TWEAK signaling drives the transition from psoriasis to atopic dermatitis–like inflammation in paradoxical eczema

Targeted biologics have transformed the treatment of inflammatory skin diseases such as plaque psoriasis. However, some patients with psoriasis paradoxically develop eczematous skin reactions after therapy targeting tumor necrosis factor (TNF), interleukin-17 (IL-17), or IL-23. Although paradoxical eczema (PE) resembles atopic dermatitis (AD) clinically and histologically, the molecular mechanisms that drive its development remain poorly understood. Here, we generated high-resolution cellular and spatial maps of human skin using single-cell RNA sequencing, spatial transcriptomics, immunohistochemistry, and in vitro assays, profiling lesional biopsies from patients with PE ( n  = 8 donors), alongside healthy control, psoriasis, and AD skin ( n  = 4 donors per group). In PE, we identified distinct transcriptional changes characterized by myeloid and T cell expansion and an altered keratinocyte phenotype shaped by TNF-like weak inducer of apoptosis (TWEAK; encoded by TNFSF12 ) signaling through its receptor TNFRSF12A , confirmed at the protein level by immunohistochemistry. To define the underlying mechanism, we stimulated immortalized (N-TERT) and primary human keratinocytes and found that TWEAK acted together with IL-13 to drive a T helper 2– and type I interferon–polarized epithelial program that partially recapitulated the keratinocyte signature of PE lesions. We validated key target genes by quantitative polymerase chain reaction in primary keratinocytes. In THP-1 cells and primary human CD14 ⁺ monocytes, anti-TNF treatment induced TWEAK expression, suggesting a compensatory inflammatory circuit. Together, these findings identify the TWEAK–IL-13 axis as a key driver of PE and suggest how cytokine blockade may reshape cutaneous immune responses.