Heparanase and autoimmune diabetes

Abstract

Heparanase (Hpse) is the only known mammalian endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS), found attached to the core proteins of heparan sulfate proteoglycans (HSPGs). Hpse plays a homeostatic role in regulating the turnover of cell-associated HS and also degrades extracellular HS in basement membranes (BMs) and the extracellular matrix (ECM), where HSPGs function as a barrier to cell migration. Secreted Hpse is harnessed by leukocytes to facilitate their migration from the blood to sites of inflammation. In the non-obese diabetic (NOD) model of autoimmune Type 1 diabetes (T1D), Hpse is also used by insulitis leukocytes to solubilize the islet BM to enable intra-islet entry of leukocytes and to degrade intracellular HS, an essential component for the survival of insulin-producing islet beta cells. Treatment of pre-diabetic adult NOD mice with the Hpse inhibitor PI-88 significantly reduced the incidence of T1D by ~50% and preserved islet HS. Hpse therefore acts as a novel immune effector mechanism in T1D. Our studies have identified T1D as a Hpse-dependent disease and Hpse inhibitors as novel therapeutics for preventing T1D progression and possibly the development of T1D vascular complications.

Keywords: diabetes; heparan sulfate; heparanase; inflammation; islet; vascular complications.

Figure 1

Autoimmune T1D in NOD/Lt mice is characterized by cell surface expression of heparanase on insulitis leukocytes. Histology (A) and immunohistochemistry (B) of a pancreatic islet in a NOD/Lt female mouse at the time of T1D onset shows islet infiltration by destructive heparanase (Hpse)-expressing insulitis leukocytes (B) localized particularly at the insulitis-islet interface, a process which leads to loss of beta cell HS and beta cell death. (A) hematoxylin and eosin; (B) HP130 anti-heparanase mAb. Ins, insulitis mononuclear cells; DI, damaged islet tissue; Hpse, heparanase.

Figure 2

Diagram showing a pancreatic islet and four stages of T1D disease driven by heparanase and loss of intra-islet HS. HS (intense blue color) is shown in normal beta cells and in intact peri-islet BM. In Stage 1 of the disease process, non-destructive insulitis mononuclear cells produce heparanase (red dots). Onset of destructive insulitis occurs when heparanase becomes catalytically active and degrades HS in the islet BM (Stage 2). Damage to the islet BM barrier allows activated autoreactive T cells to enter the islet cell mass where the local production of heparanase leads to degradation of intracellular HS in islet beta cells (paling blue color; Stage 3). Progression of HS depletion throughout the islet beta cell population results in increased beta cell death (palest blue color in “shriveled” beta cells; Stage 4), loss of insulin production and ultimately the development of T1D. MNC, mononuclear cell; BM, basement membrane; Hpse, heparanase.