Targeting ORM1-CCR5 axis inhibits the aggressive phenotype of synovial fibroblasts and alleviates RA.

OBJECTIVES: The present study focused on exploring the role of orosomucoid 1 (ORM1) in rheumatoid arthritis (RA). METHODS: Differentially expressed genes in GSE15573 dataset were analyzed by bioinformatics. Fibroblast-like synoviocytes (FLS) from RA patients were stimulated with collagen-II, followed by quantification of ORM1 and C-C chemokine receptor 5 (CCR5) expressions. The interaction between ORM1 and CCR5 in FLS was examined by Co-immunoprecipitation. After ORM1 intervention or maraviroc treatment, the effect of ORM1 or CCR5 as well as their interplay in the stimulated cells was investigated using molecular experiments, methylthiazolyldiphenyl-tetrazolium bromide assay and transwell assay. Rats underwent collagen-induced arthritis (CIA) modeling. Arthritis index scoring, western blot assay and histopathological evaluation were performed in CIA rats with ORM1 or CCR5 knockdown. RESULTS: ORM1 and CCR5 were highly expressed in collagen type II (CII)-stimulated FLS and synovial tissues of CIA rats. The expression of CCR5 was positively regulated by ORM1, and the interaction of ORM1 and CCR5 was confirmed. CII stimulation enhanced viability, migration and invasion of FLS, but these effects were antagonized in the absence of ORM1 or CCR5. Knockdown of ORM1 or CCR5 in CIA rats reduced arthritis index, while alleviating cartilage erosion, inflammatory infiltration and synovial hyperplasia of ankle joints. CONCLUSIONS: ORM1 deficiency suppresses the aggressive phenotype of FLS to reduce RA progression by downregulating CCR5.