Pathogenic GM-CSF drives functional diversification of inflammatory macrophages in autoimmune arthritis
- Hiroki Mukoyama
- Yusuke Takeuchi
- Daiya Ohara
- Yoonha Lee
- Hitomi Watanabe
- Hiroki Kato
- Gen Kondoh
- Akio Morinobu
- Keiji Hirota
2026-03-25
Autoimmune T cells orchestrate joint inflammation and pain in concert with synovial macrophages; however, the mechanisms governing the development and functional diversification of these macrophages remain unclear. Using a model of T helper 17 cell (T H 17 cell)–mediated autoimmune arthritis, we show that joint-infiltrating Ly6C hi monocytes in response to autoimmune T H 17 cells, rather than resident synovial macrophages, are the primary mediators of disease pathogenesis. Granulocyte-macrophage colony-stimulating factor (GM-CSF), a critical component of the pathogenic circuit driven by arthritogenic T H 17 cells, does not contribute to monocyte recruitment to the synovium but facilitates their subsequent differentiation into functionally distinct synovial macrophage subsets, thereby amplifying joint inflammation. Single-cell RNA sequencing identified two GM-CSF–dependent subpopulations of pathogenic synovial macrophages—Arginase-1 + and epithelial cell adhesion molecule (EpCAM) + clusters—both expressing proinflammatory cytokines and matrix metalloproteinases. Notably, EpCAM + macrophages uniquely express Ccl17 , a pronociceptive mediator implicated in arthritic pain. Collectively, these findings delineate a GM-CSF–driven program of macrophage diversification that underpins both joint inflammation and pain, implicating this axis in the chronic activation of inflammatory and nociceptive pathways in autoimmune arthritis.