Abstract
BackgroundTh17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, recent genome-wide association studies (GWAS) have identified five risk alleles for AS in PTGER4, the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS.MethodsTh17 cells from patients with AS were analyzed for the transcriptional expression of prostaglandin receptor genes by quantitative RT-PCR. Th17 cells from patients with rheumatoid arthritis (RA) and from healthy individuals served as controls. EP4 receptor expression in Th17 cells was assessed ex vivo by flow cytometry and by western blot. Functional analysis using EP4-specific agonists was performed to reveal how EP4 regulates Th17 cells.ResultsEP4 is significantly overexpressed in Th17 cells from patients with AS compared to Th17 cells from healthy individuals or patients with RA or psoriatic arthritis (PsA). EP4 upregulation is unique to Th17 cells and is not found in other CD4+ T cell subsets. Specific activation of EP4 drives Th17 cell development and promotes EP4 expression in a positive feedback loop in AS but not in RA or PsA. Mechanistically, EP4 acts via upregulation of the interleukin-23 receptor (IL-23R), by suppressing the RORγt inhibitor FoxO1 and by enhancing STAT3 phosphorylation. Increased EP4 expression levels in Th17 cells from AS patients correlate with high disease activity as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4 (r = 0.7591, p = 0.0016).ConclusionsEP4 is a potential marker of disease activity in patients with AS. Aberrant EP4 expression might contribute to pathogenic Th17 cell accumulation and represent a new target for the treatment of AS.
Highlights
Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS)
In accordance with previous reports, ex vivo flow cytometry analysis revealed that the frequency of Th17 cells is increased in the peripheral blood of patients with AS compared to healthy controls (HC) (p = 0.0066, 2.34 ± 0.56% in AS vs. 0.4 ± 0.2% in HC) (Fig. 1a–c; Additional file 1: Figure S1a)
EP4 is significantly overexpressed in Th17 cells from patients with AS compared to healthy individuals or patients with rheumatoid arthritis (RA)
Summary
Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). The prostaglandin E2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Recent genomewide association studies (GWAS) have identified five risk alleles for AS in PTGER4, the gene encoding for EP4. The aim of this study was to reveal a possible link between EP4 and disease activity in patients with AS. Ankylosing spondylitis (AS) is a multifactorial autoimmune disease leading to new bone formation and ankylosis of affected joints. Recent genome-wide association studies (GWAS) have identified the single nucleotide polymorphisms (SNPs) rs10440635, rs9283753, rs16869602, rs12186979, Th17 cells are believed to be involved in the pathogenesis of AS and anti-IL-17A-specific antibodies have been recently established as an effective treatment [6,7,8].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
