A novel 72-kDa leukocyte-derived osteoglycin enhances the activation of toll-like receptor 4 and exacerbates cardiac inflammation during viral myocarditis
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A novel 72-kDa leukocyte-derived osteoglycin enhances the activation of toll-like receptor 4 and exacerbates cardiac inflammation during viral myocarditis. / Rienks, Marieke; Papageorgiou, Anna; Wouters, Kristiaan; Verhesen, Wouter; Leeuwen, Rick van; Carai, Paolo; Summer, Georg; Westermann, Dirk; Heymans, Stephane.
in: CELL MOL LIFE SCI, Jahrgang 74, Nr. 8, 04.2017, S. 1511-1525.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - A novel 72-kDa leukocyte-derived osteoglycin enhances the activation of toll-like receptor 4 and exacerbates cardiac inflammation during viral myocarditis
AU - Rienks, Marieke
AU - Papageorgiou, Anna
AU - Wouters, Kristiaan
AU - Verhesen, Wouter
AU - Leeuwen, Rick van
AU - Carai, Paolo
AU - Summer, Georg
AU - Westermann, Dirk
AU - Heymans, Stephane
PY - 2017/4
Y1 - 2017/4
N2 - BACKGROUND: 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.METHODS AND RESULTS: 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.CONCLUSION: 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.
AB - BACKGROUND: 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.METHODS AND RESULTS: 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.CONCLUSION: 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.
KW - Animals
KW - Cytokines/immunology
KW - Disease Models, Animal
KW - Female
KW - Glycosylation
KW - HEK293 Cells
KW - Heart/virology
KW - Humans
KW - Immunity, Cellular
KW - Immunity, Innate
KW - Intercellular Signaling Peptides and Proteins/analysis
KW - Leukocytes/immunology
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Myocarditis/immunology
KW - Myocardium/immunology
KW - Toll-Like Receptor 4/immunology
U2 - 10.1007/s00018-016-2423-7
DO - 10.1007/s00018-016-2423-7
M3 - SCORING: Journal article
C2 - 27878326
VL - 74
SP - 1511
EP - 1525
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 8
ER -
