CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages

作者：Ling Yan, Yanli Li, Fengmei Fan, Mengzhuang Gou, Fang-Ling Xuan, Wei Feng, Keerthana Chithanathan, Wei Li, Junchao Huang, Hongna Li, Wenjin Chen, Baopeng Tian, Zhiren Wang, Shuping Tan, Alexander Zharkovsky, L. Elliot Hong, Yunlong Tan, Li Tian · 发表于：BMC Medicine · 年份：2023 · DOI：10.1186/s12916-023-02959-8 · 被引用次数：10 · 研究领域：Tryptophan and brain disorders、Neuroinflammation and Neurodegeneration Mechanisms、Stress Responses and Cortisol

Abstract Background Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility. Methods We recruited a cohort of first episode schizophrenia (FES) patients ( n = 51) and age- and sex-paired healthy controls (HCs) ( n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating factor 1 receptor (CSF1R). Furthermore, we studied a mouse model of chronic unpredictable stress (CUS) combined with a CSF1R inhibitor (CSF1Ri) ( n = 9 ~ 10/group) on anxiety behaviours and microglial biology. Results FES patients showed higher scores of perceived stress scale (PSS, p < 0.05), lower blood CSF1R mRNA (FDR = 0.003) and protein ( p < 0.05) levels, and smaller volumes of the superior frontal gyrus and parahippocampal gyrus (both FDR < 0.05) than HCs. In blood RNA-seq, CSF1R -associated differentially expressed blood genes were related to brain development. Importantly, CSF1R facilitated a negative association of the superior frontal gyrus with PSS ( p < 0.01) in HCs but not FES patients. In mouse CUS+CSF1Ri model, similarly as...