Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function

Abstract

Patients with protein-losing enteropathy (PLE) fail to maintain intestinal epithelial barrier function and develop an excessive and potentially fatal efflux of plasma proteins. PLE occurs in ostensibly unrelated diseases, but emerging commonalities in clinical observations recently led us to identify key players in PLE pathogenesis. These include elevated IFN-γ, TNF-α, venous hypertension, and the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells during PLE episodes. Here we show that heparan sulfate and syndecan-1, the predominant intestinal epithelial heparan sulfate proteoglycan, are essential in maintaining intestinal epithelial barrier function. Heparan sulfate-or syndecan-1-deficient mice and mice with intestinal-specific loss of heparan sulfate had increased basal protein leakage and were far more susceptible to protein loss induced by combinations of IFN-γ, TNF-α, and increased venous pressure. Similarly, knockdown of syndecan-1 in human epithelial cells resulted in increased basal and cytokine-induced protein leakage. Clinical application of heparin has been known to alleviate PLE in some patients but its unknown mechanism and severe side effects due to its anticoagulant activity limit its usefulness. We demonstrate here that non-anticoagulant 2,3-de-O-sulfated heparin could prevent intestinal protein leakage in syndecan-deficient mice, suggesting that this may be a safe and effective therapy for PLE patients.

Role of the Heparan Sulfate Proteoglycan Syndecan-1 (CD138) in Delayed-Type Hypersensitivity

“…1 and 2). This finding is in line with our previously stated hypothesis that Sdc-1 may modulate vascular permeability via its interaction with kininogens or CAP37 (7) and with an increase in paracellular protein leakage in Sdc-1 KO vs WT mice in a mouse model of protein-losing enteropathy (39). Increased leukocyte recruitment in the absence of Sdc-1 was consistently observed in different contexts of inflammation and repair, including allergic lung inflammation (24), anti-GBM nephritis (25), myocardial infarction (22), and upon TNF-␣-stimulation in vivo (20).…”

Is Endothelial Nitric Oxide Synthase a Moonlighting Protein Whose Day Job is Cholesterol Sulfate Synthesis? Implications for Cholesterol Transport, Diabetes and Cardiovascular Disease

“…The heparan sulfate chains in syndecan-1 have been shown to be essential in maintaining a healthy barrier in both mice and humans [147]. Profound abnormalities in the GAGs, in both the connective and vascular tissues, have been found in association with colitis and Crohn's disease [148], and this disruption likely is a significant factor in leaky gut syndrome.…”

Soluble Syndecan-1: Does This Biomarker Address a Seemingly Insoluble Problem in Inflammatory Bowel Disease?

“…Syndecan shedding occurs by highly regulated cleavage mechanisms in response to specific developmental and homeostatic signals, but also in response to pathophysiological signals such as inflammatory cytokines and chemokines, as illustrated in Fig. 1 [2,3]. Of the four identified syndecans, syndecan-1 is predominantly expressed by plasma cells and mucosal epithelial cells, such as intestinal epithelial cells [3].…”

“…1 [2,3]. Of the four identified syndecans, syndecan-1 is predominantly expressed by plasma cells and mucosal epithelial cells, such as intestinal epithelial cells [3]. Syndecan expression and shedding is highly modulated in inflammation-associated disease states, such as Crohn's disease or ulcerative colitis [1][2][3].…”

“…A characteristic feature of IBD is the loss of intestinal barrier integrity, characterized by major changes in intestinal permeability and the expression of tight junction proteins (claudins and occludins) and expression and shedding of syndecan-1 [3]. Intestinal permeability can be assessed by measuring the urinary excretion of carbohydrate probes such as mannitol, lactulose, and sucralose following oral ingestion [10,11].…”