Inactivation of microglial LXRβ in early postnatal mice impairs microglia homeostasis and causes long- lasting cognitive dysfunction

• 成果类型: Article
• 署名作者: Lv, Keyi; Luo, Yi; Liu, Tianyao; Xia, Meiling; Gong, Hong; Zhang, Dandan; Chen, Xuan; Jiang, Xin; Liu, Yulong; Liu, Jiayin; Cai, Yulong; Antonson, Per; Warner, Margaret; Xu, Haiwei; Gustafsson, Jan-Ake; Fan, Xiaotang
• 署名单位: Army Medical University; Army Medical University; Karolinska Institutet; University of Houston System; University of Houston
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14553
• DOI: 10.1073/pnas.2410698122
• 发表日期: 2025-04-15
• 关键词: liver-x-receptor; mouse

摘要

Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor beta (LXR beta) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects neuroinflammation and cognitive function. We used a cell-specific tamoxifen-inducible Cre-loxP-mediated recombination to remove LXR beta from microglia specifically. We now report that ablation of LXR beta in microglia in early postnatal life led to a reduction in microglial numbers, distinct morphological changes indicative of microglial activation, and enhanced synapse engulfment accompanied by cognitive deficits. Removal of LXR beta from microglia in adult mice caused no cognitive defects. RNAseq analysis of microglia revealed that loss of LXR beta led to reduced expression of SAll1, a master regulator of microglial homeostasis, while increasing expression of genes associated with microglial activation and CNS disease. This study demonstrates distinctly different functions of microglial LXR beta in developing and adult mice and points to long-term consequences of defective LXR beta signaling in microglia in early life.