TWEAK signaling as a central driver of paradoxical reactions: Linking psoriasis to atopic dermatitis-like inflammation.

Summary: Abstract Body: Psoriasis (PP) is a chronic skin condition characterized by Th1/Th17-driven inflammation and abnormal keratinocyte proliferation, while atopic dermatitis (AD) is driven by Th2-mediated responses. A subset of PP patients treated with biologics (e.g., TNF-α, IL-17, and IL-23 inhibitors) develop paradoxical reactions (PR), presenting with AD-like inflammation. The mechanisms underlying this shift remain unclear. To investigate PR, we generated a single-cell and spatial transcriptomic atlas of skin biopsies from healthy controls (NL), PP, AD, and PR patients. Analysis of 20 samples (106,331 cells) identified 16 cell types with distinct frequencies across conditions. PR uniquely exhibited enriched interferon responses, leukocyte-mediated immunity, and a Th2-dominant profile. Differential gene expression analysis revealed upregulated immune-related genes (e.g., IFITM3, STAT1, CD74) and pronounced interferon signaling in PR. PR demonstrated the highest number of cell-cell interactions, revealing a pro-inflammatory microenvironment uniquely regulated by TWEAK signaling. Key contributors to this pathway included keratinocytes, myeloid cells, and fibroblasts, with increased expression of TNFSF12 (TWEAK ligand) and TNFRSF12A (receptor). Immunohistochemistry confirmed elevated TNFSF12+ cell densities in PR, mirroring AD patterns. TNFSF12+ keratinocytes were enriched for immune and stress response pathways (e.g., “response to type II interferon”), highlighting their role in inflammation and epidermal remodeling. In contrast, TNFSF12− keratinocytes were associated with differentiation and structural maintenance. Our findings identify TWEAK signaling as a driver of the inflammatory shift in PR, validated by spatial sequencing and immunohistochemistry. Targeting TWEAK signaling offers a promising therapeutic strategy to mitigate PR’s effects while maintaining effective PP management, improving outcomes for patients with biologic-induced PR. Sahiti Marella¹, Rachael Bogle¹, Lam C. Tsoi¹, Xianying Xing¹, Allison C. Billi¹, Johann E. Gudjonsson¹, Eran Cohen Barak² 1. Dermatology, University of Michigan, Ann Arbor, MI, United States. 2. Medicine, Technion Israel Institute of Technology, Haifa, Haifa District, Israel. Cell Communication Networks and Stromal Biology