P2Y11 receptor antagonist NF340 ameliorates inflammation in human fibroblast‐like synoviocytes: An implication in rheumatoid arthritis

Abstract

Rheumatoid arthritis is a common chronic inflammatory joint disease. Fibroblast‐like synoviocytes‐mediated inflammation is closely associated with the development of rheumatoid arthritis. In this study, we report that P2Y11 receptor activity is required for cytokine‐induced inflammation in primary fibroblast‐like synoviocytes (FLS). P2Y11R is fairly expressed in primary FLS isolated from healthy subjects and is elevated to around three‐ to four‐fold in rheumatoid arthritis‐derived FLS. The expression of P2Y11R is inducible upon IL‐1β treatment. Blockage of P2Y11R by its antagonist suppresses IL‐1β‐induced TNF‐α and IL‐6 induction and ameliorates oxidative stress as determined by levels of cellular ROS and the oxidative byproduct 4‐HNE. Moreover, blockage of P2Y11R by NF340 inhibits IL‐1β‐induced matrix metalloproteinase protein expression as indicated by the levels of MMP‐1, MMP‐3, and MMP‐13. Mechanistically, blockage of P2Y11R mitigates IL‐1β‐activated NFκB signaling, which was revealed by reduced IκBα phosphorylation, nuclear p65 accumulation, and NFκB promoter activity. Our study provides evidence of a protective mechanism of P2Y11R antagonist NF340 against cytokine‐induced inflammation. Therefore, targeting P2Y11R could have potential therapeutic implication in the treatment of RA.

Damage-induced pyroptosis drives endogenous thymic regeneration via induction of Foxn1 by purinergic receptor activation

“…P2 antagonists are of increasing interest therapeutically, with a focus on developing analogous molecules to inhibit or promote these druggable targets in many disease settings, such as epilepsy 44 , rheumatoid arthritis 45 and ischemic cardiac injury 46 . Moreover, clinical trials have been carried out using antagonists for P2X3 47 , P2X7 48, 49 and P2Y12 50 .…”

Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages

“…Chronic inflammation of the joints plays an important role in the development of RA, and the synoviocytes play a key role in producing pro‐inflammatory cytokines such as IL‐1β. Suppression of P2Y 11 with an antagonist prevents the activation of NF‐κB by IL‐1β in synoviocytes and the downstream expression of additional pro‐inflammatory cytokines such as TNF‐α and IL‐6 (Gao & Li, 2019). This notion is in line with our finding that P2Y 11 can induce an inflammatory response and that this receptor has the capability to modulate the local inflammatory environment toward pro‐inflammatory signaling in specific cases.…”

Cross Talk of Purinergic and Immune Signaling: Implication in Inflammatory and Pathogenic Diseases

“…It also regulates the differentiation of Th17 cells and type II collagen-induced arthritis in mice [139]. P2Y receptor also contribute to the development of RA such as P2Y11 receptor induce inflammation in primary fibroblast-like synoviocytes [140], P2Y12 and P2Y14 receptors induce bone lysis by activating osteoclasts [141][142][143]. RA patients demonstrate differential expression of adenosine receptors on synovium with preferential expression of A3 and its variant.…”