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

TL;DR

The study reveals how GM-CSF promotes the development of different types of inflammatory macrophages in autoimmune arthritis, contributing to joint inflammation and pain.

Contribution

The novel finding is that GM-CSF drives functional diversification of macrophages, not their recruitment, in autoimmune arthritis.

Findings

GM-CSF facilitates differentiation of synovial macrophage subsets, not monocyte recruitment.

Two GM-CSF-dependent macrophage clusters (Arginase-1+ and EpCAM+) contribute to joint inflammation.

EpCAM+ macrophages uniquely express Ccl17, a mediator of arthritic pain.

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 (TH17 cell)–mediated autoimmune arthritis, we show that joint-infiltrating Ly6Chi monocytes in response to autoimmune TH17 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 TH17 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.

GM-CSF drives macrophage diversification in autoimmune arthritis.

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