Stiffness-Dependent Lysyl Oxidase Regulation through Hypoxia-Inducing Factor 1 Drives Extracellular Matrix Modifications in Psoriasis

• DOI: 10.1016/j.jid.2024.10.611
• Publication Date: 2024-11-26T06:30:35Z
• Authors: Parvaneh Balsini; Pauline Weinzettl; David Samardzic; Nina Zila; Maria Buchberger; Christian Freystä...; Philipp Tschandl; Matthias Wielscher; Wolfgang Weninger; Karin Pfisterer

Psoriasis is a common chronic inflammatory skin disease characterized by thickened epidermis with elongated rete ridges and massive immune cell infiltration. It currently unclear what impact mechanoregulatory aspects may have on progression. Using multiphoton second harmonic generation microscopy we found that the extracellular matrix (ECM) was profoundly reorganized within psoriatic dermis. Collagen fibers were highly aligned assembled into thick, long collagen bundles, whereas overall fiber density reduced. This particularly pronounced dermal papillae extending epidermis. Further, ECM-modifying enzyme LOX upregulated in dermis of psoriasis patients. In vitro experiments identified novel link between HIF-1 stabilization protein regulation mechanosensitive fibroblasts. secretion activity directly correlated substrate stiffness, independent hypoxia IL-17. Finally, scRNA-seq analysis fibroblasts expressing high amounts confirmed elevated expression psoriasis. Our findings suggest potential yet undescribed mechanical aspect Deregulated forces hence be involved initiating or maintaining positive feedback loop contribute to tissue stiffening diminished elasticity psoriasis, potentially exacerbating pathogenesis.