CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages.
CSF1R regulates schizophrenia-related stress response and vascular association of microglia/macrophages.
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DOI：
10.1186/s12916-023-02959-8
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发表时间：
2023-08-04
期刊：
影响因子：
9.3
通讯作者：
Tian, Li
中科院分区：
文献类型：
--
作者：
Yan, Ling;Li, Yanli;Fan, Fengmei;Gou, Mengzhuang;Xuan, Fangling;Feng, Wei;Chithanathan, Keerthana;Li, Wei;Huang, Junchao;Li, Hongna;Chen, Wenjin;Tian, Baopeng;Wang, Zhiren;Tan, Shuping;Zharkovsky, Alexander;Hong, L. Elliot;Tan, Yunlong;Tian, Li
在人类和动物模型中，我们都知道小胶质细胞可以调节压力和焦虑。心理社会压力是精神分裂症最常见的危险因素。然而，小胶质细胞/脑巨噬细胞如何导致精神分裂症尚不清楚。我们假设在小胶质细胞/巨噬细胞中表达的效应分子通过调节应激易感性参与精神分裂症。我们招募了一组首发精神分裂症（FES）患者（n = 51）和年龄和性别配对的健康对照（hc） （n = 46），并评估了压力感知。我们进行了血液rna测序（RNA-seq）和脑磁共振成像，并测量了血浆集落刺激因子1受体（CSF1R）的水平。此外，我们研究了慢性不可预测应激（CUS）小鼠模型联合CSF1R抑制剂（CSF1Ri） （n = 9 ~ 10/组）对焦虑行为和小胶质生物学的影响。FES患者的感知应激量表得分（PSS, p < 0.05）较高，血CSF1R mRNA （FDR = 0.003）和蛋白水平较低（p < 0.05），额上回和海马旁回体积均小于hc （FDR均< 0.05）。在血液RNA-seq中，csf1r相关的差异表达血液基因与大脑发育有关。重要的是，CSF1R促进了hcc患者额上回与PSS的负相关（p < 0.01），而非FES患者。在小鼠CUS+CSF1Ri模型中，与CUS相似，CSF1Ri增强了焦虑（p均< 0.001）。cu - csf1ri治疗后，脑组织血管生成基因和CD31+血管强度均受到抑制。此外，CSF1Ri对血管旁小胶质细胞/巨噬细胞有优先抑制作用，并诱导小胶质细胞/巨噬细胞形态学改变（均p < 0.05）。小胶质/巨噬细胞CSF1R调节精神分裂症相关应激和脑血管生成。在线版本包含补充材料，可在10.1186/s12916-023-02959-8获得。
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. 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. 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 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). Microglial/macrophagic CSF1R regulated schizophrenia-associated stress and brain angiogenesis. The online version contains supplementary material available at 10.1186/s12916-023-02959-8.
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影响因子：
5
作者：
COHEN, S;KAMARCK, T;MERMELSTEIN, R
通讯作者：
MERMELSTEIN, R
脑血管功能障碍伴有压力和抑郁。
影响因子：
1.9
作者：
Burrage E;Marshall KL;Santanam N;Chantler PD
通讯作者：
Chantler PD
parahampocampal皮层在认知中的作用。
影响因子：
19.9
作者：
Aminoff, Elissa M;Kveraga, Kestutis;Bar, Moshe
通讯作者：
Bar, Moshe
影响因子：
11
作者：
Greene C;Kealy J;Humphries MM;Gong Y;Hou J;Hudson N;Cassidy LM;Martiniano R;Shashi V;Hooper SR;Grant GA;Kenna PF;Norris K;Callaghan CK;Islam MD;O'Mara SM;Najda Z;Campbell SG;Pachter JS;Thomas J;Williams NM;Humphries P;Murphy KC;Campbell M
通讯作者：
Campbell M
影响因子：
4.8
作者：
Bernstein, DP;Stein, JA;Zule, W
通讯作者：
Zule, W