Heparanase is preferentially expressed in human psoriatic lesions and induces development of psoriasiform skin inflammation in mice

Abstract

Heparanase is the sole mammalian endoglycosidase that selectively degrades heparan sulfate, the key polysaccharide associated with the cell surface and extracellular matrix of a wide range of tissues. Extensively studied for its capacity to promote cancer progression, heparanase enzyme was recently implicated as an important determinant in several inflammatory disorders as well. Applying immunohistochemical staining, we detected preferential expression of heparanase by epidermal keratinocytes in human psoriatic lesions. To investigate the role of the enzyme in the pathogenesis of psoriasis, we utilized heparanase transgenic mice in a model of 12-O-tetradecanoyl phorbol 12-myristate 13-acetate (TPA)-induced cutaneous inflammation. We report that over-expression of the enzyme promotes development of mouse skin lesions that strongly recapitulate the human disease in terms of histomorphological appearance and molecular/cellular characteristics. Importantly, heparanase of epidermal origin appears to facilitate abnormal activation of skin-infiltrating macrophages, thus generating psoriasis-like inflammation conditions, characterized by induction of STAT3, enhanced NF-κB signaling, elevated expression of TNFα and increased vascularization. Taken together, our results reveal, for the first time, involvement of heparanase in the pathogenesis of psoriasis and highlight a role for the enzyme in facilitating abnormal interactions between immune and epithelial cell subsets of the affected skin. Heparanase inhibitors (currently under clinical testing in malignant diseases) could hence turn highly beneficial in psoriatic patients as well.

Role of Heparanase-Driven Inflammatory Cascade in Pathogenesis of Diabetic Nephropathy

“…The emerging role of heparanase in modulating macrophage activation is further supported by recent findings in additional inflammatory models other than DN, including inflammatory bowel disease (32), atherosclerotic plaque progression toward vulnerability (52), and psoriasis (33). While the exact mechanism underlying heparanase-dependent activation of macrophages is not fully understood, the stimulation of pattern recognition receptors, such as TLRs, is among the candidate pathways.…”

“…Heparanase was recently shown to create a chronic inflammatory microenvironment, preserving abnormal activation of macrophages and preventing inflammation resolution in chronic colitis (32) and psoriasis (33). These findings, together with the preferential overexpression of heparanase in diabetic kidneys, led us to assume that in the DN setting heparanase facilitates inflammatory responses induced by the DM, sustaining continuous activation of kidney-damaging macrophages, thus fostering DN development and progression.…”

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

“…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). With the accumulation of experimental data, a complex picture of the versatile role of heparanase in inflammation is evolving, whereby heparanase may act either in facilitating or limiting inflammatory responses, depending on the cellular/extracellular context.…”

“…The above examples illustrate the complexity and duality of heparanase function in inflammatory conditions. Regardless, increased heparanase levels in the course of Crohn’s disease, ulcerative colitis (Waterman et al, 2007), empyema (Lapidot et al, 2015), psoriasis (Lerner et al, 2014), pancreatitis (Koliopanos et al, 2001) and arthritis (Li et al, 2008), and the reduced severity of sepsis (Schmidt et al, 2012) and diabetic nephropathy (Gil et al, 2012) in heparanase knockout mice implies that heparanase inhibitors may prove beneficial in some of these pathological conditions. The ability of heparanase inhibitors (i.e., PG545, SST0001, PI-88) to restrain experimental acute pancreatitis (Khamaysi et al, unpublished data), diabetic nephropathy (Gil et al, 2012), and autoimmune type 1 diabetes (Parish et al, 2013; Ziolkowski et al, 2012) provides hope that these and other heparanase inhibitors will restrain the expanding variety of inflammation-based disorders.…”

Involvement of Heparanase in Empyema: Implication for Novel Therapeutic Approaches

“…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]. The results presented here indicate that heparanase is also involved in the pathogenesis of pleural empyema, an inflammatory condition that progresses from acute to chronic, life-threatening phase.…”