Department of Anatomy, Yonsei University College of Medicine, Seoul, South Korea.
Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea.
Front Immunol. 2022 May 12;13:876033. doi: 10.3389/fimmu.2022.876033. eCollection 2022.
Microglia, resident macrophages in the brain, play major roles in neuroinflammation after an acute many neurological diseases, including stroke. Our recent animal stroke model showed that interleukin (IL)-4 and IL-13 released by microglia are converted into monocyte-derived macrophages. However, the correlation with the migration mechanism of these cells is still unclear. This study aimed to clarify the effect of these cells on their migration and to identify potential targets that influence neuroinflammatory conditions. Inflammatory conditions were induced by lipopolysaccharide (LPS) treatment in and models. Cell migration was observed using transwell assay, and target chemokines were screened using the proteome profiler array in the model. Intravital, IVIS, and CLARITY imaging were used in the model. After LPS (1 ng/ml) treatment in BV2 (microglia cell line) and J774 (monocyte/macrophage cell line) cells, BV2 migration was approximately two-fold more enhanced compared to J774 migration. Overall, six types of chemokine C-C motif ligands (CCLs) were detected from the BV2 conditioned medium with LPS. These CCLs were related to C-C motif receptor (CCR)4 and CCR5. In the model, CCR4 and CCR5 antagonist significantly inhibited the migration of monocyte-derived macrophages to brain tissue following LPS (5 µg) treatment. In conclusion, the chemokines released by microglia may influence migration of monocyte-derived macrophages in necroinflammation conditions inducted by microglial activation. CCR4 and CCR5 expressed on monocyte-derived macrophages interacted with these chemokines and induced migration. Therefore, CCR4 and CCR5 may be explored as new therapeutic targets for neuroinflammation.
小胶质细胞是大脑中的固有巨噬细胞，在多种急性神经疾病（包括中风）后的神经炎症中发挥重要作用。我们最近的动物中风模型表明，小胶质细胞释放的白细胞介素（IL）-4 和 IL-13 被转化为单核细胞衍生的巨噬细胞。然而，这些细胞的迁移机制与它们的相关性仍不清楚。本研究旨在阐明这些细胞对其迁移的影响，并确定影响神经炎症状态的潜在靶点。采用脂多糖（LPS）处理构建 和 模型诱导炎症状态。通过 Transwell 测定观察细胞迁移，在 模型中使用蛋白质组谱分析筛选靶趋化因子。在 模型中使用活体、IVIS 和 CLARITY 成像。在 LPS（1ng/ml）处理 BV2（小胶质细胞系）和 J774（单核细胞/巨噬细胞系）细胞后，与 J774 迁移相比，BV2 迁移增强约 2 倍。总体而言，从 LPS 处理的 BV2 条件培养基中检测到 6 种 C-C 基序趋化因子（CCL）。这些 CCL 与 C-C 基序受体（CCR）4 和 CCR5 有关。在 模型中，CCR4 和 CCR5 拮抗剂显著抑制 LPS（5μg）处理后单核细胞衍生的巨噬细胞向脑组织的迁移。综上所述，小胶质细胞释放的趋化因子可能影响小胶质细胞激活诱导的坏死性炎症条件下单核细胞衍生的巨噬细胞的迁移。表达于单核细胞衍生的巨噬细胞上的 CCR4 和 CCR5 与这些趋化因子相互作用并诱导迁移。因此，CCR4 和 CCR5 可能被探索为神经炎症的新治疗靶点。
