Versatile role of heparanase in inflammation

Abstract

Heparanase is the only known mammalian endoglycosidase capable of degrading heparan sulfate glycosaminoglycan, both in extracellular space and within the cells. It is tightly implicated in cancer progression and over the past few decades significant progress has been made in elucidating the multiple functions of heparanase in malignant tumor development, neovascularization and aggressive behavior. Notably, current data show that in addition to its well characterized role in cancer, heparanase activity may represent an important determinant in the pathogenesis of several inflammatory disorders, such as inflammatory lung injury, rheumatoid arthritis and chronic colitis. Nevertheless, the precise mode of heparanase action in inflammatory reactions remains largely unclear and recent observations suggest that heparanase can either facilitate or limit inflammatory responses, when tissue/cell -specific contextual cues may dictate an outcome of heparanase action in inflammation. In this review the involvement of heparanase in modulation of inflammatory reactions is discussed through a few illustrative examples, including neuroinflammation, sepsis-associated lung injury and inflammatory bowel disease. We also discuss possible action of the enzyme in coupling inflammation and tumorigenesis in the setting of inflammation-triggered cancer.

NK cell heparanase controls tumor invasion and immune surveillance

“…LWT1 (60) and RMA-S-RAE-1β (25) cell lines were cultured in complete RPMI 1640 (cRPMI) media containing 10% FBS, 100 U/ml penicillin, 100 μg/ml streptomycin, 2 mM glutamax, 55 μM 2-mercaptoethanol, HEPES, and sodium pyruvate. sis, and various rare diseases (10,(46)(47)(48). We have explored the importance of heparanase production by NK cells in their infiltration into Matrigel and tumors, but it might be interesting to assess the impact of heparanase loss in other NK cell-dependent conditions such as Herpes virus infections or recruitment into inflammatory sites caused by TLR agonists or similar danger signals, in which NK cells are known to be critical in host defense (49,50).…”

Heparanase Upregulation Contributes to Porcine Reproductive and Respiratory Syndrome Virus Release

“…It has been reported that dengue virus nonstructural protein 1 (NS1) disrupts the endothelial glycocalyx layer on human pulmonary microvascular endothelial cells by NS1-induced expression of sialidases and heparanase (23). Furthermore, heparanase is upregulated in numerous human diseases such as cancer, diabetes, renal disease, and Alzheimer's disease (35,36).…”

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

“…The resulting low molecular weight (LMW)-HA fragments accumulate and stimulate TLR2/4 and inflammatory gene expression, thereby promoting angiogenesis and cancer metastasis (7,23,24). Furthermore, active heparan sulfate (HS) fragments generated by heparanase-1 from extracellular barriers (25) and HS proteoglycan sources, such as the basement membrane perlecan (26), the cell surface syndecans (27), and glypicans (28), serve as TLR4-interacting DAMPs (29,30) (Fig. 1).…”

“…In the case of biglycan and decorin, interaction with TLRs is most likely mediated by LRRs present in the ligands (14 -16). HS and LMW-HA both activate TLR4 (25,81).…”