Interleukin 4-driven loss of stromal LIF signaling affects immune responses and cell-cell adhesion in atopic dermatitis.

Atopic dermatitis (AD) involves immune dysregulation, epidermal barrier defects, and impaired cell-cell adhesion, yet the contribution of dermal fibroblasts (FBs) remains poorly understood. Here we show that leukemia inhibitory factor (LIF), a cytokine produced by dermal FBs, is downregulated in AD skin-driven by the Th2 cytokine IL-4-and that this loss triggers a self-amplifying inflammatory circuit. Using single-cell RNA sequencing, immunofluorescence, keratinocyte (KCs)-FBs co-cultures, and functional adhesion assays, we demonstrate that reduced LIF signaling elevates IL-6 production in KCs, activates ERK1/2, and decreases membrane expression of the desmosomal protein desmoglein 1 (DSG1), impairing epidermal cohesion. DSG1 loss further amplifies IL-6 secretion, perpetuating the cycle. Blocking IL-6 or ERK1/2 signaling rescues adhesion defects. These findings identify a stromal-epidermal axis linking Th2 inflammation to barrier dysfunction and offer mechanistic insights into AD chronicity.