Fcγ 受体介导的 S100A8/A9 产生中性粒细胞内流作为抗原诱导关节炎期间骨侵蚀的诱导剂。
Fcγ receptor-mediated influx of S100A8/A9-producing neutrophils as inducer of bone erosion during antigen-induced arthritis.
机构信息
Experimental Rheumatology, Radboud university medical center, Geert Grooteplein Zuid 28, 6525 GA, Nijmegen, the Netherlands.
Institute of Immunology, University of Münster, Münster, Germany.
出版信息
Arthritis Res Ther. 2018 May 2;20(1):80. doi: 10.1186/s13075-018-1584-1.
BACKGROUND
Osteoclast-mediated bone erosion is a central feature of rheumatoid arthritis (RA). Immune complexes, present in a large percentage of patients, bind to Fcγ receptors (FcγRs), thereby modulating the activity of immune cells. In this study, we investigated the contribution of FcγRs, and FcγRIV in particular, during antigen-induced arthritis (AIA).
METHODS
AIA was induced in knee joints of wild-type (WT), FcγRI,II,III, and FcγRI,II,III,IV mice. Bone destruction, numbers of tartrate-resistant acid phosphatase-positive (TRAP) osteoclasts, and inflammation were evaluated using histology; expression of the macrophage marker F4/80, neutrophil marker NIMPR14, and alarmin S100A8 was evaluated using immunohistochemistry. The percentage of osteoclast precursors in the bone marrow was determined using flow cytometry. In vitro osteoclastogenesis was evaluated with TRAP staining, and gene expression was assessed using real-time PCR.
RESULTS
FcγRI,II,III,IV mice showed decreased bone erosion compared with WT mice during AIA, whereas both the humoral and cellular immune responses against methylated bovine serum albumin were not impaired in FcγRI,II,III,IV mice. The percentage of osteoclast precursors in the bone marrow of arthritic mice and their ability to differentiate into osteoclasts in vitro were comparable between FcγRI,II,III,IV and WT mice. In line with these observations, numbers of TRAP osteoclasts on the bone surface during AIA were comparable between the two groups. Inflammation, a process that strongly activates osteoclast activity, was reduced in FcγRI,II,III,IV mice, and of note, mainly decreased numbers of neutrophils were present in the joint. In contrast to FcγRI,II,III,IV mice, AIA induction in knee joints of FcγRI,II,III mice resulted in increased bone erosion, inflammation, and numbers of neutrophils, suggesting a crucial role for FcγRIV in the joint pathology by the recruitment of neutrophils. Finally, significant correlations were found between bone erosion and the number of neutrophils present in the joint as well as between bone erosion and the number of S100A8-positive cells, with S100A8 being an alarmin strongly produced by neutrophils that stimulates osteoclast resorbing activity.
CONCLUSIONS
FcγRs play a crucial role in the development of bone erosion during AIA by inducing inflammation. In particular, FcγRIV mediates bone erosion in AIA by inducing the influx of S100A8/A9-producing neutrophils into the arthritic joint.
背景
破骨细胞介导的骨质侵蚀是类风湿关节炎（RA）的一个核心特征。免疫复合物存在于很大比例的患者中，与 Fcγ 受体（FcγRs）结合，从而调节免疫细胞的活性。在这项研究中，我们研究了 FcγRs，特别是 FcγRIV，在抗原诱导关节炎（AIA）中的作用。
方法
在野生型（WT）、FcγRI、II、III 和 FcγRI、II、III、IV 小鼠的膝关节中诱导 AIA。使用组织学评估骨破坏、抗酒石酸酸性磷酸酶阳性（TRAP）破骨细胞数量和炎症；使用免疫组织化学评估巨噬细胞标志物 F4/80、中性粒细胞标志物 NIMPR14 和警报素 S100A8 的表达。使用流式细胞术测定骨髓中破骨细胞前体的百分比。使用 TRAP 染色评估体外破骨细胞生成，并使用实时 PCR 评估基因表达。
结果
与 WT 小鼠相比，FcγRI、II、III、IV 小鼠在 AIA 期间骨侵蚀减少，而 FcγRI、II、III、IV 小鼠针对甲基化牛血清白蛋白的体液和细胞免疫反应并未受损。关节炎小鼠骨髓中破骨细胞前体的百分比及其在体外分化为破骨细胞的能力在 FcγRI、II、III、IV 和 WT 小鼠之间相当。与这些观察结果一致，在两组中，AIA 期间骨表面上的 TRAP 破骨细胞数量相当。在 FcγRI、II、III、IV 小鼠中，炎症（强烈激活破骨细胞活性的过程）减少，值得注意的是，关节中主要存在较少数量的中性粒细胞。与 FcγRI、II、III、IV 小鼠不同，在 FcγRI、II、III 小鼠的膝关节中诱导 AIA 导致骨侵蚀、炎症和中性粒细胞数量增加，表明 FcγRIV 通过招募中性粒细胞在关节病理中发挥关键作用。最后，在关节中存在的破骨细胞数量与存在的中性粒细胞数量之间以及在骨侵蚀与 S100A8 阳性细胞数量之间发现了显著的相关性，S100A8 是一种强烈由中性粒细胞产生的警报素，刺激破骨细胞的吸收活性。
结论
FcγRs 通过诱导炎症在 AIA 期间骨侵蚀的发展中发挥关键作用。特别是，FcγRIV 通过诱导 S100A8/A9 产生的中性粒细胞流入关节炎关节来介导 AIA 中的骨质侵蚀。
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