Unexpected new roles for heparanase in Type 1 diabetes and immune gene regulation

Abstract

Heparanase (Hpse) is an endo-β-d-glucuronidase that degrades the glycosaminoglycan heparan sulfate (HS) in basement membranes (BMs) to facilitate leukocyte migration into tissues. Heparanase activity also releases HS-bound growth factors from the extracellular matrix (ECM), a function that aids wound healing and angiogenesis. In disease states, the degradation of HS in BMs by heparanase is well recognized as an invasive property of metastatic cancer cells. Recent studies by our group, however, have identified unexpected new roles for heparanase and HS. First, we discovered that in Type 1 diabetes (T1D) (i) HS in the pancreatic islet BM acts as a barrier to invading cells and (ii) high levels of HS within the insulin-producing islet beta cells themselves are critical for beta cell survival, protecting the cells from free radical-mediated damage. Furthermore, catalytically active heparanase produced by autoreactive T cells and other insulitis mononuclear cells was shown to degrade intra-islet HS, increasing the susceptibility of islet beta cells to free radical damage and death. This totally novel molecular explanation for the onset of T1D diabetes opens up new therapeutic approaches for preventing disease progression. Indeed, administration of the heparanase inhibitor, PI-88, dramatically reduced T1D incidence in diabetes-prone NOD mice, preserved islet beta cell HS and reduced islet inflammation. Second, in parallel studies it has been shown that heparanase and HS can be transported to the nucleus of cells where they impact directly or indirectly on gene transcription. Based on ChIP-on-chip studies heparanase was found to interact with the promoters and transcribed regions of several hundred genes and micro-RNAs in activated Jurkat T cells and up-regulate transcription, with many of the target genes/micro-RNAs being involved in T cell differentiation. At the molecular level, nuclear heparanase appears to regulate histone 3 lysine 4 (H3K4) methylation by influencing the recruitment of demethylases to transcriptionally active genes. These studies have unveiled new functions for heparanase produced by T lymphocytes, with the enzyme mediating unexpected intracellular effects on T cell differentiation and insulin-producing beta cell survival in T cell-dependent autoimmune T1D.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…Because these molecules regulate HA binding to CD44, they may affect the phenotypes associated with HA (32). Other components of the ECM are also reported to contribute to the development and progression of insulitis, either through HA-dependent or -independent mechanisms (6,(33)(34)(35)(36)(37). Taken together with our recent work on HA in human T1D (6), the progression to autoimmune diabetes is associated with profound changes in the ECM architecture.…”

NK cell heparanase controls tumor invasion and immune surveillance

“…For example, pro-heparanase can induce cell signaling via PI3-kinase-mediated phosphorylation of AKT (38,39) and even act as a transcription factor regulating genes involved in cell differentiation, inflammation, and glucose metabolism (40)(41)(42). Other studies reported that heparanase enzymatic activity upregulates proinflammatory cytokines from human peripheral blood leukocytes (IL-1β, IL-6, IL-8, IL-10, and TNF), as well as mouse splenocytes (IL-6, MCP-1, and TNF) (43).…”

The Role of Heparanase in the Pathogenesis of Acute Pancreatitis: A Potential Therapeutic Target

“…More specifically, it has recently been shown that HS is essential for the survival of pancreatic beta cells; In vivo , autoimmune destruction of islets was associated with production of catalytically active heparanase by islet-infiltrating mononuclear cells, and loss of islet HS 25, 26 . Furthermore, treatment with a heparanase inhibitor preserved intra islet HS and protected mice from type I diabetes 25, 26 . Thus, heparanase inhibitors may turn even more important for chronic pancreatitis, protecting beta cell islets from destructive heparanase produced by pancreatic acinar cells (Fig.…”