Granulocyte–macrophage colony-stimulating factor (GM-CSF), an important cytokine in the development and progression of inflammatory arthritis, is produced by a variety of different cells including T helper 17 (TH17) cells, well-known contributors to arthritis pathology. “We have demonstrated that a non-T cell source of GM-CSF is indispensable for the development of autoimmune arthritis and highlighted GM-CSF-producing synovial innate lymphoid cells (ILCs) as a previously unappreciated population in inflamed joints,” reports Keiji Hirota, co-corresponding author of a new study published in Immunity.

Credit: Susanne Harris/Macmillan Publishers Limited

To investigate the various sources of GM-CSF and their contribution to autoimmune pathology, Hirota and colleagues used SKG mice, a model of spontaneous T cell-mediated autoimmune arthritis. As expected, GM-CSF-deficient mice were highly resistant to disease induction. Using an adoptive T cell transfer system, they showed that although GM-CSF production by T cells augmented chronic inflammation, this process was dispensable for arthritis initiation.

... although GM-CSF production by T cells augmented chronic inflammation, this process was dispensable for arthritis initiation

Instead, GM-CSF production by radio-resistant stromal cells, including fibroblast-like synoviocytes (FLSs) and ILCs, was crucial for the development of autoimmunity. In vitro, FLSs secreted GM-CSF in response to recombinant IL-17, whereas ILCs produced GM-CSF in response to IL-2, IL-33 and Toll-like receptor 9 (TLR9) ligands. Thus, various mechanisms can contribute to the production of this pathogenic cytokine.

“GM-CSF-producing synovial ILCs were present in the inflamed joints of SKG mice and patients with rheumatoid arthritis (RA), augmenting the disease,” explains Hirota. ILCs of a similar phenotype were present in the joints of healthy C57/BL6 mice, and this population expanded following induction of collagen-induced arthritis (another model of RA).

“Our findings provide new insight into our understanding of the cellular sources of GM-CSF and the inflammatory cascade instigated by autoimmune TH17 cells,” says co-corresponding author Shimon Sakaguchi. “Targeting this pathway might be a key therapeutic strategy for the treatment of autoimmune diseases including RA.”