Arthritis Rheumatol. 2022 Mar 3. doi: 10.1002/art.42104. Online ahead of print.
ABSTRACT
OBJECTIVES: Systemic juvenile idiopathic arthritis (sJIA) is a systemic inflammatory disease of childhood-onset. sJIA is associated with neutrophilia, including immature granulocytes, potentially driven by the growth factor granulocyte-colony stimulating factor (G-CSF). This study aimed to unravel the role of G-CSF in the pathology of sJIA.
METHODS: Injection of complete Freund’s adjuvant (CFA) in BALB/c mice induces mild inflammation and neutrophilia in wild-type (WT) mice and a more pronounced disease, reminiscent to patients, in interferon-γ (IFN-γ) knock-out (KO) mice. Extramedullary myelopoiesis was studied in CFA-immunised mice by single-cell RNA-sequencing and the effect of G-CSFR-blockage on neutrophil development and sJIA pathology was evaluated. Additionally, in patients, plasma G-CSF-levels were measured.
RESULTS: Both in sJIA patients and in a corresponding mouse model, plasma levels of G-CSF are increased. Using the model, we demonstrate 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-CSF-receptor antagonising antibody blocked the maturation and differentiation of neutrophils in CFA-immunised mice. In IFN-γ KO mice, treatment was associated with almost complete inhibition of arthritis due to its reduced neutrophilia and osteoclast formation. Disease symptoms were ameliorated although slight increases in IL-6, TNF-α and IL-17 were detected upon G-CSFR inhibition in the IFN-γ KO mice, associated with mild increases in weight loss, tail damage and immature RBCs.
CONCLUSION: We described the role of G-CSF in a sJIA-like mouse model and point towards an important role for G-CSF-induced myelopoiesis and neutrophilia, regulating the development of arthritis.
PMID:35243819 | DOI:10.1002/art.42104
