Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: Another role for CXCL4?

Lenny van Bon, Marta Cossu, Alwin Scharstuhl, Bas W C Pennings, Madelon C. Vonk, Hendrik J. Vreman, Robert L. Lafyatis, Wim van den Berg, Frank A D T G Wagener, Timothy R D J Radstake

Research output: Contribution to journalArticle

Abstract

Objective. 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. Methods. 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. Results. 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. Conclusion. 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 antiinflammatory effects of HO-1.

Original languageEnglish
Pages (from-to)2066-2073
Number of pages8
JournalRheumatology
Volume55
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

Fingerprint

Heme Oxygenase-1
Systemic Scleroderma
Toll-Like Receptors
Inflammation
Bilirubin
Dendritic Cells
Monocytes
Heme
Fibrosis
Anti-Inflammatory Agents
Western Blotting
Cytokines
Ligands

Keywords

  • Heme oxygenase-1
  • Platelet factor 4/CXCL4
  • Systemic sclerosis
  • Toll-like receptors

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

Cite this

van Bon, L., Cossu, M., Scharstuhl, A., Pennings, B. W. C., Vonk, M. C., Vreman, H. J., ... Radstake, T. R. D. J. (2016). Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: Another role for CXCL4? Rheumatology, 55(11), 2066-2073. https://doi.org/10.1093/rheumatology/kew251

Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response : Another role for CXCL4? / van Bon, Lenny; Cossu, Marta; Scharstuhl, Alwin; Pennings, Bas W C; Vonk, Madelon C.; Vreman, Hendrik J.; Lafyatis, Robert L.; van den Berg, Wim; Wagener, Frank A D T G; Radstake, Timothy R D J.

In: Rheumatology, Vol. 55, No. 11, 01.11.2016, p. 2066-2073.

Research output: Contribution to journalArticle

van Bon, L, Cossu, M, Scharstuhl, A, Pennings, BWC, Vonk, MC, Vreman, HJ, Lafyatis, RL, van den Berg, W, Wagener, FADTG & Radstake, TRDJ 2016, 'Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response: Another role for CXCL4?', Rheumatology, vol. 55, no. 11, pp. 2066-2073. https://doi.org/10.1093/rheumatology/kew251
van Bon, Lenny ; Cossu, Marta ; Scharstuhl, Alwin ; Pennings, Bas W C ; Vonk, Madelon C. ; Vreman, Hendrik J. ; Lafyatis, Robert L. ; van den Berg, Wim ; Wagener, Frank A D T G ; Radstake, Timothy R D J. / Low heme oxygenase-1 levels in patients with systemic sclerosis are associated with an altered Toll-like receptor response : Another role for CXCL4?. In: Rheumatology. 2016 ; Vol. 55, No. 11. pp. 2066-2073.
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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 = "Objective. 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. Methods. 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. Results. 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. Conclusion. 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 antiinflammatory effects of HO-1.",
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T2 - Another role for CXCL4?

AU - van Bon, Lenny

AU - Cossu, Marta

AU - Scharstuhl, Alwin

AU - Pennings, Bas W C

AU - Vonk, Madelon C.

AU - Vreman, Hendrik J.

AU - Lafyatis, Robert L.

AU - van den Berg, Wim

AU - Wagener, Frank A D T G

AU - Radstake, Timothy R D J

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N2 - Objective. 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. Methods. 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. Results. 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. Conclusion. 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 antiinflammatory effects of HO-1.

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KW - Platelet factor 4/CXCL4

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