EPCR deficiency ameliorates inflammatory arthritis in mice by suppressing the activation and migration of T cells and dendritic cells

Abstract

Objectives Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with rheumatoid arthritis (RA), but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms. Methods Collagen-induced arthritis (CIA) was induced in EPCR gene knockout (KO) and matched wild type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCRKO and WT mice, RA patients and healthy controls (HC) were detected by flow cytometry and ELISA. Results EPCRKO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT. EPCRKO mice also had significantly less Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCRKO mice expressed less chemokine receptors CXCR3, CXCR5 and CCR6 than WT. In vitro, EPCRKO spleen cells contained less Th1 and more Th2 and Th17 cells than WT, and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCRKO bone marrow were less mature and produced less matrix metalloproteinase-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro. Conclusion Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment.

Endothelial Protein C Receptor and Its Impact on Rheumatic Disease

“…This may lead to an increase in pathogenic Th17 cell differentiation in RA patients [146]. Contrarily, mice with severe EPCR deficiency displayed more than 40% reduced arthritis incidence and 50% decreased disease severity when compared to normal mice [147].…”

“…The same mechanism may apply to RA, although there is no confirmation yet. However, studies have shown that mice with severe EPCR deficiency had a much lower disease incidence and milder arthritis [147], indicating that EPCR could also be a potential therapeutic target for RA. Therefore, it is essential to validate these findings in large clinical cohorts to assess EPCR function and its potential as a therapeutic target for rheumatoid diseases.…”