Prostaglandin receptor EP4 expression by Th17 cells is associated with high disease activity in ankylosing spondylitis

Abstract

Background: Th17 cells are involved in the pathogenesis of ankylosing spondylitis (AS). However, the mechanism underlying enhanced Th17 cell accumulation in AS remains unknown. The prostaglandin E 2 receptor EP2/EP4 signaling pathway plays a critical role in the development of autoimmune Th17 cells. Interestingly, 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. Methods: Th17 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. Results: EP4 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). Conclusions: EP4 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.

Punicalagin Exerts Protective Effects against Ankylosing Spondylitis by Regulating NF-κB-TH17/JAK2/STAT3 Signaling and Oxidative Stress

“…Punicalagin-mediated reduced TNF- α , IL-1 β , IL-6, and NO serum levels in AS-induced mice illustrate the anti-inflammatory efficacy. Further, it has been shown that Janus kinases (JAK) are major transducers of cytokine signals in Th17 cells [ 40 , 41 ]. Th17 cells, which is a key player in AS, secrete various inflammatory mediators such as IL-17, IL- 6, IL-22, IL-26, interferon- (IFN-) γ , and TNF- α [ 8 ].…”

Regulatory T cell frequencies in patients with rheumatoid arthritis are increased by conventional and biological DMARDs but not by JAK inhibitors

“…The peripheral blood of patients with RA is characterised by a higher percentage of Th17 cells and the balance between Th17 cells and Treg cells is shifted 6. In RA patients, the Th17/Treg cell balance is not recovered by JAK inhibitors, although the percentage of Th17 cells is significantly suppressed (figure 1E).…”

Intestinal and enthesis innate immunity in early axial spondyloarthropathy

“…Furthermore, activation of prostaglandin E2 receptor 4 (EP4), the protein product of prostaglandin EP4 receptor (PTGER4) promotes development of Th17 cells by increasing the IL-23 expression level. PTGER4 polymorphisms have been shown to be associated with axSpA [ 61 ]. In addition to the increase in IL-23 secretion, it has been shown that prostaglandin E2 (PGE2) levels were significantly elevated in mice patellar and Achilles tendons in response to rigorous treadmill training [ 62 ].…”