Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18–dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets.
Louis, Cynthia; Souza-Fonseca-Guimaraes, Fernando; Yang, Yuyan; D'Silva, Damian; Kratina, Tobias; Dagley, Laura; Hediyeh-Zadeh, Soroor; Rautela, Jai; Masters, Seth Lucian; Davis, Melissa J; Babon, Jeffrey J; Ciric, Bogoljub; Vivier, Eric; Alexander, Warren S; Huntington, Nicholas D; and Wicks, Ian P, "NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS" (2020). Department of Neurology Faculty Papers. Paper 245.
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