Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Institute for Immunology, University Medical Center, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
Brain Behav Immun. 2022 Nov;106:49-66. doi: 10.1016/j.bbi.2022.07.164. Epub 2022 Aug 3.
There is a need for early therapeutic interventions after traumatic brain injury (TBI) to prevent neurodegeneration. Microglia/macrophage (M/M) depletion and repopulation after treatment with colony stimulating factor 1 receptor (CSF1R) inhibitors reduces neurodegeneration. The present study investigates short- and long-term consequences after CSF1R inhibition during the early phase after TBI.
Sex-matched mice were subjected to TBI and CSF1R inhibition by PLX3397 for 5 days and sacrificed at 5 or 30 days post injury (dpi). Neurological deficits were monitored and brain tissues were examined for histo- and molecular pathological markers. RNAseq was performed with 30 dpi TBI samples.
At 5 dpi, CSF1R inhibition attenuated the TBI-induced perilesional M/M increase and associated gene expressions by up to 50%. M/M attenuation did not affect structural brain damage at this time-point, impaired hematoma clearance, and had no effect on IL-1β expression. At 30 dpi, following drug discontinuation at 5 dpi and M/M repopulation, CSF1R inhibition attenuated brain tissue loss regardless of sex, as well as hippocampal atrophy and thalamic neuronal loss in male mice. Selected gene markers of brain inflammation and apoptosis were reduced in males but increased in females after early CSF1R inhibition as compared to corresponding TBI vehicle groups. Neurological outcome in behaving mice was almost not affected. RNAseq and gene set enrichment analysis (GSEA) of injured brains at 30 dpi revealed more genes associated with dendritic spines and synapse function after early CSF1R inhibition as compared to vehicle, suggesting improved neuronal maintenance and recovery. In TBI vehicle mice, GSEA showed high oxidative phosphorylation, oxidoreductase activity and ribosomal biogenesis suggesting oxidative stress and increased abundance of metabolically highly active cells. More genes associated with immune processes and phagocytosis in PLX3397 treated females vs males, suggesting sex-specific differences in response to early CSF1R inhibition after TBI.
M/M attenuation after CSF1R inhibition via PLX3397 during the early phase of TBI reduces long-term brain tissue loss, improves neuronal maintenance and fosters synapse recovery. Overall effects were not sex-specific but there is evidence that male mice benefit more than female mice.
外伤性脑损伤（TBI）后需要早期的治疗干预，以防止神经退行性变。集落刺激因子 1 受体（CSF1R）抑制剂治疗后的小胶质细胞/巨噬细胞（M/M）耗竭和再定植可减少神经退行性变。本研究探讨了 TBI 后早期 CSF1R 抑制后的短期和长期后果。
雌雄匹配的小鼠接受 TBI 和 PLX3397 治疗 5 天，并在损伤后 5 或 30 天（dpi）处死。监测神经功能缺损，并检查脑组织的组织学和分子病理学标志物。用 30 dpi TBI 样本进行 RNAseq。
在 5 dpi 时，CSF1R 抑制可使 TBI 诱导的病变周围 M/M 增加及其相关基因表达减少高达 50%。M/M 衰减此时不会影响结构脑损伤，会损害血肿清除，并且对 IL-1β表达没有影响。在 30 dpi 时，5 dpi 停药和 M/M 再定植后，CSF1R 抑制可减少脑组织损失，无论性别如何，以及雄性小鼠的海马萎缩和丘脑神经元丢失。与相应的 TBI 载体组相比，早期 CSF1R 抑制后雄性小鼠的一些脑炎症和细胞凋亡的基因标志物减少，但雌性小鼠增加。行为小鼠的神经功能结局几乎不受影响。30 dpi 受伤大脑的 RNAseq 和基因集富集分析（GSEA）显示，与载体相比，早期 CSF1R 抑制后与树突棘和突触功能相关的基因更多，提示神经元维持和恢复更好。在 TBI 载体小鼠中，GSEA 显示高氧化磷酸化、氧化还原酶活性和核糖体生物发生，提示氧化应激和代谢活跃细胞的丰度增加。PLX3397 治疗的雌性小鼠与雄性小鼠相比，更多的基因与免疫过程和吞噬作用相关，提示 TBI 后早期 CSF1R 抑制的反应存在性别差异。
TBI 早期通过 PLX3397 抑制 CSF1R 可减少长期脑组织损失，改善神经元维持，并促进突触恢复。总体效果无性别特异性，但有证据表明雄性小鼠比雌性小鼠获益更多。
