Activation of the proton- sensing GPCR, GPR65 on fibroblast- like synoviocytes contributes to inflammatory joint pain

• 成果类型: Article
• 署名作者: Pattison, Luke A.; Rickman, Rebecca H.; Hilton, Helen; Dannawi, Maya; Wijesinghe, Susanne N.; Ladds, Graham; Yang, Li, V; Jones, Simon W.; Smith, Ewan St John
• 署名单位: University of Cambridge; University of Birmingham; University of North Carolina; East Carolina University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10853
• DOI: 10.1073/pnas.2410653121
• 发表日期: 2024-12-09
• 关键词: synovial-fluid ph; rheumatoid-arthritis; extracellular acidification; cytokine production; rat skin; receptor; acidosis; osteoarthritis; interleukin-6; sensitization

摘要

Inflammation is associated with localized acidosis, however, attributing physiological and pathological roles to proton- sensitive receptors is challenging due to their diversity and widespread expression. Here, agonists of the proton- sensing GPCR, GPR65, were proton- induced signaling events and demonstrated selectivity for GPR65. BTB was used to show that GPR65 activation on fibroblast- like synoviocytes (FLS), cells that line synovial joints, results in the secretion of proinflammatory mediators capable of recruiting immune cells and sensitizing sensory neurons. Intra- articular injection of BTB resulted in GPR65- dependent sensitization of knee- innervating neurons and nocifensive behaviors in mice. Stimulation of GPR65 on human FLS also triggered the release of inflammatory mediators and synovial fluid samples from human osteoarthritis patients were shown to activate GPR65. These results suggest a role of GPR65 in mediating cell-cell interactions that drive inflammatory joint pain in both mice and humans.