Inflammatory macrophages exacerbate neutrophil-driven joint damage through ADP/P2Y1 signaling in rheumatoid arthritis.
Sci China Life Sci
; 65(5): 953-968, 2022 05.
Article
en En
| MEDLINE
| ID: mdl-34480694
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Artritis Experimental
/
Artritis Reumatoide
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci China Life Sci
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2022
Tipo del documento:
Article
País de afiliación:
China