Loss of endothelial sulfatase-1 after experimental sepsis attenuates subsequent pulmonary inflammatory responses

Abstract

Sepsis patients are at increased risk for hospital-acquired pulmonary infections, potentially due to postseptic immunosuppression known as the compensatory anti-inflammatory response syndrome (CARS). CARS has been attributed to leukocyte dysfunction, with an unclear role for endothelial cells. The pulmonary circulation is lined by an endothelial glycocalyx, a heparan sulfate-rich layer essential to pulmonary homeostasis. Heparan sulfate degradation occurs early in sepsis, leading to lung injury. Endothelial synthesis of new heparan sulfates subsequently allows for glycocalyx reconstitution and endothelial recovery. We hypothesized that remodeling of the reconstituted endothelial glycocalyx, mediated by alterations in the endothelial machinery responsible for heparan sulfate synthesis, contributes to CARS. Seventy-two hours after experimental sepsis, coincident with glycocalyx reconstitution, mice demonstrated impaired neutrophil and protein influx in response to intratracheal lipopolysaccharide (LPS). The postseptic reconstituted glycocalyx was structurally remodeled, with enrichment of heparan sulfate disaccharides sulfated at the 6- O position of glucosamine. Increased 6- O-sulfation coincided with loss of endothelial sulfatase-1 (Sulf-1), an enzyme that specifically removes 6- O-sulfates from heparan sulfate. Intravenous administration of Sulf-1 to postseptic mice restored the pulmonary response to LPS, suggesting that loss of Sulf-1 was necessary for postseptic suppression of pulmonary inflammation. Endothelial-specific knockout mice demonstrated that loss of Sulf-1 was not sufficient to induce immunosuppression in non-septic mice. Knockdown of Sulf-1 in human pulmonary microvascular endothelial cells resulted in downregulation of the adhesion molecule ICAM-1. Taken together, our study indicates that loss of endothelial Sulf-1 is necessary for postseptic suppression of pulmonary inflammation, representing a novel endothelial contributor to CARS.

Endothelial Heparan Sulfate Proteoglycans in Sepsis: The Role of the Glycocalyx

“…The patterning of sulfation (and thus negative charge) along the heparan polysaccharide allows for specific electrostatic interactions with positively charged residues of proteins. Image courtesy: Oshima et al 85…”

Variability in proteoglycan biosynthetic genes reveals new facets of heparan sulfates diversity. A systematic review and analysis

“…Concerning the HS chain biosynthetic genes, none of these clustered in this group. Instead, Group III clustered genes involved in the control of HS levels and quality, including EXTL2 82,83 , HPSE 84-86 and SULF1 70,87-89 (Fig. 5).…”

HS and Inflammation: A Potential Playground for the Sulfs?

“…This study showed that HS of lung endothelial glycocalyx displayed higher 6-O-sulfation content after septic injury, which was due to a downregulation of Sulf-1. Interestingly, the post-septic loss of Sulf-1 was necessary for CARS to occur, as the administration of exogenous recombinant Sulf-1 intravenously reversed the immunosuppression phenotype (92). In the same context, Sulfs could also participate in the degradation of the basement membrane, along with Heparanase and proteases to facilitate leukocyte migration toward inflammatory sites.…”