Katholieke Universiteit (KU) Leuven, Leuven, Belgium.
KU Leuven and Vlaams Instituut voor Biotechnolgie-KU Leuven, Leuven, Belgium.
Arthritis Rheumatol. 2022 Jul;74(7):1257-1270. doi: 10.1002/art.42104. Epub 2022 May 31.
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.
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.
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.
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.
全身型幼年特发性关节炎（JIA）是一种儿童发病的系统性炎症性疾病。全身型 JIA 与中性粒细胞增多有关，包括不成熟的粒细胞，这可能是由粒细胞集落刺激因子（G-CSF）驱动的。本研究旨在探讨 G-CSF 在全身型 JIA 发病机制中的作用。
在 BALB/c 小鼠中注射弗氏完全佐剂（CFA）可诱导野生型（WT）小鼠出现轻度炎症和中性粒细胞增多，并可诱导干扰素-γ 敲除（IFNγ-KO）小鼠出现更明显的疾病，类似于 JIA 患者的疾病。通过单细胞 RNA 测序研究 CFA 免疫小鼠中的骨髓外髓样细胞生成，评估 G-CSF 受体（G-CSFR）阻断对中性粒细胞发育和全身型 JIA 病理的影响。此外，还测量了患者的血浆 G-CSF 水平。
在全身型 JIA 患者和相应的小鼠模型中，血浆 G-CSF 水平均升高。在小鼠模型中，我们证明 G-CSF 负责观察到的中性粒细胞增多和骨髓外髓样细胞生成，以及未成熟中性粒细胞和髓系来源抑制性细胞的诱导。在 CFA 免疫小鼠中，给予 G-CSFR 拮抗抗体可阻断中性粒细胞的成熟和分化。在 IFNγ-KO 小鼠中，由于中性粒细胞减少和破骨细胞形成减少，治疗与关节炎几乎完全抑制有关。在 IFNγ-KO 小鼠中抑制 G-CSFR 可改善疾病症状，但检测到白细胞介素-6（IL-6）、肿瘤坏死因子和 IL-17 略有增加，同时体重减轻、尾巴损伤和未成熟红细胞也略有增加。
我们描述了 G-CSF 在全身型 JIA 小鼠模型中的作用，并提出 G-CSF 诱导的髓样细胞生成和中性粒细胞增多在调节关节炎发生发展中起重要作用。
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