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

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 217 Issue 5 (05 04 2020) ISSN: 1540-9538 [Electronic] United States
• PMID: 32097462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Louis et al.

Chemical References

• Autoantibodies
• Interleukin-18
• STAT5 Transcription Factor
• Suppressor of Cytokine Signaling Proteins
• cytokine inducible SH2-containing protein
• Granulocyte-Macrophage Colony-Stimulating Factor
• Janus Kinase 2

Topics

• Animals
• Arthritis, Rheumatoid (immunology, pathology)
• Autoantibodies
• Female
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Humans
• Inflammation (immunology, pathology)
• Interleukin-18 (metabolism)
• Janus Kinase 2 (metabolism)
• Killer Cells, Natural (metabolism)
• Male
• Mice, Inbred C57BL
• Myeloid Cells (metabolism)
• Neutrophils (metabolism)
• STAT5 Transcription Factor (metabolism)
• Signal Transduction
• Suppressor of Cytokine Signaling Proteins (metabolism)
• Synovial Fluid (metabolism)
• Synovial Membrane (metabolism, pathology)