Rheumatoid arthritis synovial fibroblasts promote TREM-1 expression in monocytes via COX-2/PGE2 pathway

Abstract

Background Triggering 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. Methods Synovial 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 PGE 2 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. Results TREM-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 PGE 2 in a cyclooxygenase (COX)-2-dependent manner. PGE 2 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/PGE 2 /EP2,4 signaling. Conclusions Our 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. Electronic supplementary material The online version of this article (10.1186/s13075-019-1954-3) contains supplementary material, which is available to authorized users.

Serum COX‑2 and FOXO3a in patients with rheumatoid arthritis and correlation with disease activity

“…In this study, the expression of COX-2 in the study group was significantly higher than that in the control group. A large number of studies have shown that COX-2 is highly expressed in patients with RA ( 20 , 21 ), which is consistent with our findings. Therefore, COX-2 inhibitors have been widely used in clinical practice, especially in the treatment of RA ( 22 , 23 ).…”

The effects of garlic (Allium sativum) supplementation on inflammatory biomarkers, fatigue, and clinical symptoms in patients with active rheumatoid arthritis: A randomized, double‐blind, placebo‐controlled trial

“…MMPs expressed by synovial cells and chondrocytes in RA are thought to play a pivotal role in cartilage destruction (Takaishi, Kimura, Dalal, Okada, & D'Armiento, 2008). In addition, these cytokines appear to play a critical role in up-regulation of cyclooxygenase-2 (COX-2) expression and subsequent production of prostaglandin E2 (PGE2) resulting in cartilage degradation and inflammation (Mateen et al, 2016;Peng et al, 2019 1β-induced prostaglandins E2 and MMPs, thereby acting as potential compounds to ameliorate the clinical outcomes in arthirits (Li et al, 2007;Meyer, Ueberham, & Gebhardt, 2004). Dehghani et al indicated that 1,000 mg garlic supplementation for 12 weeks might reduce pain severity in women with knee osteoarthritis (Dehghani et al, 2018).…”

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis

“…Frommer et al showed that FFA contribute to the pathogenesis and damage in RA, OA, and PsA, since stimulation of FLS with oleic, palmitic, and linoleic acid induced the secretion of proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix metalloproteinases pro-MMP1 and MMP3 [185]. Arachidonic acid (ARA) is the precursor of classically described prostaglandins (PGE2), which are known to be involved in inflammation in general, but also in arthritis [186,187].…”