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

Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D'Silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa J. Davis, Jeffrey J. Babon, Bogoljub Ciric, Eric Vivier, Warren S. Alexander, Nicholas D. Huntington, Ian P. Wicks

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article numbere20191421
Number of pages19
JournalJournal of Experimental Medicine
Volume217
Issue number5
DOIs
Publication statusPublished - 4 May 2020

Keywords

  • autoimmunity
  • innate immunity
  • inflammation

Cite this

Louis, C., Souza-Fonseca-Guimaraes, F., Yang, Y., D'Silva, D., Kratina, T., Dagley, L., Hediyeh-Zadeh, S., Rautela, J., Masters, S. L., Davis, M. J., Babon, J. J., Ciric, B., Vivier, E., Alexander, W. S., Huntington, N. D., & Wicks, I. P. (2020). NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS. Journal of Experimental Medicine, 217(5), [e20191421]. https://doi.org/10.1084/jem.20191421