Display options
Cite
Ottria A, Zimmermann M, Paardekooper LM, et al. Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α. Rheumatology (Oxford). 2021;doi: 10.1093/rheumatology/keab532.
Ottria, A., Zimmermann, M., Paardekooper, L. M., Carvalheiro, T., Vazirpanah, N., Silva-Cardoso, S., Affandi, A. J., Chouri, E., V D Kroef, M., Tieland, R. G., Bekker, C. P. J., Wichers, C. G. K., Rossato, M., Mocholi-Gimeno, E., Tekstra, J., Ton, E., van Laar, J. M., Cossu, M., Beretta, L., Garcia Perez, S., Pandit, A., Bonte-Mineur, F., Reedquist, K. A., van den Bogaart, G., Radstake, T. R. D. J., & Marut, W. (2021). Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α. Rheumatology (Oxford, England), . https://doi.org/10.1093/rheumatology/keab532
Ottria, Andrea, et al. "Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α." Rheumatology (Oxford, England) vol. (2021). doi: https://doi.org/10.1093/rheumatology/keab532
Ottria A, Zimmermann M, Paardekooper LM, Carvalheiro T, Vazirpanah N, Silva-Cardoso S, Affandi AJ, Chouri E, V D Kroef M, Tieland RG, Bekker CPJ, Wichers CGK, Rossato M, Mocholi-Gimeno E, Tekstra J, Ton E, van Laar JM, Cossu M, Beretta L, Garcia Perez S, Pandit A, Bonte-Mineur F, Reedquist KA, van den Bogaart G, Radstake TRDJ, Marut W. Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α. Rheumatology (Oxford). 2021 Sep 24; doi: 10.1093/rheumatology/keab532. Epub 2021 Sep 24. PMID: 34559222.
Copy Download .nbib Format: NLM
Share it on

Rheumatology (Oxford). 2021 Sep 24; doi: 10.1093/rheumatology/keab532. Epub 2021 Sep 24.

Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α.

Rheumatology (Oxford, England)

Andrea Ottria, Maili Zimmermann, Laurent M Paardekooper, Tiago Carvalheiro, Nadia Vazirpanah, Sandra Silva-Cardoso, Alsya J Affandi, Eleni Chouri, Maarten V D Kroef, Ralph G Tieland, Cornelis P J Bekker, Catharina G K Wichers, Marzia Rossato, Enric Mocholi-Gimeno, Janneke Tekstra, Evelien Ton, Jaap M van Laar, Marta Cossu, Lorenzo Beretta, Samuel Garcia Perez, Aridaman Pandit, Femke Bonte-Mineur, Kris A Reedquist, Geert van den Bogaart, Timothy R D J Radstake, Wioleta Marut

Affiliations

  1. Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  2. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  3. Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
  4. Referral Center for Systemic Autoimmune Diseases, University of Milan & Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via Pace 9, Milan, Italy.
  5. Department of Rheumatology and Clinical Immunology, Maasstad Hospital, Rotterdam, the Netherlands.
  6. Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands.

PMID: 34559222 DOI: 10.1093/rheumatology/keab532

Abstract

OBJECTIVE: Systemic sclerosis (SSc) is a complex disease characterized by vascular abnormalities and inflammation culminating in hypoxia and excessive fibrosis. Previously, we identified CXCL4 as a novel predictive biomarker in SSc. Although CXCL4 is well-studied, the mechanisms driving its production are unclear. The aim of this study was to elucidate the mechanisms leading to CXCL4 production.

METHODS: Plasmacytoid dendritic cells (pDCs) from 97 healthy controls and 70 SSc patients were cultured in the presence of hypoxia or atmospheric oxygen level and/or stimulated with several TLR-agonists. Further, pro-inflammatory cytokine production, CXCL4, HIF-1α and HIF-2α gene and protein expression were assessed using ELISA, Luminex, qPCR, FACS and western blot assays.

RESULTS: CXCL4 release was potentiated only when pDCs were simultaneously exposed to hypoxia and TLR9 agonist (p < 0.0001). Here, we demonstrated that CXCL4 production is dependent on the overproduction of mitochondrial reactive oxygen species (mtROS) (p = 0.0079) leading to stabilization of HIF-2α (p = 0.029). In addition, we show that hypoxia is fundamental for CXCL4 production by umbilical cord (uc)CD34 derived pDCs.

CONCLUSION: TLR-mediated activation of immune cells in the presence of hypoxia underpins the pathogenic production of CXCL4 in SSc. Blocking either mtROS or HIF-2α pathways may therapeutically attenuate the contribution of CXCL4 to SSc and other inflammatory diseases driven by CXCL4.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: [email protected].

Keywords: CXCL4; HIF-2α; Hypoxia; Plasmacytoid dendritic cells; Systemic sclerosis; TLRs; mtROS

Publication Types