title: Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury.
abstract: OBJECTIVE
  Adiponectin (APN) is an immunomodulatory and cardioprotective adipocytokine. Toll-like receptor (TLR) 4 mediates autoimmune reactions that cause myocarditis resulting in inflammation-induced cardiac injury. Here, we investigated whether APN inhibits inflammation and injury in autoimmune myocarditis by interfering with TLR4 signalling.
  
  
  RESULTS
  APN overexpression in murine experimental autoimmune myocarditis (EAM) down-regulated cardiac expression of TLR4 and its downstream targets tumour necrosis factor (TNF)α, interleukin (IL)-6, IL-12, CC chemokine ligand (CCL)2, and intercellular adhesion molecule (ICAM)-1 resulting in reduced infiltration with cluster of differentiation (CD)3+, CD14+, and CD45+ immune cells as well as diminished myocardial apoptosis. Expression of TLR4 signalling pathway components was unchanged in hearts and spleens of APN-knockout (APN-KO) mice. In vitro APN had no effect on TLR4 expression in cardiac and immune cells but induced dissociation of APN receptors from the activated TLR4/CD14 signalling complex. APN inhibited the expression of a TLR4-mediated inflammatory phenotype induced by exogenous and endogenous TLR4 ligands as assessed by attenuated nuclear factor (NF)-κB activation and reduced expression of TNFα, IL-6, CCL2, and ICAM-1. Accordingly, following TLR4 ligation, splenocytes from APN-KO mice showed enhanced expression of TNFα, IL-6, IL-12, CCL2, and ICAM-1, whereas dendritic cells (DCs) from APN-KO mice demonstrated increased activation and T-cell priming capacity. Moreover, APN diminished TLR4-mediated splenocyte migration towards cardiac cells as well as cardiomyocyte apoptosis after co-cultivation with splenocytes. Mechanistically, APN inhibited TLR4 signalling through cyclooxygenase (COX)-2, protein kinase A (PKA), and meiosis-specific serine/threonine kinase (MEK)1.
  
  
  CONCLUSIONS
  Our observations indicate that APN protects against inflammation and injury in autoimmune myocarditis by diminishing TLR4 signalling thereby attenuating inflammatory activation and interaction of cardiac and immune cells.
authors.affiliation: Department of Cardiology and Pneumology, Charité University Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin 12200, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Jenke
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wilk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Alan
authors.initials: A
authors.lastname: Valaperti
authors.forename: Bernhard Hermann
authors.initials: BH
authors.lastname: Rauch
authors.forename: Andrea
authors.initials: A
authors.lastname: Stroux
authors.forename: Peter
authors.initials: P
authors.lastname: Liu
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carmen
authors.initials: C
authors.lastname: Scheibenbogen
authors.forename: Carsten
authors.initials: C
authors.lastname: Skurk
mesh_terms: D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000276:immunology / Q000473:pathology / Q000502:physiology; D018995:Myosin Heavy Chains / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; C499920:Adipoq protein, rat; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D018995:Myosin Heavy Chains
keywords: Adiponectin; Autoimmune myocarditis; TLR4