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

Abstract

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 gene deletion in five Chinese populations and protective association with nasopharyngeal carcinoma

“…in fibroblast-like synoviocytes of patients afflicted with rheumatoid arthritis, facilitating inflammation (Liu et al, 2023). Nevertheless, the mechanisms underlying the association between CNV of the LILRA3 gene and NPC await further exploration.…”

Human leukocyte immunoglobulin-like receptors in health and disease

“…Significantly lower numbers of LILRA2 + , LILRB2 + and LILRB3 + inflammatory cells were detected in RA patients who responded to anti-rheumatic therapy compared to healthy controls, as a result of the partial blocking of LILRA2-mediated secretion of TNF-a (63, 87, 257). Additionally, LILRA3 promotes proinflammatory responses in fibroblast-like synoviocytes, promoting their activation, migration and invasion in vitro (73). Antirheumatic drugs downregulate synovial expression of LILRB2, LILRB3 and LILRA2 in responding patients.…”

“…Aberrant expression of LILRs has been associated with several arthritis syndromes. LILRA2, LILRA3, LILRA5, LILRB2, and LILRB3 are found at elevated levels in the sera and synovial fluid of RA patients, correlating with disease severity (25,63,72,73,87,257). Significantly lower numbers of LILRA2 + , LILRB2 + and LILRB3 + inflammatory cells were detected in RA patients who responded to anti-rheumatic therapy compared to healthy controls, as a result of the partial blocking of LILRA2-mediated secretion of TNF-a (63, 87, 257).…”