Department of Immunology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo, Japan.
Front Immunol. 2022 Mar 15;13:764557. doi: 10.3389/fimmu.2022.764557. eCollection 2022.
Mounting evidence indicates the importance of aberrant Toll-like receptor 7 (TLR7) signaling in the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanism of disease progression remains unclear. An imiquimod (IMQ)-induced lupus model was used to analyze the lupus mechanism related to the aberrant TLR7 signals. C57BL/6 mice and NZB/NZW mice were treated with topical IMQ, and peripheral blood, draining lymph nodes, and kidneys were analyzed focusing on monocytes and monocyte-related cells. Monocytes expressed intermediate to high levels of TLR7, and the long-term application of IMQ increased Ly6C monocytes in the peripheral blood and Ly6C monocyte-like cells in the lymph nodes and kidneys, whereas Ly6C monocyte-like cell numbers were increased in lymph nodes. Ly6C monocyte-like cells in the kidneys of IMQ-induced lupus mice were supplied by bone marrow-derived cells as demonstrated using a bone marrow chimera. Ly6C monocytes obtained from IMQ-induced lupus mice had upregulated adhesion molecule-related genes, and after adoptive transfer, they showed greater infiltration into the kidneys compared with controls. RNA-seq and PCR analyses revealed Ly6C monocyte-like cells in the kidneys of IMQ-induced lupus mice had upregulated macrophage-related genes compared with peripheral blood Ly6C monocytes and downregulated genes compared with kidney macrophages (MF). Ly6C monocyte-like cells in the kidneys upregulated and chemoattracting genes including and . The higher expression of in Ly6C monocyte-like cells compared with MF suggested these cells were more inflammatory than MF. However, MF in IMQ-induced lupus mice were characterized by their high expression of . Genes of proinflammatory cytokines in Ly6C and Ly6C monocytes were upregulated by stimulation with IMQ but only Ly6C monocytes upregulated IFN-α genes upon stimulation with 2'3'-cyclic-GMP-AMP, an agonist of stimulator of interferon genes. Ly6C and Ly6C monocytes in IMQ-induced lupus mice had different features. Ly6C monocytes responded in the lymph nodes of locally stimulated sites and had a higher expression of IFN-α upon stimulation, whereas Ly6C monocytes were induced slowly and tended to infiltrate into the kidneys. Infiltrated monocytes in the kidneys likely followed a trajectory through inflammatory monocyte-like cells to MF, which were then involved in the development of nephritis.
越来越多的证据表明，异常 Toll 样受体 7（TLR7）信号在系统性红斑狼疮（SLE）发病机制中起重要作用。然而，疾病进展的机制尚不清楚。本研究采用咪喹莫特（IMQ）诱导的狼疮模型来分析与异常 TLR7 信号相关的狼疮机制。用局部 IMQ 处理 C57BL/6 小鼠和 NZB/NZW 小鼠，重点分析外周血、引流淋巴结和肾脏中的单核细胞和单核细胞相关细胞。单核细胞表达中等到高水平的 TLR7，长期应用 IMQ 增加外周血中的 Ly6C 单核细胞和淋巴结及肾脏中的 Ly6C 单核细胞样细胞，而淋巴结中的 Ly6C 单核细胞样细胞数量增加。骨髓嵌合体实验表明，IMQ 诱导狼疮小鼠肾脏中的 Ly6C 单核细胞样细胞由骨髓来源的细胞供应。从 IMQ 诱导狼疮小鼠中获得的 Ly6C 单核细胞具有上调黏附分子相关基因，并且在过继转移后，与对照组相比，它们在肾脏中的浸润更多。RNA-seq 和 PCR 分析显示，与外周血 Ly6C 单核细胞相比，IMQ 诱导狼疮小鼠肾脏中的 Ly6C 单核细胞样细胞上调了与巨噬细胞相关的基因，而与肾脏巨噬细胞（MF）相比则下调了基因。与外周血 Ly6C 单核细胞相比，IMQ 诱导狼疮小鼠肾脏中的 Ly6C 单核细胞样细胞上调了趋化因子基因，包括 、 、 等。与 MF 相比，Ly6C 单核细胞样细胞中 基因的高表达表明这些细胞比 MF 更具炎症性。然而，IMQ 诱导狼疮小鼠中的 MF 特征是其高表达 。刺激 Ly6C 和 Ly6C 单核细胞后，促炎细胞因子基因的表达上调，但只有 Ly6C 单核细胞在刺激 2'3'-环鸟苷酸-AMP（干扰素基因刺激物的激动剂）时上调 IFN-α 基因。IMQ 诱导狼疮小鼠中的 Ly6C 和 Ly6C 单核细胞具有不同的特征。Ly6C 单核细胞在外周淋巴结中对局部刺激部位作出反应，并在刺激后表达更高水平的 IFN-α，而 Ly6C 单核细胞则缓慢诱导并倾向于浸润肾脏。肾脏中的浸润单核细胞可能沿着从炎症性单核细胞样细胞到 MF 的轨迹发展，MF 随后参与肾炎的发展。
