Pathogenic GM-CSF drives functional diversification of inflammatory macrophages in autoimmune arthritis.

Abstract

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_H17 cell)-mediated autoimmune arthritis, we show that joint-infiltrating Ly6C^hi monocytes in response to autoimmune T_H17 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_H17 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 <i>Ccl17</i>, 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.