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Mechanistic impasses: tofacitinib treatment ameliorates GM-CSF-driven macrophage inflammation

Cellular & Molecular Immunology (2026)Cite this article

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The Original Article was published on 04 March 2026

Granulocyte‒macrophage colony-stimulating factor (GM-CSF, CSF2) has long been recognized as a therapeutic target in inflammatory diseases such as rheumatoid arthritis (RA), despite the complication of its steady-state role in the lung. The receptor for GM-CSF is composed of an α-chain specific to GM-CSF and a β-chain that is common to IL-3 and IL-5. Signaling is principally mediated by the PI3K-Akt, JAK-STAT, NFκB and ERK pathways, and the relative contributions of these pathways are recognized for the potent effect of GM-CSF on macrophages (Mϕs), which polarizes them to an “M1-like” phenotype and contributes to disease activity. Satoeya et al. [1] reported that tofacitinib (a JAK inhibitor) can therapeutically reprogram GM-CSF-primed macrophages (GM-Mϕs) derived from RA patients.

The authors first demonstrated that GM-Mϕs form a distinct inflammatory phenotype in RA, revealing an IL‑1β⁺S100A⁺HIF‑1⁺IL‑10ˡᵒNFIL‑3/6ˡᵒ profile with mitochondrial oxidative stress and fragmentation. Mϕs activated by TLR ligands and proinflammatory mediators such as GM-CSF increase the levels of mitochondrial reactive oxygen species (ROS), contributing to oxidative stress, which strengthens their inflammatory phenotype [2]. The mitochondria in these cells often have a greater degree of fragmentation, which further increases ROS accumulation. The resulting Mϕ phenotype contributes to a sustained inflammatory response, as observed in RA.

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Fig. 1: Therapeutic targeting of GM-CSF-primed macrophages.

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  1. Kennedy Institute of Rheumatology, Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK

    Felix I. L. Clanchy

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  1. Felix I. L. Clanchy
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Correspondence to Felix I. L. Clanchy.

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Clanchy, F.I.L. Mechanistic impasses: tofacitinib treatment ameliorates GM-CSF-driven macrophage inflammation. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01406-x

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