CD200R1 regulates synovial inflammation through neutrophil LTB4 (66.3)

Abstract

Abstract Rheumatoid arthritis (RA) is a debilitating disease afflicting over 2 million Americans. The K/BxN model of synovial inflammation shares several key aspects of pathology in common with human RA, and is an accepted model of synovial inflammation. The 5-lipoxygenase (LO) pathway product leukotriene (LT)B4, generated by polymorphonuclear leukocytes (PMNs) and macrophages, plays a requisite role in this model by initiating and amplifying the recruitment and activation of PMN in joints. Mechanisms that down-regulate LTB4 synthesis have the potential to play a major role in inhibiting synovial inflammation and provide novel therapeutic targets. To explore the role of the inhibitory CD200:CD200R1 axis in this process, we developed CD200R1-/- mice and examined them in the K/BxN arthritis model. We observed that CD200R1-/- mice show increased severity as compared to CD200R1+/+ mice. Synovial fibroblasts were found to express CD200 and are in close proximity to CD200R1-expressing macrophages in inflamed ankle sections. Finally, CD200R1-/- PMN generated approximately 50% more LTB4 in response to C5a or to a combination of GM-CSF and C5a. Together, these observations indicate that CD200R1 plays a key role in regulating LTB4 synthesis and synovial inflammation in the K/BxN model of RA.