Leukocyte Ig-like receptor A3 facilitates inflammation, migration and invasion of synovial tissue-derived fibroblasts via ERK/JNK activation

Objective: LILRA3 is a soluble receptor belongs to the immunoglobulin superfamily. Our previous studies demonstrated that LILRA3 is a common genetic risk for multiple autoimmune diseases, including rheumatoid arthritis (RA). Functional LILRA3 conferred increased risk of joint destruction in patients with early RA. We undertook this study to further investigate the pathological role of LILRA3 in joint inflammation of RA.

Methods: Soluble LILRA3 were measured by ELISA. LILRA3 plasmids were transfected into human fibroblast-like synoviocytes (FLSs) using electroporation. Activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were determined by Western blots. Cytokine transcripts were quantified by Real-Time PCR. Migratory and invasive capacities of FLSs were evaluated using transwell migration and matrigel invasion assays. FLS Apoptosis was analyzed using flow cytometry. Co-localization of LILRA3, LILRB1, and HLA-G in RA-FLSs were visualized by immunofluorescence staining.

Results: Soluble LILRA3 was specifically expressed in synovial fluids and serum LILRA3 was significantly increased and positively correlated with disease activity/severity in RA patients. LILRA3 induced an increased expression of interleukin (IL)-6, IL-8 and matrix metalloproteinase (MMP) 3 in RA-FLSs. In vitro LILRA3 stimulation/overexpression promoted RA-FLS migration and invasion, and enhanced phosphorylation of ERK/JNK. Inhibition of ERK/JNK resulted in suppression of IL-6/IL-8 expression in LILRA3-stimulated RA-FLSs. LILRA3 was co-localized with its homologue LILRB1 and shared ligand HLA-G in RA-FLSs.

Conclusion: The present study provides the first evidence that soluble LILRA3 is a novel proinflammatory mediator involved in synovial inflammation by promoting RA-FLS activation, migration and invasion, probably through the ERK/JNK signalling pathways.

Leukocyte immunoglobulin-like receptor A3; fibroblast-like synoviocyte; rheumatoid arthritis; the ERK and JNK signaling.