Department of Rheumatology, Kanazawa University Graduate School of Medical Sciences.
Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa.
Rheumatology (Oxford). 2022 Jul 6;61(7):3033-3048. doi: 10.1093/rheumatology/keab825.
LN comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions.
MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice [wild type (WT)] to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analysed by quantitative real-time PCR and IF. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc.
2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5 and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68 -positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5 and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1 and CCR2. When 2B11.3 was injected, CCR2-/- and CCR5-/-, but not CX3CR1-/-, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration and improved serum blood urea nitrogen levels. Only CCR2-/- mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum blood urea nitrogen levels.
CCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in LN. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.
LN 包含各种肾小球病变，包括伴有巨噬细胞浸润的毛细血管内细胞增生。本研究旨在阐明巨噬细胞趋化因子受体在这些肾小球病变发病机制中的作用。
将 MRL/lpr 小鼠源性单克隆 IgG3 抗体产生杂交瘤 2B11.3 和 B1 经腹腔注射入 BALB/c 小鼠（野生型 [WT]），分别诱导毛细血管内细胞增生和线状环病变。通过定量实时 PCR 和免疫荧光法分析趋化因子和趋化因子受体的表达。使用趋化因子受体缺陷小鼠或选择性 CCR5 拮抗剂 maraviroc 评估趋化因子受体在这些病变中的作用。
2B11.3 导致肾小球毛细血管内细胞增生，伴有大量肾小球 CD68 阳性巨噬细胞。此外，与诱导线状环病变的 B1 注射相比，在肾脏皮质中观察到 CCL2、CCL3、CCR2、CCR5 和 CX3CR1 的表达增强。在 2B11.3 诱导的肾小球病变中，CD68 阳性肾小球巨噬细胞表达 CCL2、CCL3、CCR2、CCR5 和 CX3CR1，而肾小球内皮细胞表达 CCL2、CCL3、CX3CL1 和 CCR2。当注射 2B11.3 时，CCR2-/-和 CCR5-/-，而不是 CX3CR1-/-，小鼠表现出毛细血管内细胞增生减少，肾小球巨噬细胞浸润减弱，血清血尿素氮水平改善。只有 CCR2-/-小鼠发展为线状环病变。在这些趋化因子受体缺陷小鼠中，B1 注射引起的线状环病变与 WT 相似。Maraviroc 治疗可减少 2B11.3 诱导的毛细血管内细胞增生并改善血清血尿素氮水平。
CCR2 和 CCR5 调节肾小球巨噬细胞浸润，并有助于 LN 中肾小球毛细血管内细胞增生的发展。CCR5 抑制可能是一种针对毛细血管内细胞增生的特异性治疗方法，而不会引起线状环病变。
