Role for Granulocyte Colony‐Stimulating Factor in Neutrophilic Extramedullary Myelopoiesis in a Murine Model of Systemic Juvenile Idiopathic Arthritis

Abstract

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‐γ–knockout (IFNγ‐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 IFNγ‐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 IFNγ‐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.

Mouse models of systemic juvenile idiopathic arthritis and macrophage activation syndrome

“…Characterization of neutrophils using surface markers and single-cell RNA sequencing revealed that G-CSF induced immature neutrophils and myeloid derived suppressor-like cells. Intriguingly, manifestations such as extramedullary myelopoiesis and arthritis were ameliorated by G-CSF blockade but weight loss and elevation of plasma cytokine levels such as IL-6, IL-17, and TNF-α were worsened [ 69 ]. Overall, G-CSF and neutrophils appear to play both pathogenic and protective roles in this model.…”

Bone marrow inflammatory memory in cardiometabolic disease and inflammatory comorbidities

“…Animal studies have clearly demonstrated that enhanced myelopoiesis and activation of HSPCs is a characteristic of experimental arthritis. 58 , 59 Similarly, myeloid skewing of HSPCs has been observed in patients and mice with systemic lupus erythematosus (SLE). 60 Finally, bone marrow inflammation has been found in patients with periodontitis, a disorder that is also associated with cardiometabolic risk.…”

Myeloid‐derived suppressor cells in the therapy of autoimmune diseases

“…The adoptively transferred MDSCs exacerbated the disease and expanded the differentiation of Th17 cells in an IL-1β-dependent manner [79]. G-CSF-induced extramedullary myelopoiesis was shown critical for the expansion of PMN-MDSCs in juvenile idiopathic arthritis, as its blockage in CFA-immunized IFN-γ KO mice, could ameliorate the arthritis [80]. In other studies, a significant increase in circulating MDSCs in RA patients and plasma Arg-1 levels inversely correlated with the frequency of Th17 cells, suggesting their beneficial role in RA [81].…”