Open AccessNK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS
Author(s) -
Cynthia Louis,
Fernando SouzaFonsecaGuimaraes,
Yuyan Yang,
Damian B D'Silva,
Tobias Kratina,
Laura F. Dagley,
Soroor Hediyeh-Zadeh,
Jai Rautela,
Seth L. Masters,
Melissa J. Davis,
Jeffrey J. Babon,
Bogoljub Ćirić,
Éric Vivier,
Warren S. Alexander,
Nicholas D. Huntington,
Ian P. Wicks
Publication year - 2020
Publication title -
the journal of experimental medicine/the journal of experimental medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.483
H-Index - 448
eISSN - 1540-9538
pISSN - 0022-1007
DOI - 10.1084/jem.20191421
Subject(s) - inflammation , arthritis , immunology , experimental autoimmune encephalomyelitis , cytokine , granulocyte macrophage colony stimulating factor , inflammatory arthritis , biology
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.