4.7 Article

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

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JOURNAL OF EXPERIMENTAL MEDICINE
卷 217, 期 5, 页码 -

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ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20191421

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资金

  1. National Health and Medical Research Council of Australia [1113577, 1124784, 1066770, 1057852, 1124907, 1140406]
  2. John T. Reid Charitable Trusts
  3. National Health and Medical Research Council Medical Research Future Fund Practitioner Fellowship [1154325]
  4. National Health and Medical Research Council [1088703]
  5. National Breast Cancer Foundation Fellowship [PF-15-008]
  6. Priority-Driven Collaborative Cancer Research Scheme [1120725]
  7. Cure Cancer Australia Foundation
  8. Cancer Australia
  9. Melanoma Research Grant from the Harry J. Lloyd Charitable Trust
  10. Melanoma Research Alliance Young Investigator Award
  11. Ian Potter Foundation
  12. Cancer Research Institute
  13. Tour De Cure research grant
  14. 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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