title: Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: another role for CXCL4?
abstract: SSc is a disease characterized by inflammation and fibrosis. Heme Oxygenase-1 (HO-1) is a haem-degrading enzyme that mediates resolution of inflammation and is induced upon mediators abundantly present in SSc. We aimed to assess whether HO-1 expression/function is disturbed in SSc patients and could therefore be contributing to the ongoing inflammation.
  
  
  
  In total, 92 SSc patients and 48 healthy controls were included. By measuring total bilirubin in plasma in vivo, HO-activity was assessed. HO-1 expression levels were determined with western blot in monocytes before and after induction of HO-1 with cobalt protoporphyrin (CoPP) with or without CXCL4. Monocyte-derived dendritic cells (DCs) were stimulated with several Toll-like receptor (TLR) ligands with or without pre-stimulation with CoPP for 24 h. Cytokine levels were measured in the supernatants using the Luminex Bead Array.
  
  
  
  SSc patients have lower plasma levels of bilirubin, suggestive of an aberrant HO-1 function. We demonstrated low HO-1 expression in immune cells from SSc patients, whereas induction with CoPP was able to restore HO-1 levels in DCs from SSc patients, almost normalizing the increased TLR response observed in SSc. Co-exposure to CXCL4 completely abrogated CoPP-induced HO-1 expression, suggesting that the high CXCL4 levels present in SSc patients block the normal induction of HO-1 and its function.
  
  
  
  We demonstrate that HO activity in SSc patients is decreased and show its functional consequences. Since CXCL4 blocks the induction of HO-1 expression, neutralization of CXCL4 in SSc patients could have clinical benefits by diminishing overactivation of immune cells and other anti-inflammatory effects of HO-1.
authors.affiliation: Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht.|Department of Rheumatology.
authors.forename: Lenny
authors.initials: L
authors.lastname: van Bon
authors.affiliation: Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht.
authors.forename: Marta
authors.initials: M
authors.lastname: Cossu
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Alwin
authors.initials: A
authors.lastname: Scharstuhl
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Bas W C
authors.initials: BW
authors.lastname: Pennings
authors.affiliation: Department of Rheumatology.
authors.forename: Madelon C
authors.initials: MC
authors.lastname: Vonk
authors.affiliation: Neonatal and Developmental Medicine Laboratory, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
authors.forename: Hendrik J
authors.initials: HJ
authors.lastname: Vreman
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Lafyatis
authors.affiliation: Department of Rheumatology.
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.affiliation: Department of Rheumatology & Clinical Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht T.R.D.J.Radstake@UMCutrecht.nl.|Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC.
authors.forename: Timothy R D J
authors.initials: TR
authors.lastname: Radstake
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D010978:Platelet Factor 4 / Q000502:physiology*; D012595:Scleroderma, Systemic / Q000201:enzymology*; D051193:Toll-Like Receptors / Q000502:physiology*
chemical_list: D016207:Cytokines; D051193:Toll-Like Receptors; D010978:Platelet Factor 4; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D001663:Bilirubin
keywords: heme oxygenase-1; platelet factor 4/CXCL4.; systemic sclerosis; toll-like receptors