Myeloid-Specific Heparanase Aggravates Insulitis in Type 1 Diabetes via Heparan Sulfate Fragment-Dependent...

The intraislet heparan sulfate (HS) barrier is essential for β-cell survival, yet its role in type 1 diabetes (T1D) remains incompletely understood. We investigated the expression pattern, pathogenic function, and therapeutic potential of the heparanase (HPSE)-HS axis in T1D by integrating single-cell RNA sequencing data sets from human and mouse islets and peripheral immune cells, together with genetic mouse models and pharmacological intervention. HPSE was selectively enriched in myeloid cells, particularly CD14++ classical monocytes from patients with T1D and NOD mice and was associated with activated proinflammatory and interferon signaling. In diabetic islets, increased HPSE expression was accompanied by marked degradation of the HS barrier. Myeloid-specific Hpse deficiency improved glucose tolerance, enhanced insulin secretion, and reduced infiltration of inducible nitric oxide synthase-positive macrophages and T cells, whereas islet-specific Hpse overexpression accelerated autoimmune diabetes and insulitis. Mechanistically, HPSE-mediated HS cleavage generated bioactive fragments that acted as costimulatory signals, amplifying IFN-γ-STAT1 signaling and promoting M1 macrophage polarization. Pharmacological inhibition of HPSE with muparfostat preserved the intraislet HS barrier and improved glucose homeostasis in nonobese T1D models. Collectively, these findings identify myeloid-derived HPSE as a key driver of T1D pathogenesis through dual effects on HS barrier disruption and inflammatory amplification and establish the HPSE-HS axis as an important regulator of the islet inflammatory microenvironment and a promising adjuvant therapeutic target for T1D.

The role of the heparanase (HPSE)-heparan sulfate (HS) axis in type 1 diabetes remains incompletely defined. We examined whether myeloid-derived HPSE drives islet inflammation, how HS fragments influence macrophage polarization, and whether pharmacological inhibition is protective. We found that myeloid HPSE disrupts the intraislet HS barrier and that the resulting HS fragments potentiate interferon-γ-STAT1 signaling to promote proinflammatory macrophage polarization. Genetic or pharmacological inhibition of HPSE preserved islet integrity and ameliorated diabetes, identifying this pathway as a potential therapeutic target in type 1 diabetes.