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

BMC Medicine

Research Article

L. Elliot Hong¹  Alexander Zharkovsky²  Fangling Xuan²  Ling Yan²  Keerthana Chithanathan²  Li Tian³  Fengmei Fan⁴  Zhiren Wang⁴  Junchao Huang⁴  Mengzhuang Gou⁴  Hongna Li⁴  Wei Li⁴  Wei Feng⁴  Yunlong Tan⁴  Yanli Li⁴  Wenjin Chen⁴  Baopeng Tian⁴  Shuping Tan⁴ 

[1] Department of Psychiatry, School of Medicine, Maryland Psychiatric Research Center, University of Maryland, Baltimore, USA;Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Peking University HuiLongGuan Clinical Medical School, Beijing, P. R. China;Psychiatry Research Centre, Beijing Huilongguan Hospital, Peking University Health Science Center, Peking University HuiLongGuan Clinical Medical School, Beijing, P. R. China;

关键词: Microglia/Brain macrophages;    CSF1R;    Angiogenesis;    First episode schizophrenia;    Stress;    Anxiety;   

DOI  :  10.1186/s12916-023-02959-8

 received in 2023-02-28, accepted in 2023-06-22,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMicroglia 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.MethodsWe 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.ResultsFES 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 CUS, CSF1Ri enhanced anxiety (both p < 0.001). Genes for brain angiogenesis and intensity of CD31+-blood vessels were dampened after CUS-CSF1Ri treatment. Furthermore, CSF1Ri preferentially diminished juxta-vascular microglia/macrophages and induced microglia/macrophages morphological changes (all p < 0.05).ConclusionMicroglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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