title: A novel 72-kDa leukocyte-derived osteoglycin enhances the activation of toll-like receptor 4 and exacerbates cardiac inflammation during viral myocarditis.
abstract: Viral myocarditis can severely damage the myocardium through excessive infiltration of immune cells. Osteoglycin (OGN) is part of the small leucine-rich repeat proteoglycan (SLRP) family. SLRP's may affect inflammatory and fibrotic processes, but the implication of OGN in cardiac inflammation and the resulting injury upon viral myocarditis is unknown.
  
  
  
  This study uncovered a previously unidentified 72-kDa variant of OGN that is predominant in cardiac human and mouse samples of viral myocarditis. Its absence in mice significantly decreased cardiac inflammation and injury in Coxsackievirus-B3-induced myocarditis. It also delayed mortality in lipopolysaccharide-induced endotoxemia going along with a reduced systemic production of pro-inflammatory cytokines. This 72-kDa OGN is expressed in the cell membrane of circulating and resident cardiac macrophages and neutrophils. Co-immunoprecipitation and OGN siRNA experiments revealed that this 72-kDa variant activates the toll-like receptor-4 (TLR4) with a concomitant increase in IL-6, TNF-α, IL-1β, and IL-12 expression. This immune cell activation by OGN occurred via MyD88 and increased phosphorylation of c-jun. Finally, the 72-kDa chondroitin sulfate is the result of O-linked glycosylation of the 32-kDa protein core of OGN. In contrast, the 34-kDa dermatan sulfate-OGN, involved in collagen cross linking, was also the result of O-linked glycosylation.
  
  
  
  The current study discovered a novel 72-kDa chondroitin sulfate-OGN that is specific for innate immune cells. This variant is able to bind and activate TLR4. The absence of OGN decreases cytokine production by both circulating and cardiac leukocytes upon (systemic) LPS exposure, and reduces cardiac inflammation and injury in viral myocarditis.
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands. m.rienks@maastrichtuniversity.nl.
authors.forename: Marieke
authors.initials: M
authors.lastname: Rienks
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.|Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Papageorgiou
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Kristiaan
authors.initials: K
authors.lastname: Wouters
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: Verhesen
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Rick van
authors.initials: RV
authors.lastname: Leeuwen
authors.affiliation: Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carai
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors.forename: Georg
authors.initials: G
authors.lastname: Summer
authors.affiliation: Centre for Cardiology Research, Hamburg University, Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.affiliation: Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.|Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Hamburg, Germany.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006031:Glycosylation; D057809:HEK293 Cells; D006321:Heart / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; C063488:OGN protein, human; C512906:Ogn protein, mouse; D051197:Toll-Like Receptor 4
keywords: Glycosylation; Inflammation; Osteoglycin; TLR4; Viral myocarditis