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

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