Decoding heterogeneity and specialisation of interstitial synovial macrophages: what, where and how

Synovial macrophages are a highly heterogeneous population of tissue-resident cells, and they have distinct functions at steady-state and during synovial inflammation. We have identified that their heterogeneity reflects distinct ontogeny, localisation, and function at least in two subsets of murine synovial macrophages. AQP1-positive macrophages are localised in a specific niche in the interior of the murine knee joint, near the structural elements including the patella, menisci, and cruciate ligaments. They can self-maintain by proliferation and only a minority of them is replenished by monocytes at steady-state. Furthermore, these cells appear to function as tissue-resident precursors of lining macrophages and their functions may be shaped by biophysical forces including mechanical and osmotic pressure. Conversely, RELM⍺-positive macrophages are localised in the vicinity of blood vessels in the interstitium, they are largely replenished by monocytes, and they secrete the monocyte chemoattractant CCL2 to recruit monocytes to the interstitium at the onset of synovial inflammation. Overall, we have identified that macrophage localisation in the synovium significantly impacts their function and that biophysical forces may be important contributors to their phenotype, particularly in mechano-sensitive organs such as the knee.