GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica

Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR. Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22; healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12; controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7; healthy controls, n = 7). Monocytes (CD14highCD16- and CD14highCD16+) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMR-affected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-γ) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor β ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-γ significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF. The monocyte compartment is expanded and activated in PMR. Macrophages in PMR-affected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-γ, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic targets for PMR.