The extracellular heparan sulfatase SULF2 limits myeloid IFNβ signaling and Th17 responses in inflammatory arthritis
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 wasSulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generatedSulf2+/-bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloidSulf2+/-chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic andin vitroanalyses indicated thatSulf2deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL-6. This establishes that dynamic remodeling of HS bySulf2limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 18. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Swart, Maarten [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.03.13.584823 |
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| PPN (Katalog-ID): |
XBI042950570 |
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| 520 | |a 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 wasSulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generatedSulf2+/-bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloidSulf2+/-chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic andin vitroanalyses indicated thatSulf2deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL-6. This establishes that dynamic remodeling of HS bySulf2limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology. | ||
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| 700 | 1 | |a Redpath, Andia |4 aut | |
| 700 | 1 | |a Ogbechi, Joy |4 aut | |
| 700 | 1 | |a Cardenas, Ryan |4 aut | |
| 700 | 1 | |a Topping, Louise |4 aut | |
| 700 | 1 | |a Compeer, Ewoud B. |4 aut | |
| 700 | 1 | |a Goddard, Michael |4 aut | |
| 700 | 1 | |a Chanalaris, Anastasios |4 aut | |
| 700 | 1 | |a Williams, Richard |4 aut | |
| 700 | 1 | |a Brewer, Daniel S. |4 aut | |
| 700 | 1 | |a Smart, Nicola |0 (orcid)0000-0002-3501-7254 |4 aut | |
| 700 | 1 | |a Monaco, Claudia |4 aut | |
| 700 | 1 | |a Troeberg, Linda |4 aut | |
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