Prokineticin 2 promotes endoplasmic reticulum stress in rheumatoid arthritis by potentiating IL-1β–induced inflammation

Background Rheumatoid arthritis(RA) is a long-standing autoimmune condition that is marked by persistent inflammation of the synovium and ongoing damage to the joints. Current therapeutic strategies have dramatically enhanced patient’s management; however, many patients develop resistance or refractory to current therapies. Identifying the most forward-thinking molecular targets is crucial for enhancing treatment results. Methods Transcriptomic sequencing was conducted on synovial tissues taken from individuals with RA to pinpoint potential genes linked to disease severity. Fibroblast-like synoviocytes isolated from RA patients (RA-FLS) were subjected to exposure with several pro-inflammatory cytokines, including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), to assess alterations in gene expression. Gene set enrichment analysis (GSEA) was combined with functional experiments to investigate potential signalling pathways controlled by the candidate gene. The expression of pathway-related markers was validated using qRT-PCR and western blotting. Finally, the candidate gene's in vivo function was assessed through a mouse model of collagen-induced arthritis (CIA). Results PK2 levels were markedly elevated in the synovial tissue of individuals with RA.In vitro experiments verified that IL-1β and TNF-α, among inflammatory cytokines, caused an increase in PK2 expression in RA-FLS. Transcriptomic analysis revealed that co-stimulation with PK2 and IL-1β strongly enriched pathways related to protein processing in the endoplasmic reticulum. Subsequent experiment confirmation demonstrated that a combination of PK2 and IL-1β stimulation leads to elevated expression levels of key factors in the pathway, namely XBP1, GRP78, CHOP and HSPA6. In vivo, PK2 made joint inflammation and tissue damage much worse in CIA mice. However, PK2 antagonist PKRA7 significantly alleviated the disease. Conclusion Researchers find PK2 to be a key gene that associates with RA and closely involved in protein processing within endoplasmic reticulum pathway. Targeting the PK2-mediated ER stress pathway may provide a potential therapeutic strategy for RA.