Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Background/Purpose: CCL25 and its receptor CCR9 have been detected in the inflamed joint; however their role is undefined in rheumatoid arthritis (RA). Hence studies were conducted to characterize the expression and functional significance of CCL25 and CCR9 in the inflammatory & erosive phases of RA.
Methods: Methods: For this purpose, expression pattern of CCR9 was determined in RA, osteoarthritis (OA) and normal (NL) synovial tissues (STs) as well as in RA ST fibroblasts (FLS) & in vitro differentiated macrophages (Mφ). Protein levels of CCL25 were quantified in synovial fluid (SF) and plasma from RA, OA and/or NL donors. Next role of CCL25 was evaluated in RA FLS and Mφ trafficking & inflammatory response in addition to identifying the signaling pathways linked to these functions. Last CCL25 potency was examined in the remodeling of RA naïve cells into mature osteoclasts.
Results: Results: We show that CCR9 is highly expressed on RA ST lining, sublining and endothelial cells compared to OA and NL STs. While CCL25 expression is markedly elevated in RA & OA ST lining, sublining and endothelial cells relative to NL ST counterparts. Consistent with this notion, we found that CCR9 was expressed on unstimulated RA FLS (35%) and activation with IL-1β, TNF, IL-6 and RA SF can further accentuate its cell surface expression by 4-5 fold. In contrast, these inflammatory mediators did not impact CCR9 cell surface expression on RA Mφs. Nevertheless, we demonstrate that CCR9 cell surface expression is enhanced by 10 fold when RA monocytes (4%) are differentiated into Mφs (48%). Corroborating the histological findings, we reveal that CCL25 protein levels are comparable in RA and OA SF; which was significantly higher than those detected in RA and NL plasma. Interestingly, we showed that CCL25 present in RA SF can dose responsively attract RA FLS and monocytes into the joint and this process was suppressed by ERK and p38 inhibitors. On the contrary, stimulation with CCL25 did not instigate phagocytosis in fully differentiated RA Mφ. Next impact of CCL25 was examined on RA FLS and RA Mφ inflammatory response. We demonstrated that unlike RA FLS that were unaffected by CCL25 activation; stimulation of RA Mφ with CCL25 enhanced IL-8 production by 2 fold which was dependent on p38 and ERK signaling. However addition of RA FLS to RA Mφs in culture did not amplify CCL25’s inflammatory response detected in myeloid cells. We also established that in later stages of disease, CCL25 was capable of remodeling RA myeloid progenitor cells into mature osteoclasts potentially by IL-8 induction.
Conclusion: Conclusion: We have uncovered that elevated levels of CCL25 in RA SF trigger infiltration of CCR9+ RA fibroblast and monocyte into the joint and accelerates transformation of myeloid cells into bone eroding osteoclasts. Our results suggest that CCL25 and CCR9 play an important role in the early and the later phases of RA pathology.
To cite this abstract in AMA style:Umar S, Raemdonck K, Palasiewicz K, Volin M, Arami S, Volkov S, Sweiss N, Amin M, shahrara S. CCL25, a Novel Fibroblast and Macrophage Chemoattractant That Potentiates RA Bone Erosion [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/ccl25-a-novel-fibroblast-and-macrophage-chemoattractant-that-potentiates-ra-bone-erosion/. Accessed October 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ccl25-a-novel-fibroblast-and-macrophage-chemoattractant-that-potentiates-ra-bone-erosion/