL-4 and IL-13 signalling via JAK1-STAT6 drives barrier dysfunction through suppression of filaggrin, loricrin, and other structural proteins, perpetuating a cycle of allergen sensitisation and inflammation. IL-13 mediates mucus hypersecretion and subepithelial fibrosis in the airway, driving airway hyperresponsiveness in asthma and nasal polyp formation in chronic rhinosinusitis. In prurigo nodularis, IL-4/IL-13 signalling contributes to intense pruritus and epidermal thickening through direct neuronal sensitisation and keratinocyte activation.

Dupilumab targets IL-4Ralpha, simultaneously blocking both IL-4 and IL-13 type II signalling. IL-13-selective approaches (tralokinumab, lebrikizumab) offer an alternative strategy with a narrower target profile. The relative contribution of IL-4 versus IL-13 to specific disease endotypes remains an area of active clinical investigation, with the axis demonstrating centrality across multiple type 2 inflammatory diseases including atopic dermatitis, asthma, CRSwNP, prurigo nodularis, and eosinophilic oesophagitis.