Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.
NICO-Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Orbassano, Italy.
Glia. 2024 Jul;72(7):1273-1289. doi: 10.1002/glia.24526. Epub 2024 Mar 21.
Tamoxifen-inducible systems are widely used in research to control Cre-mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off-target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)-induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four-day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons. These effects were counteracted by a two-day tamoxifen pre-treatment. Through selective microglia depletion, we elucidated that both LPS and tamoxifen influenced astrogliogenesis via microglia mediated mechanisms, while the effects on neurogenesis persisted even in a microglia-depleted environment. Notably, changes in radial glial cells resulted from a combination of microglia-dependent and -independent mechanisms. Overall, our data reveal that tamoxifen treatment per se does not alter the balance between adult neurogenesis and astrogliogenesis but does modulate cellular responses to inflammatory stimuli exerting a protective role within the adult hippocampal neurogenic niche.
他莫昔芬诱导系统广泛用于研究中，以控制遗传修饰动物中 Cre 介导的基因缺失。除 Cre 激活外，他莫昔芬还具有脱靶效应，其后果仍未得到充分解决。在这里，我们研究了他莫昔芬对脂多糖 (LPS) 诱导的神经炎症反应的影响，重点关注成年小鼠齿状回中的神经发生活性。我们证明，为期四天的 LPS 处理导致小胶质细胞、星形胶质细胞和放射状胶质细胞增加，同时新生神经元减少。这些影响被两天的他莫昔芬预处理所抵消。通过选择性小胶质细胞耗竭，我们阐明 LPS 和他莫昔芬通过小胶质细胞介导的机制影响星形胶质细胞发生，而对神经发生的影响即使在小胶质细胞耗竭的环境中仍然存在。值得注意的是，放射状胶质细胞的变化源自小胶质细胞依赖和非依赖机制的结合。总体而言，我们的数据表明，他莫昔芬治疗本身不会改变成年神经发生和星形胶质细胞发生之间的平衡，但会调节细胞对炎症刺激的反应，在成年海马神经发生龛内发挥保护作用。
