title: Glycosaminoglycans are important mediators of neutrophilic inflammation in vivo.
abstract: The pro-inflammatory chemokine interleukin-8 (CXCL8) exerts its function by establishing a chemotactic gradient in infected or damaged tissues to guide neutrophil granulocytes to the site of inflammation via its G protein-coupled receptors (GPCRs) CXCR1 and CXCR2 located on neutrophils. Endothelial glycosaminoglycans (GAGs) have been proposed to support the chemotactic gradient formation and thus the inflammatory response by presenting the chemokine to approaching leukocytes. In this study, we show that neutrophil transmigration in vitro can be reduced by adding soluble GAGs and that this process is specific with respect to the nature of the glycan. To further investigate the GAG influence on neutrophil migration, we have used an engineered CXCL8 mutant protein (termed PA401) which exhibits a much higher affinity towards GAGs and an impaired GPCR activity. This dominant-negative mutant chemokine showed anti-inflammatory activity in various animal models of neutrophil-driven inflammation, i.e. in urinary tract infection, bleomycin-induced lung fibrosis, and experimental autoimmune uveitis. In all cases, treatment with PA401 resulted in a strong reduction of transmigrated inflammatory cells which became evident from histology sections and bronchoalveolar lavage. Since our CXCL8-based decoy targets GAGs and not GPCRs, our results show for the first time the crucial involvement of this glycan class in CXCL8/neutrophil-mediated inflammation and will thus pave the way to novel approaches of anti-inflammatory treatment.
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1/1, 8010 Graz, Austria. Electronic address: martha.gschwandtner@edu.uni-graz.at.
authors.forename: Martha
authors.initials: M
authors.lastname: Gschwandtner
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1/1, 8010 Graz, Austria. Electronic address: elisabeth.strutzmann@gmail.com.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Strutzmann
authors.affiliation: Institute of Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas, Avenida Antonio Carlos, Belo Horizonte 31270-901, Brazil. Electronic address: mmtex@icb.ufmg.br.
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.affiliation: Institute of Clinical Biochemistry, Medical Policlinic, Klinikum der Universität München, Schillerstr. 42, 80336 München, Germany.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Anders
authors.affiliation: Section of Immunobiology, Department of Ophthalmology, Klinikum der Universität München, Mathildenstr. 8, 80336 München, Germany. Electronic address: Maria.Diedrichs-Moehring@med.uni-muenchen.de.
authors.forename: Maria
authors.initials: M
authors.lastname: Diedrichs-Möhring
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1/1, 8010 Graz, Austria; ProtAffin Biotechnolgie AG, Reininghausstraße 13a, 8020 Graz, Austria. Electronic address: tanja.gerlza@uni-graz.at.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gerlza
authors.affiliation: Section of Immunobiology, Department of Ophthalmology, Klinikum der Universität München, Mathildenstr. 8, 80336 München, Germany. Electronic address: Gerhild.Wildner@med.uni-muenchen.de.
authors.forename: Gerhild
authors.initials: G
authors.lastname: Wildner
authors.affiliation: Institute of Immunology, Department of Biochemistry and Immunology, Universidade Federal de Minas, Avenida Antonio Carlos, Belo Horizonte 31270-901, Brazil. Electronic address: remo@icb.ufmg.br.
authors.forename: Remo C
authors.initials: RC
authors.lastname: Russo
authors.affiliation: ProtAffin Biotechnolgie AG, Reininghausstraße 13a, 8020 Graz, Austria. Electronic address: tadage@hotmail.com.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Adage
authors.affiliation: Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Schubertstraße 1/1, 8010 Graz, Austria; ProtAffin Biotechnolgie AG, Reininghausstraße 13a, 8020 Graz, Austria. Electronic address: andreas.kungl@uni-graz.at.
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Kungl
mesh_terms: D006025:Glycosaminoglycans / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000276:immunology
chemical_list: C508606:CXCL8 protein, human; D006025:Glycosaminoglycans; D018836:Inflammation Mediators; D016209:Interleukin-8
keywords: Bleomycin model; CXCL8; Chemokine; Experimental autoimmune uveitis; Glycosaminoglycan; Urinary tract infection