Mice deficient in heparanase exhibit impaired dendritic cell migration and reduced airway inflammation

Abstract

Heparanase is a β-D-endoglucuronidase that cleaves heparan sulphate, a key component of the ECM and basement membrane. The remodelling of the ECM by heparanase has been proposed to regulate both normal physiological and pathological processes, including wound healing, inflammation, tumour angiogenesis and cell migration. Heparanase is also known to exhibit non-enzymatic functions by regulating cell adhesion, cell signalling and differentiation. In this study, constitutive heparanase-deficient (Hpse −/− ) mice were generated on a C57BL/6 background using the Cre/loxP recombination system, with a complete lack of heparanase mRNA, protein and activity. Although heparanase has been implicated in embryogenesis and development, Hpse −/− mice are anatomically normal and fertile. Interestingly, consistent with the suggested function of heparanase in cell migration, the trafficking of dendritic cells from the skin to the draining lymph nodes was markedly reduced in Hpse −/− mice. Furthermore, the ability of Hpse −/− mice to generate an allergic inflammatory response in the airways, a process that requires dendritic cell migration, was also impaired. These findings establish an important role for heparanase in immunity and identify the enzyme as a potential target for regulation of an immune response.

Heparanase: From basic research to therapeutic applications in cancer and inflammation

“…Notably, heparanase gene silencing resulted in decreased delayed-type hypersensitivity (DTH) reaction (Edovitsky et al, 2006), and heparanase knockout mice showed reduced airway and acute lung injury responses in models of allergy and sepsis (Poon et al, 2014; Schmidt et al, 2012). Furthermore, transgenic mice overexpressing heparanase are endowed with increased DTH (Edovitsky et al, 2006), colon (colitis) (Lerner et al, 2011), pancreas (unpublished data) and skin (psoriasis-like) (Lerner et al, 2014) inflammation, collectively implying that heparanase is an important player in the inflammatory reaction (Goldberg et al, 2013; Li and Vlodavsky, 2009; Zhang et al, 2014).…”

NK cell heparanase controls tumor invasion and immune surveillance

“…DNA was purified from FACS-sorted mouse NK cells using QuickExtract DNA Extraction Solution (Epicentre). The primer sets and conditions for expression of the mouse Hpse gene have been published previously (6). For genotyping of the NKp46-iCre allele, the following primers were used in 1 reaction (giving rise to a product of approximately 400 bp for the WT …”

“…In mammals, the only enzyme known to degrade HSPGs is the endo-β-D-glucuronidase heparanase. There is only 1 enzymatically active form of heparanase in mammals that is expressed at very low levels in normal tissues, and heparanase deficiency in mice causes no obvious pathophysiologies (5,6). Heparanase is secreted as an enzymatically inactive pro-heparanase and requires reuptake into the cell and processing by cathepsin-L in lysosomes (7) or α granules (8) in order to give rise to the enzymatically active heparanase protein.…”

“…Recently generated heparanase gene-targeted (Hpse-targeted) mice were used to investigate the role of heparanase in immune cell subtypes in response to different stimuli. Whereas heparanase was proven important for the migration of DCs (6,18) and eosinophils (19) in response to inflammation and allergic sensitization, heparanase appeared dispensable for the extravasation of mouse neutrophils and T cells under inflammatory conditions (19,20). In contrast, heparanase reportedly enhances the tumor NK cells are highly efficient at preventing cancer metastasis but are infrequently found in the core of primary tumors.…”

Involvement of Heparanase in Empyema: Implication for Novel Therapeutic Approaches

“…In line with this notion, heparanase up-regulation was observed in different inflammatory conditions [25-28] and is thought to promote inflammation. Indeed, heparanase gene silencing resulted in decreased delayed-type hypersensitivity reaction [25], and heparanase knockout mice showed reduced airway and acute lung injury responses in models of allergy and sepsis [29,30]. Furthermore, transgenic mice over expressing heparanase are endowed with increased colon (colitis) and skin (psoriasis-like) inflammation [26,31], collectively implying that heparanase is an important player in the inflammatory reaction [32-35].…”