title: Syndecan-4 regulates early neutrophil migration and pulmonary inflammation in response to lipopolysaccharide.
abstract: Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC-chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-α. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury.
authors.affiliation: Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, Japan. ytanino@fmu.ac.jp
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanino
authors.forename: Mary Y
authors.initials: MY
authors.lastname: Chang
authors.forename: Xintao
authors.initials: X
authors.lastname: Wang
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: Shawn
authors.initials: S
authors.lastname: Skerrett
authors.forename: John K
authors.initials: JK
authors.lastname: McGuire
authors.forename: Suguru
authors.initials: S
authors.lastname: Sato
authors.forename: Takefumi
authors.initials: T
authors.lastname: Nikaido
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Munakata
authors.forename: Steve
authors.initials: S
authors.lastname: Mongovin
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D055370:Lung Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D053671:Syndecan-4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D006495:Heparin, Low-Molecular-Weight; D016209:Interleukin-8; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D053671:Syndecan-4; D014409:Tumor Necrosis Factor-alpha