Release of High-Mobility Group Box-1 after a Raynaud’s Attack Leads to Fibroblast Activation and Interferon-γ Induced Protein-10 Production: Role in Systemic Sclerosis Pathogenesis

Yehya Al-Adwi; Isabella M. Atzeni; Berber Doornbos-van der Meer; Amaal Eman Abdulle; Anniek M. van Roon; Alja Stel; Harry van Goor; Andries J. Smit; Johanna Westra; Douwe J. Mulder

doi:10.3390/antiox12040794

Antioxidants (Mar 2023)

Release of High-Mobility Group Box-1 after a Raynaud’s Attack Leads to Fibroblast Activation and Interferon-γ Induced Protein-10 Production: Role in Systemic Sclerosis Pathogenesis

Yehya Al-Adwi,
Isabella M. Atzeni,
Berber Doornbos-van der Meer,
Amaal Eman Abdulle,
Anniek M. van Roon,
Alja Stel,
Harry van Goor,
Andries J. Smit,
Johanna Westra,
Douwe J. Mulder

Affiliations

Yehya Al-Adwi: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Isabella M. Atzeni: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Berber Doornbos-van der Meer: Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Amaal Eman Abdulle: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Anniek M. van Roon: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Alja Stel: Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Harry van Goor: Department of Pathology and Medical Biology, Section Pathology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Andries J. Smit: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Johanna Westra: Department of Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands
Douwe J. Mulder: Department of Internal Medicine, Division of Vascular Medicine, University Medical Centre Groningen, University of Groningen, 9700 RB Groningen, The Netherlands

DOI: https://doi.org/10.3390/antiox12040794
Journal volume & issue: Vol. 12, no. 4
p. 794

Abstract

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Raynaud’s Phenomenon (RP) leading to repetitive ischemia and reperfusion (IR) stress, is the first recognizable sign of systemic sclerosis (SSc) leading to increased oxidative stress. High-mobility group box-1 (HMGB1) is a nuclear factor released by apoptotic and necrotic cells after oxidative stress. Since HMGB1 can signal through the receptor for advanced glycation end products (RAGE), we investigated whether an RP attack promotes the release of HMGB1, leading to fibroblast activation and the upregulation of interferon (IFN)-inducible genes. A cold challenge was performed to simulate an RP attack in patients with SSc, primary RP (PRP), and healthy controls. We measured levels of HMGB1 and IFN gamma-induced Protein 10 (IP-10) at different time points in the serum. Digital perfusion was assessed by photoplethysmography. In vitro, HMGB1 or transforming growth factor (TGF-β1) (as control) was used to stimulate healthy human dermal fibroblasts. Inflammatory, profibrotic, and IFN-inducible genes, were measured by RT-qPCR. In an independent cohort, sera were obtained from 20 patients with SSc and 20 age- and sex-matched healthy controls to determine HMGB1 and IP-10 levels. We found that HMGB1 levels increased significantly 30 min after the cold challenge in SSc compared to healthy controls. In vitro stimulation with HMGB1 resulted in increased mRNA expression of IP-10, and interleukin-6 (IL-6) while TGF-β1 stimulation promoted IL-6 and Connective Tissue Growth Factor (CTGF). In serum, both HMGB1 and IP-10 levels were significantly higher in patients with SSc compared to healthy controls. We show that cold challenge leads to the release of HMGB1 in SSc patients. HMGB1 induces IP-10 expression in dermal fibroblasts partly through the soluble RAGE (sRAGE) axis suggesting a link between RP attacks, the release of HMGB1 and IFN-induced proteins as a putative early pathogenetic mechanism in SSc.

Published in Antioxidants

ISSN: 2076-3921 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.mdpi.com/journal/antioxidants

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