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Swart, Maarten, Redpath, Andia N., Ogbechi, Joy, Cardenas, Ryan, Topping, Louise, Compeer, Ewoud B., Goddard, Michael, Chanalaris, Anastasios, Williams, Richard, Brewer, Daniel S. 
ORCID: https://orcid.org/0000-0003-4753-9794, Smart, Nicola, Monaco, Claudia and Troeberg, Linda ORCID: https://orcid.org/0000-0003-0939-4651
(2024)
The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis.
Cellular and Molecular Life Sciences, 81.
ISSN 1420-682X
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Abstract
Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/− bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/− chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.
| Item Type: | Article |
|---|---|
| Additional Information: | Data availability statement: The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Funding information: MS, AC and LT were supported by a Versus Arthritis PhD Scholarship (21245) and project grant (20887). AR and NS received support from British Heart Foundation (BHF) Project grant (PG/16/27/32114); BHF Ian Fleming Senior Basic Science Research Fellowship (FS/19/32/34376) and BHF Centre of Regenerative Medicine, Oxford (RM/13/3/30159). EBC was supported by European Research Council Advanced Grant ERC-2014-AdG_670930. |
| Uncontrolled Keywords: | heparan sulfate,inflammation,interferon,macrophage,molecular medicine,molecular biology,pharmacology,cellular and molecular neuroscience,cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1313 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 20 Aug 2024 14:30 |
| Last Modified: | 25 Sep 2024 18:01 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/96285 |
| DOI: | 10.1007/s00018-024-05333-w |
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