Abstract
BackgroundTriggering receptor expressed on myeloid cells-1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and amplifies the inflammatory response. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism.MethodsSynovial fluid and paired peripheral blood from rheumatoid arthritis (RA) patients were analyzed using flow cytometry. Expression of TREM-1 in monocytes was detected after co-culture with RASF, with or without pre-treatment with toll-like receptor (TLR) ligands. Whether RASF-regulated TREM-1 level in monocytes require direct cell contact or soluble factors was evaluated by transwell experiment. COX-2 expression and PGE2 secretion in RASF were determined by quantitative PCR (qPCR) and ELISA. RASF, with and without TLR ligand stimulation, were treated with COX-2 inhibitors, COX-2 siRNA (siCOX-2) or EP1–4 antagonists, and the resulting TREM-1 level in CD14+ monocytes was measured using flow cytometry.ResultsTREM-1 was highly expressed in CD14+ cells from peripheral blood and especially synovial fluid from RA patients. The expression of TREM-1 in monocytes was increased by co-culture with RASF. TLR-ligand-activated RASF further elevated TREM-1 level. Transwell assay indicated that soluble factors played a key role in RASF-promoted expression of TREM-1 in monocytes. RASF, with or without stimulation by TLR ligands, increased secretion of PGE2 in a cyclooxygenase (COX)-2-dependent manner. PGE2 enhanced the increase in TREM-1 level in monocytes. Finally, studies using COX-2 inhibitors, COX-2 siRNA (siCOX-2) and EP1–4 antagonists, showed that RASF promotion of TREM-1 expression in monocytes was mediated by COX-2/PGE2/EP2,4 signaling.ConclusionsOur data is the first report to reveal the critical role of RASF in upregulating TREM-1 expression in monocytes, which indicates that TREM-1 might be a novel target for RA therapy.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and progressive destruction of the joints [1]
Triggering receptor expressed on myeloid cells-1 (TREM-1, CD354), a recently identified immunoglobulin superfamily member, mainly expresses on myeloid cells, such as neutrophils, monocytes, and tissue macrophages [11, 12]
We used flow cytometry analysis to study the expression of TREM-1 in CD14+ peripheral blood monocytes from RA patients and healthy donors
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and progressive destruction of the joints [1] Infiltrating immune cells such as neutrophils, monocytes/macrophages, and T cells, proliferating rheumatoid arthritis synovial fibroblasts (RASF), extracellular matrix components, and. RASF can interact with infiltrating immune cells through cell-cell contact as well as elaboration of soluble factors like IL-6, IL-8, and IL-15, which promote the recruitment, activation, expansion, and production of inflammatory cytokines of infiltrating immune cells. These processes develop and maintain the inflammatory response network in the synovial microenvironment and exacerbate RA inflammation. The aim of this study was to determine whether rheumatoid arthritis synovial fibroblasts (RASF) promote the expression of TREM-1 in monocytes and its potential regulatory mechanism
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