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

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 ce...

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Detalles Bibliográficos
Autores principales: Louis, Cynthia, Fonseca-Guimaraes, Fernando Souza-, 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., Wicks, Ian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201918/
https://www.ncbi.nlm.nih.gov/pubmed/32097462
http://dx.doi.org/10.1084/jem.20191421
Descripción
Sumario: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.