A recent study published in Annals of the Rheumatic Diseases uncovered that granulocyte-macrophage colony-stimulating factor (GM-CSF) played a pivotal role in promoting IL-6 production by macrophages in polymyalgia rheumatica (PMR), reinforcing the pathogenic significance of these cells in the disease.
Investigators analyzed monocyte phenotypes in peripheral blood from 22 PMR patients and 20 healthy controls, and in paired subacromial-subdeltoid (SASD) bursal fluid from 9 PMR patients. Monocytes, particularly CD14^high^CD16⁻ and CD14^high^CD16⁺ subsets, were found to be expanded in peripheral blood and showed signs of activation in bursal fluid. Within PMR-affected bursal tissue, macrophages were the dominant immune population and expressed multiple proinflammatory cytokines. IL-6 and interferon-gamma (IFN-γ) were detected in both PMR and control tissues, but GM-CSF and macrophage colony-stimulating factor (M-CSF) were markedly elevated in PMR samples. Macrophages from PMR tissue demonstrated a skewed activation profile, indicated by a higher CD206/folate receptor β ratio, consistent with GM-CSF-driven polarization. In vitro experiments confirmed that GM-CSF, in combination with M-CSF and IFN-γ, significantly amplified IL-6 production by monocyte-derived macrophages. Minimal IL-6 induction occurred in the absence of GM-CSF.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a cytokine primarily produced by activated T cells and macrophages. It activates mature neutrophils, eosinophils, and macrophages to produce proinflammatory cytokines. GM-CSF production is induced by lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-23. It is a 23-kDa glycoprotein with a four–α-helical structure that signals through a heterodimeric receptor composed of an α subunit and a common β chain (βc/GM-CSFRβ). The α subunit binds GM-CSF with low affinity; high-affinity binding and signal transduction occur upon dimerization with the β chain. The GM-CSF receptor is expressed on neutrophils, dendritic cells, macrophages, eosinophils, and endothelial cells. The GM-CSFR complex activates the Ras-MAPK and JAK2-STAT (STAT1, STAT3, STAT5) pathways, regulated by SOCS1 and SOCS3.
The study findings highlighted the expansion and activation of the monocyte-macrophage axis in PMR and positioned GM-CSF as a central cytokine driving proinflammatory responses. The results underscored the potential of targeting GM-CSF-mediated macrophage activation in PMR management.GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica
References
- Jiemy WF, Zhang A, Abdulahad WH, Reitsema RD, van Sleen Y, Sandovici M, Alegria GC, Cornec D, Devauchelle-Pensec V, Hemon P, Quéré B, Boukhlal S, Roozendaal C, Kwee TC, Dasgupta B, Diepstra A, Heeringa P, Brouwer E, van der Geest KSM. GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica. Ann Rheum Dis. 2025 May;84(5):833-843.
- Gizinski AM, Fox DA. 65 – Emerging therapeutic targets: GM-CSF, IL-17, and IL-23. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, editors. Rheumatology (Sixth Edition) [Internet]. Philadelphia: Mosby; 2015 [cited 2025 May 29]. p. 518–21. Available from: https://www.sciencedirect.com/science/article/pii/B9780323091381000656