NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Louis, Souza-Fonseca-Guimaraes, Yang, D'Silva, Kratina, Dagley, Hediyeh-Zadeh, Rautela, Masters, Davis, Babon, Ciric, Vivier, Alexander, Huntington, Wicks (2020) NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS J Exp Med (IF: 15.3) 217(5)
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Abstract

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.© 2020 Louis et al.

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201918
http://www.ncbi.nlm.nih.gov/pubmed/32097462
http://dx.doi.org/10.1084/jem.20191421

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