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 anti-inflammatory effects of HO-1.

• Authors: 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
• Journal: Rheumatology (Oxford, England) (Rheumatology (Oxford)) Vol. 55 Issue 11 Pg. 2066-2073 (11 2016) ISSN: 1462-0332 [Electronic] England
• PMID: 27411481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Cytokines
• Toll-Like Receptors
• Platelet Factor 4
• Carbon Monoxide
• Heme Oxygenase-1
• Bilirubin

Topics

• Adult
• Bilirubin (metabolism)
• Carbon Monoxide (metabolism)
• Case-Control Studies
• Cytokines (metabolism)
• Dendritic Cells (metabolism)
• Female
• Fibroblasts (metabolism)
• Heme Oxygenase-1 (deficiency)
• Humans
• Leukocytes, Mononuclear (metabolism)
• Male
• Platelet Factor 4 (physiology)
• Scleroderma, Systemic (enzymology)
• Toll-Like Receptors (physiology)