The Alarmin S100a8/A9 Affects Macrophage Phenotype In A Time-Dependent Manner And Favors M2-Like Macrophage Differentiation After Long-Term Exposure

Purpose: Synovitis is found in the majority of osteoarthritis (OA) patients and is important in disease progression. Especially macrophages have been attributed a key role in the orchestration of the OA-associated inflammatory response. Macrophages present themselves in a broad spectrum ranging from a destructive, pro-inflammatory (M1) phenotype to a reparative, anti-inflammatory (M2) phenotype. The balance between these phenotypes likely steers catabolic processes, like cartilage degeneration, and more anabolic processes, including fibrosis and ectopic bone formation, that characterize the OA environment. Macrophage phenotypic characteristics are highly dependent on environmental cues like growth factors and inflammatory factors. An inflammatory factor that is present in high quantities throughout the course of OA is the alarmin S100A8/A9. Stimulation of various cell types that are found in the joint, including mature macrophages and chondrocytes, with this factor results in production of high levels of pro-inflammatory and catabolic factors. Interestingly, next to decreased catabolic processes, S100a9-/- mice showed decreased OA-associated anabolic processes such as osteophyte formation in an experimental model mimicking post-traumatic OA. Here, we investigated how chronic exposure of monocytes to S100A8/A9, as is present during OA, affects macrophage differentiation and phenotype.