NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS
Details
Publication Year 2020-05-04, Volume 217, Issue #5, Page e20191421
Journal Title
Journal of Experimental Medicine
Publication Type
Journal Article
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.
Publisher
Rockefeller University Press
WEHI Research Division(s)
Blood Cells And Blood Cancer; Structural Biology; Immunology; Inflammation; Advanced Technology And Biology; Bioinformatics
PubMed ID
32097462
Open Access at Publisher's Site
https://doi.org/10.1084/jem.20191421
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-03-24 01:39:41
Last Modified: 2020-03-24 02:15:44
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