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

• Published in: The Journal of experimental medicine 2020-05, Vol.217 (5)
• Main Authors: 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, Wicks, Ian P
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Autoantibodies; Autoimmunity; Female; Granulocyte-Macrophage Colony-Stimulating Factor - metabolism; Human health and pathology; Humans; Immunology; Inflammation - immunology; Inflammation - pathology; Innate immunity; Innate Immunity and Inflammation; Interleukin-18 - metabolism; Janus Kinase 2 - metabolism; Killer Cells, Natural - metabolism; Life Sciences; Male; Mice, Inbred C57BL; Myeloid Cells - metabolism; Neutrophils - metabolism; Rhumatology and musculoskeletal system; Signal Transduction; STAT5 Transcription Factor - metabolism; Suppressor of Cytokine Signaling Proteins - metabolism; Synovial Fluid - metabolism; Synovial Membrane - metabolism; Synovial Membrane - pathology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20191421

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.