Stiffness-dependent LOX regulation via HIF-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 (ECM) 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. Further, the ECM-modifying enzyme LOX was highly upregulated in the dermis of psoriasis patients. In vitro experiments identified a novel link between HIF-1 stabilization and LOX protein regulation in mechanosensitive skin fibroblasts. LOX secretion and activity directly correlated with substrate stiffness, and was independent of hypoxia and IL-17. Finally, scRNA-seq analysis identified skin fibroblasts expressing high amounts of LOX and confirmed elevated HIF-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.