Journal
ARTHRITIS & RHEUMATOLOGY
Volume 74, Issue 7, Pages 1257-1270Publisher
WILEY
DOI: 10.1002/art.42104
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Funding
- FWO [G0A3218N, 1S75320N, 1S10618N, 11K0722N]
- Katholieke Universiteit Leuven C1 grant [C16/17/010]
- Novartis
- Roche
- GSK Immuno-inflammation
- Pfizer
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This study investigates the role of G-CSF in systemic JIA and suggests that G-CSF-induced myelopoiesis and neutrophilia play an important role in regulating arthritis development. In a mouse model, plasma G-CSF levels were increased in systemic JIA patients, and G-CSF was shown to be responsible for neutrophilia and extramedullary myelopoiesis, with G-CSFR blockage inhibiting the maturation and differentiation of neutrophils.
Objective Systemic juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease with childhood onset. Systemic JIA is associated with neutrophilia, including immature granulocytes, potentially driven by the growth factor granulocyte-colony stimulating factor (G-CSF). This study was undertaken to investigate the role of G-CSF in the pathology of systemic JIA. Methods Injection of Freund's complete adjuvant (CFA) in BALB/c mice induces mild inflammation and neutrophilia in wild-type (WT) mice and a more pronounced disease, reminiscent to that of JIA patients, in interferon-gamma-knockout (IFN gamma-KO) mice. Extramedullary myelopoiesis was studied in CFA-immunized mice by single-cell RNA sequencing, and the effect of G-CSF receptor (G-CSFR) blockage on neutrophil development and systemic JIA pathology was evaluated. Additionally, plasma G-CSF levels were measured in patients. Results Both in systemic JIA patients and in a corresponding mouse model, plasma G-CSF levels were increased. In the mouse model, we demonstrated that G-CSF is responsible for the observed neutrophilia and extramedullary myelopoiesis and the induction of immature neutrophils and myeloid-derived suppressor-like cells. Administration of a G-CSFR antagonizing antibody blocked the maturation and differentiation of neutrophils in CFA-immunized mice. In IFN gamma-KO mice, treatment was associated with almost complete inhibition of arthritis due to reduced neutrophilia and osteoclast formation. Disease symptoms were ameliorated, but slight increases in interleukin-6 (IL-6), tumor necrosis factor, and IL-17 were detected upon G-CSFR inhibition in the IFN gamma-KO mice, and were associated with mild increases in weight loss, tail damage, and immature red blood cells. Conclusion We describe the role of G-CSF in a mouse model of systemic JIA and suggest an important role for G-CSF-induced myelopoiesis and neutrophilia in regulating the development of arthritis.
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