Heparanase 1 produced by keratinocytes contributes to psoriatic inflammation by promoting neutrophil infiltration.

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation, abnormal differentiation, and immune cell infiltration, driven by a pro-inflammatory microenvironment involving cytokines, and diverse enzymatic activities. Among them, are the two heparanases, Heparanase 1 (HPA1), an endo-β-D-glucuronidase that cleaves heparan sulfate and contributes to extracellular matrix remodeling and inflammatory cell recruitment, and Heparanase 2 (HPA2), which lacks enzymatic activity and acts as an antagonist of HPA1. While their roles are established in cancer and inflammation, their involvment in psoriasis remains underexplored, despite the intense matrix remodeling and inflammatory cell recruitment characteristic of the disease. We found increased HPA1 and decreased HPA2 expression in human psoriatic lesions, with normalization following anti-TNF-α therapy. In vitro, HPA1 expression and activity are enhanced in keratinocytes stimulated with the psoriasiform cytokine combination IL-1α, IL-17A and TNF-α, while HPA1 inhibition dampens pro-inflammatory cytokine production. In vivo, imiquimod-induced psoriasiform inflammation in mice shows similar patterns of Hpa1 upregulation, Hpa2 downregulation, and Hpa1-dependent chemokines production and neutrophils recruitmentto lesional sites. These findings suggest that HPA1 and HPA2 contribute to the establishment and/or maintenance of psoriatic lesions. Modulating their expression or activity could provide a more precise understanding of their contribution to skin inflammation.