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 (T17 cell)-mediated autoimmune arthritis, we show that joint-infiltrating Ly6Cmonocytes in response to autoimmune T17 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 T17 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-1and epithelial cell adhesion molecule (EpCAM)clusters-both expressing proinflammatory cytokines and matrix metalloproteinases. Notably, EpCAMmacrophages uniquely express, 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.