Monocytes/macrophages express chemokine receptor CCR9 in rheumatoid arthritis and CCL25 stimulates their differentiation

Abstract

IntroductionMonocytes/macrophages accumulate in the rheumatoid (RA) synovium where they play a central role in inflammation and joint destruction. Identification of molecules involved in their accumulation and differentiation is important to inform therapeutic strategies. This study investigated the expression and function of chemokine receptor CCR9 in the peripheral blood (PB) and synovium of RA, non-RA patients and healthy volunteers.MethodsCCR9 expression on PB monocytes/macrophages was analysed by flow cytometry and in synovium by immunofluorescence. Chemokine receptor CCR9 mRNA expression was examined in RA and non-RA synovium, monocytes/macrophages from PB and synovial fluid (SF) of RA patients and PB of healthy donors using the reverse transcription polymerase chain reaction (RT-PCR). Monocyte differentiation and chemotaxis to chemokine ligand 25 (CCL25)/TECK were used to study CCR9 function.ResultsCCR9 was expressed by PB monocytes/macrophages in RA and healthy donors, and increased in RA. In RA and non-RA synovia, CCR9 co-localised with cluster of differentiation 14+ (CD14+) and cluster of differentiation 68+ (CD68+) macrophages, and was more abundant in RA synovium. CCR9 mRNA was detected in the synovia of all RA patients and in some non-RA controls, and monocytes/macrophages from PB and SF of RA and healthy controls. CCL25 was detected in RA and non-RA synovia where it co-localised with CD14+ and CD68+ cells. Tumour necrosis factor alpha (TNFα) increased CCR9 expression on human acute monocytic leukemia cell line THP-1 monocytic cells. CCL25 induced a stronger monocyte differentiation in RA compared to healthy donors. CCL25 induced significant chemotaxis of PB monocytes but not consistently among individuals.ConclusionsCCR9 expression by monocytes is increased in RA. CCL25 may be involved in the differentiation of monocytes to macrophages particularly in RA.

Prokaryotic expression, purification, and refolding of leukocyte cell-derived chemotaxin 2 and its effect on gene expression of head kidney-derived macrophages of a teleost fish, ayu (Plecoglossus altivelis)

“…CCR9 is the principal chemokine receptor for the thymus expressed chemokine [41]. Some data also suggest that regulated expression of CCR9 is critical for normal development of immature thymocytes and CCR9 on these CD14þ cells may play a role in the differentiation of recently immigrated monocytes [42,43].…”

Anti-CCL25 Antibody Prolongs Skin Allograft Survival by Blocking CCR9 Expression and Impairing Splenic T-Cell Function

“…CCR9, one of the CC subset chemokine receptors, was initially reported in thymus and small intestine (Vicari et al 1997;Wurbel et al 2000). More recent studies have shown that CCR9 was highly expressed in other tissues besides thymus and intestine, which were involved in many kinds of disease processes, including rheumatoid arthritis, inflammatory bowel disease and hepatitis (Apostolaki et al 2008;Nakamoto et al 2012;Schmutz et al 2010), while the role of CCR9 in acute transplant rejection remains unclear.…”

“…Originally, the CCR9-CCL25 interaction was found to be involved in T cell development in the thymus (Vicari et al 1997) and T-cell homing to the small intestine (Kunkel et al 2000;Wurbel et al 2000). However, accumulating evidences showed that the CCR9/ CCL25 axis participated in a variety of disease processes (Johnson-Holiday et al 2011;Nakamoto et al 2012;Schmutz et al 2010). In Crohn's disease patients (M et al 2007) and in a murine model (Apostolaki et al 2008;Rivera-Nieves et al 2006), CCL25 was up-regulated following accumulation of CCR9…”

CCR9+ macrophages are required for eradication of peritoneal bacterial infections and prevention of polymicrobial sepsis

“…Recently, it has been reported that expression of CCR9 on macrophages is required for inflammatory response in Con A-induced hepatitis and rheumatoid arthritis [16,17]. To investigate additional roles of CCR9, we examined its expression on peritoneal macrophages.…”

“…CCL25 is induced in the colon in a murine model of acute colitis, and ameliorates colitis severity by recruiting tolerogenic CCR9 + pDCs [15]. Recently, we and other groups have shown that CCR9 is also expressed on macrophages, and that its expression is required for induction or maintenance of inflammation in Concanavalin A (Con A)-induced hepatitis and human rheumatoid arthritis [16,17]. It is also known that CCR9/CCL25 interaction induces not only chemotaxis, but also activation and development of macrophages [16,17].…”