Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 217, Issue 5, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20191421
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Funding
- National Health and Medical Research Council of Australia [1113577, 1124784, 1066770, 1057852, 1124907, 1140406]
- John T. Reid Charitable Trusts
- National Health and Medical Research Council Medical Research Future Fund Practitioner Fellowship [1154325]
- National Health and Medical Research Council [1088703]
- National Breast Cancer Foundation Fellowship [PF-15-008]
- Priority-Driven Collaborative Cancer Research Scheme [1120725]
- Cure Cancer Australia Foundation
- Cancer Australia
- Melanoma Research Grant from the Harry J. Lloyd Charitable Trust
- Melanoma Research Alliance Young Investigator Award
- Ian Potter Foundation
- Cancer Research Institute
- Tour De Cure research grant
- National Health and Medical Research Council of Australia [1140406, 1124784, 1124907, 1088703, 1066770, 1057852] Funding Source: NHMRC
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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.
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