Deciphering Heparanase enzyme mediated-Inflammatory mechanisms in Skin disease using a natural marine polysaccharide-derived inhibitor – HeparInfSkin

The skin lesions observed in psoriasis patients are characterised by chronic inflammation in which the overexpression of heparanase 1 (Hpa1) contributes, although its precise role remains to be demonstrated. Indeed, Hpa1 could participate in the inflammatory processes through its unique ability to degrade heparan sulphates in humans on the one hand or independently on the other hand. Heparanase 2 (Hpa2), a protein related to Hpa1, has anti-inflammatory properties and seems to be able to inhibit the enzymatic activity of Hpa1 by a mechanism that remains to be elucidated. The precise contribution of the imbalance between Hpa1 and Hpa2 expression and their activities in an inflammatory context has not yet been assessed. Hpa1 is naturally inhibited by heparin, which cannot be used as an anti-inflammatory strategy due to its anti-thrombotic properties. We have thus developed an oligosaccharide called lambda-CO derived from algal polysaccharides. The latter is an inhibitor of Hpa1 and also seems to have anti-inflammatory properties. In this context, the HeparInfSkin project aims i) to describe the mode of interaction between the two heparanases and their respective roles in the regulation of inflammation in macrophages, keratinocytes and skin fibroblasts; ii) to characterise the Hpa1-dependent and -independent mode of action of lambda-CO; iii) to evaluate the expression of the two heparanases in psoriasis patients; and finally iv) to validate the beneficial effects of lambda-CO in a relevant mouse model of psoriasis. For this purpose, different cell culture models of macrophages, epidermis and reconstructed skin will be set up from original mouse models, where the expression of the two heparanases will be specifically controlled. The HeparInfSkin project gathers the strengths of three French laboratories, with complementary and recognised expertise in their respective fields, combining the mastery of biochemistry, biotechnology, immunology, pharmacology, biophysics and structural biology approaches. This original and ambitious project, at the interface of fundamental and clinical research, will make it possible to characterise the contribution of heparanases during the different phases of the disease, particularly in the initiation, maintenance or resolution of cutaneous inflammatory processes and the mechanisms of action of lambda-CO, particularly its capacity to inhibit Hpa1 without interfering with the beneficial effects of Hpa2 on Hpa1. This project, which has no national competition, will certainly pave the way for new anti-inflammatory therapeutic strategies in humans based on the use of oligosaccharide of marine origin that modulates heparanase metabolism.