Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α
Ottria, Andrea; Zimmermann, Maili; Paardekooper, Laurent M; Carvalheiro, Tiago; Vazirpanah, Nadia; Silva-Cardoso, Sandra; Affandi, Alsya J; Chouri, Eleni; V D Kroef, Maarten; Tieland, Ralph G; Bekker, Cornelis P J; Wichers, Catharina G K; Rossato, Marzia; Mocholi-Gimeno, Enric; Tekstra, Janneke; Ton, Evelien; van Laar, Jaap M; Cossu, Marta; Beretta, Lorenzo; Garcia Perez, Samuel; Pandit, Aridaman; Bonte-Mineur, Femke; Reedquist, Kris A; van den Bogaart, Geert; Radstake, Timothy R D J; Marut, Wioleta
(2022) Rheumatology (Oxford, England), volume 61, issue 6, pp. 2682 - 2693
(Article)
Abstract
OBJECTIVE: SSc is a complex disease characterized by vascular abnormalities and inflammation culminating in hypoxia and excessive fibrosis. Previously, we identified chemokine (C-X-C motif) ligand 4 (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
... read more
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 toll-like receptor (TLR) agonists. Further, pro-inflammatory cytokine production, CXCL4, hypoxia-inducible factor (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 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.
show less
Download/Full Text
The full text of this publication is not available.
Keywords: CXCL4, HIF-2 alpha, TLRs, hypoxia, mtROS, plasmacytoid dendritic cells, systemic sclerosis, HIF-2α, Pharmacology (medical), Rheumatology
ISSN: 1462-0324
Publisher: Oxford University Press
Note: Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved.
(Peer reviewed)