Department of Nephrology and Rheumatology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Division of Cancer and Senescent Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
J Pathol. 2024 Oct;264(2):174-185. doi: 10.1002/path.6331. Epub 2024 Jul 26.
The CCL2-CCR2 axis is involved in lupus nephritis, however the precise roles in the mechanisms by which different pathological lesions develop after glomerular immune complex deposition remain elusive. Previously, we demonstrated that genetic CCR2 inhibition induced a histological switch from glomerular endocapillary hypercellularity to wire-loop lesions in murine lupus nephritis. This study aimed to clarify the CCL2-CCR2 axis-mediated cellular mechanism in the formation of these different pathological lesions. We injected MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 or B1, into wild-type (WT) mice to selectively induce glomerular endocapillary hypercellularity or wire-loop lesions. The expression of chemokine and chemokine receptors was analyzed using RT-quantitative PCR and/or immunofluorescence. We found 2B11.3 caused glomerular endocapillary hypercellularity in WT mice with glomerular infiltration of larger numbers of CCR2-expressing macrophages and neutrophils phagocyting immune complex, whereas B1 induced wire-loop lesions. In glomerular endocapillary hypercellularity, CCL2 was identified as the ligand involved in the CCR2-positive cell infiltration; it was expressed by glomerular endothelial cells and macrophages. Notably, 2B11.3-induced glomerular endocapillary hypercellularity converted to wire-loop lesions with reduced glomerular macrophage and neutrophil infiltration in CCL2-deficient (Ccl2) mice similarly observed in Ccr2 mice. Moreover, this histological conversion was also observed when both glomerular macrophage and neutrophil infiltration were inhibited in anti-Ly6G antibody-treated Ccr5 mice but not when only glomerular macrophage infiltration was inhibited in Ccr5 mice or when only glomerular neutrophil infiltration was inhibited in anti-Ly6G antibody-treated WT mice. In contrast, B1 injection caused wire-loop lesions in Ccl2 and Ccr2 mice, as observed in WT mice. Moreover, 2B11.3 induced CCL2 from glomerular endothelial cells to a larger extent than B1 when injected into Ccr2 mice. In conclusion, the CCL2-CCR2 axis determines whether glomerular endocapillary hypercellularity or wire-loop lesions develop by regulating glomerular infiltration of phagocytic cells: macrophages and neutrophils. © 2024 The Pathological Society of Great Britain and Ireland.
CCL2-CCR2 轴参与狼疮肾炎，然而，在肾小球免疫复合物沉积后不同病理损伤发展的机制中，其确切作用仍不清楚。先前，我们证明了遗传 CCR2 抑制会诱导小鼠狼疮肾炎中从肾小球毛细血管内细胞增生到线状环病变的组织学转换。本研究旨在阐明 CCL2-CCR2 轴在形成这些不同病理损伤中的细胞机制。我们将 MRL/lpr 小鼠来源的单克隆 IgG3 抗体产生杂交瘤 2B11.3 或 B1 注射到野生型（WT）小鼠中，以选择性诱导肾小球毛细血管内细胞增生或线状环病变。使用 RT 定量 PCR 和/或免疫荧光分析趋化因子和趋化因子受体的表达。我们发现 2B11.3 在 WT 小鼠中引起肾小球毛细血管内细胞增生，其特征是有更多表达 CCR2 的巨噬细胞和中性粒细胞吞噬免疫复合物浸润肾小球；而 B1 诱导线状环病变。在肾小球毛细血管内细胞增生中，CCL2 被鉴定为参与 CCR2 阳性细胞浸润的配体；它由肾小球内皮细胞和巨噬细胞表达。值得注意的是，2B11.3 诱导的肾小球毛细血管内细胞增生在 CCL2 缺陷（Ccl2）小鼠中转化为线状环病变，与 Ccr2 小鼠中观察到的情况相似，即肾小球巨噬细胞和中性粒细胞浸润减少。此外，当在 Ccr5 小鼠中用抗 Ly6G 抗体抑制肾小球巨噬细胞和中性粒细胞浸润时，也观察到这种组织学转换，但当仅抑制 Ccr5 小鼠中的肾小球巨噬细胞浸润或仅抑制抗 Ly6G 抗体处理的 WT 小鼠中的肾小球中性粒细胞浸润时，不会观察到这种转换。相反，B1 注射在 Ccl2 和 Ccr2 小鼠中引起线状环病变，与在 WT 小鼠中观察到的情况相同。此外，与 B1 相比，2B11.3 在注射到 Ccr2 小鼠中时更能从肾小球内皮细胞诱导 CCL2。总之，CCL2-CCR2 轴通过调节吞噬细胞（巨噬细胞和中性粒细胞）对肾小球的浸润来决定是否发生肾小球毛细血管内细胞增生或线状环病变。
