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Dynamic changes in microglia in the mouse hippocampus during administration and withdrawal of the CSF1R inhibitor PLX3397
Journal of Anatomy ( IF 1.8 ) Pub Date : 2023-04-11 , DOI: 10.1111/joa.13874
Qirun Wang 1, 2 , Yi-Yan Wang 1, 2 , Wen-Jun Pu 1, 2 , Xiaohong Ma 1, 2 , Rong-Jun Ni 1, 2
Journal of Anatomy ( IF 1.8 ) Pub Date : 2023-04-11 , DOI: 10.1111/joa.13874
Qirun Wang 1, 2 , Yi-Yan Wang 1, 2 , Wen-Jun Pu 1, 2 , Xiaohong Ma 1, 2 , Rong-Jun Ni 1, 2
Affiliation
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Pexidartinib (PLX3397), a colony-stimulating factor-1 receptor (CSF1R) inhibitor, is currently in phase 1–3 clinical trials as a treatment for a variety of tumours. CSF1R signalling regulates the development, survival and maintenance of microglia, the resident brain innate immune cells. In this study, we examined the effects of PLX3397 in the drinking water of mice on microglia in the hippocampus using ionized calcium-binding adapter molecule 1 (Iba1, a microglial marker) immunocytochemistry. A high concentration of PLX3397 (1 mg/mL) significantly decreased the density of Iba1-immunoreactive cells after 7 days of exposure, but a low concentration of PLX3397 (0.5 mg/mL) did not. In addition, both low and high concentrations of PLX3397 significantly increased the intersection number, total length and maximum length of microglial processes in male mice. PLX3397 administered for 21 days eliminated microglia with 78% efficiency in males and 84% efficiency in females. Significant increases in microglial processes were found after both seven and 21 days of PLX3397 exposure in males, whereas decreases in microglial processes were observed after both 14 and 21 days of exposure in females. After PLX3397 withdrawal following its administration for 14 days in males, the soma size quickly returned to normal levels within a week. However, the microglial density, intersection number and total length of microglial processes after 3 days of recovery stabilized to untreated levels. In summary, these findings provide detailed insight into the dynamic changes in microglial number and morphology in the hippocampus in a dose- and time-dependent manner after PLX3397 treatment and withdrawal.
中文翻译：
CSF1R抑制剂PLX3397给药和停药期间小鼠海马小胶质细胞的动态变化
Pexidartinib (PLX3397) 是一种集落刺激因子 1 受体 (CSF1R) 抑制剂，目前正处于 1-3 期临床试验中，用于治疗多种肿瘤。CSF1R 信号传导调节小胶质细胞（大脑固有免疫细胞）的发育、存活和维持。在本研究中，我们使用离子钙结合接头分子 1（Iba1，小胶质细胞标记物）免疫细胞化学检查了小鼠饮用水中的 PLX3397 对海马小胶质细胞的影响。暴露 7 天后，高浓度的 PLX3397 (1 mg/mL) 显着降低了 Iba1 免疫反应细胞的密度，但低浓度的 PLX3397 (0.5 mg/mL) 则没有。此外，低浓度和高浓度的PLX3397均显着增加雄性小鼠小胶质细胞突起的交叉数量、总长度和最大长度。施用 PLX3397 21 天，消除小胶质细胞的效率在男性中为 78%，在女性中为 84%。在雄性中暴露于 PLX3397 7 天和 21 天后，发现小胶质细胞突起显着增加，而在雌性中暴露 14 天和 21 天后，观察到小胶质细胞突起减少。雄性 PLX3397 给药 14 天后停药后，体细胞大小在一周内迅速恢复到正常水平。然而，恢复3天后小胶质细胞密度、交叉点数量和小胶质细胞突起的总长度稳定到未处理的水平。总之，这些发现为 PLX3397 治疗和停药后海马小胶质细胞数量和形态以剂量和时间依赖性方式的动态变化提供了详细的见解。
更新日期：2023-04-11
中文翻译：
CSF1R抑制剂PLX3397给药和停药期间小鼠海马小胶质细胞的动态变化
Pexidartinib (PLX3397) 是一种集落刺激因子 1 受体 (CSF1R) 抑制剂，目前正处于 1-3 期临床试验中，用于治疗多种肿瘤。CSF1R 信号传导调节小胶质细胞（大脑固有免疫细胞）的发育、存活和维持。在本研究中，我们使用离子钙结合接头分子 1（Iba1，小胶质细胞标记物）免疫细胞化学检查了小鼠饮用水中的 PLX3397 对海马小胶质细胞的影响。暴露 7 天后，高浓度的 PLX3397 (1 mg/mL) 显着降低了 Iba1 免疫反应细胞的密度，但低浓度的 PLX3397 (0.5 mg/mL) 则没有。此外，低浓度和高浓度的PLX3397均显着增加雄性小鼠小胶质细胞突起的交叉数量、总长度和最大长度。施用 PLX3397 21 天，消除小胶质细胞的效率在男性中为 78%，在女性中为 84%。在雄性中暴露于 PLX3397 7 天和 21 天后，发现小胶质细胞突起显着增加，而在雌性中暴露 14 天和 21 天后，观察到小胶质细胞突起减少。雄性 PLX3397 给药 14 天后停药后，体细胞大小在一周内迅速恢复到正常水平。然而，恢复3天后小胶质细胞密度、交叉点数量和小胶质细胞突起的总长度稳定到未处理的水平。总之，这些发现为 PLX3397 治疗和停药后海马小胶质细胞数量和形态以剂量和时间依赖性方式的动态变化提供了详细的见解。
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