title: Heparan Sulfate Modulates Neutrophil and Endothelial Function in Antibacterial Innate Immunity.
abstract: Recently, we showed that endothelial heparan sulfate facilitates entry of a bacterial pathogen into the central nervous system. Here, we show that normal bactericidal activity of neutrophils is influenced by the sulfation pattern of heparan sulfate. Inactivation of heparan sulfate uronyl 2-O-sulfotransferase (Hs2st) in neutrophils substantially reduced their bactericidal activity, and Hs2st deficiency rendered mice more susceptible to systemic infection with the pathogenic bacterium group B Streptococcus. Specifically, altered sulfation of heparan sulfate in mutant neutrophils affected formation of neutrophil extracellular traps while not influencing phagocytosis, production of reactive oxygen species, or secretion of granular proteases. Heparan sulfate proteoglycan(s) is present in neutrophil extracellular traps, modulates histone affinity, and modulates their microbial activity. Hs2st-deficient brain endothelial cells show enhanced binding to group B Streptococcus and are more susceptible to apoptosis, likely contributing to the observed increase in dissemination of group B Streptococcus into the brain of Hs2st-deficient mice following intravenous challenge. Taken together, our data provide strong evidence that heparan sulfate from both neutrophils and the endothelium plays important roles in modulating innate immunity.
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA Department of Oral Biology, University at Buffalo, School of Dental Medicine, The State University of New York, Buffalo, New York, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Olson
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Pediatrics, University of California, San Diego, La Jolla, California, USA School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Jason N
authors.initials: JN
authors.lastname: Cole
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Xander M
authors.initials: XM
authors.lastname: van Wijk
authors.affiliation: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.affiliation: Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Arturo
authors.initials: A
authors.lastname: Zychlinsky
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Pediatrics, University of California, San Diego, La Jolla, California, USA Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA jesko@ucsd.edu yungchiychang@ntu.edu.tw.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA Department of Pediatrics, University of California, San Diego, La Jolla, California, USA Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan jesko@ucsd.edu yungchiychang@ntu.edu.tw.
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology*; D065206:Extracellular Traps / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008855:Microscopy, Electron, Scanning; D009504:Neutrophils / Q000276:immunology*; D013290:Streptococcal Infections / Q000276:immunology; D013292:Streptococcus agalactiae / Q000276:immunology; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D019812:Heparan Sulfate Proteoglycans; D015238:Sulfotransferases; C106358:heparan-sulfate 2-sulfotransferase