Inflammatory macrophages exacerbate neutrophil-driven joint damage through ADP/P2Y1 signaling in rheumatoid arthritis
© 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature..
Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints and is associated with excessive immune cell infiltration. However, the complex interactions between the immune cell populations in the RA synovium remain unknown. Here, we demonstrate that inflammatory macrophages in the synovium exacerbate neutrophil-driven joint damage in RA through ADP/P2Y1 signaling. We show that extracellular ADP (eADP) and its receptors are obviously increased in synovial tissues of RA patients as well as collagen-induced arthritis (CIA) mice, and eADP enhances neutrophil infiltration into joints through macrophages producing the chemokine CXCL2, aggravating disease development. Accordingly, the arthritis mouse model had more neutrophils in inflamed joints following ADP injection, whereas P2Y1 deficiency and pharmacologic inhibition restored arthritis severity to basal levels, suggesting a dominant role of ADP/P2Y1 signaling in RA pathology. Moreover, cellular activity of ADP/P2Y1-mediated CXCL2 production was dependent on the Gαq/Ca2+-NF-κB/NFAT pathway in macrophages. Overall, this study reveals a non-redundant role of eADP as a trigger in the pathogenesis of RA through neutrophil recruitment and disrupted tissue homeostasis and function.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
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| Enthalten in: |
Science China. Life sciences - 65(2022), 5 vom: 04. Mai, Seite 953-968 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Xiaoyu [VerfasserIn] |
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| Links: |
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| Themen: |
61D2G4IYVH |
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| Anmerkungen: |
Date Completed 12.05.2022 Date Revised 24.06.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s11427-020-1957-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM330231235 |
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| 520 | |a © 2021. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the joints and is associated with excessive immune cell infiltration. However, the complex interactions between the immune cell populations in the RA synovium remain unknown. Here, we demonstrate that inflammatory macrophages in the synovium exacerbate neutrophil-driven joint damage in RA through ADP/P2Y1 signaling. We show that extracellular ADP (eADP) and its receptors are obviously increased in synovial tissues of RA patients as well as collagen-induced arthritis (CIA) mice, and eADP enhances neutrophil infiltration into joints through macrophages producing the chemokine CXCL2, aggravating disease development. Accordingly, the arthritis mouse model had more neutrophils in inflamed joints following ADP injection, whereas P2Y1 deficiency and pharmacologic inhibition restored arthritis severity to basal levels, suggesting a dominant role of ADP/P2Y1 signaling in RA pathology. Moreover, cellular activity of ADP/P2Y1-mediated CXCL2 production was dependent on the Gαq/Ca2+-NF-κB/NFAT pathway in macrophages. Overall, this study reveals a non-redundant role of eADP as a trigger in the pathogenesis of RA through neutrophil recruitment and disrupted tissue homeostasis and function | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a P2Y1 | |
| 650 | 4 | |a extracellular ADP | |
| 650 | 4 | |a joint inflammation | |
| 650 | 4 | |a macrophage | |
| 650 | 4 | |a rheumatoid arthritis | |
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| 700 | 1 | |a Zhao, Yihan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Zeda |e verfasserin |4 aut | |
| 700 | 1 | |a Lv, Zhangsheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Qin |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Mingyao |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Du, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Qin, Juliang |e verfasserin |4 aut | |
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