A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone

AbstractInflammation regulates neurogenesis, and the brains of patients with schizophrenia and bipolar disorder have reduced expression of neurogenesis markers in the subependymal zone (SEZ), the birthplace of inhibitory interneurons. Inflammation is associated with cortical interneuron deficits, but the relationship between inflammation and reduced neurogenesis in schizophrenia and bipolar disorder remains unexplored. Therefore, we investigated inflammation in the SEZ by defining those with low and high levels of inflammation using cluster analysis of IL6, IL6R, IL1R1 and SERPINA3 gene expression in 32 controls, 32 schizophrenia and 29 bipolar disorder cases. We then determined whether mRNAs for markers of glia, immune cells and neurogenesis varied with inflammation. A significantly greater proportion of schizophrenia (37%) and bipolar disorder cases (32%) were in high inflammation subgroups compared to controls (10%, p < 0.05). Across the high inflammation subgroups of psychiatric disorders, mRNAs of markers for phagocytic microglia were reduced (P2RY12, P2RY13), while mRNAs of markers for perivascular macrophages (CD163), pro-inflammatory macrophages (CD64), monocytes (CD14), natural killer cells (FCGR3A) and adhesion molecules (ICAM1) were increased. Specific to high inflammation schizophrenia, quiescent stem cell marker mRNA (GFAPD) was reduced, whereas neuronal progenitor (ASCL1) and immature neuron marker mRNAs (DCX) were decreased compared to low inflammation control and schizophrenia subgroups. Thus, a heightened state of inflammation may dampen microglial response and recruit peripheral immune cells in psychiatric disorders. The findings elucidate differential neurogenic responses to inflammation within psychiatric disorders and highlight that inflammation may impair neuronal differentiation in the SEZ in schizophrenia.

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O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED SUBEPENDYMAL ZONE NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa028.065 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S28-S29

Author(s):

Hayley North ◽

Christin Weissleder ◽

Maina Bitar ◽

Janice M Fullerton ◽

Rachel Sager ◽

...

Keyword(s):

Gene Expression ◽

Bipolar Disorder ◽

Cluster Analysis ◽

Stem Cell ◽

Neural Stem Cell ◽

Differentially Expressed Gene ◽

Inhibitory Interneuron ◽

Stem Cell Marker ◽

Neuronal Progenitor ◽

Subependymal Zone

Abstract Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the subependymal zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.

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Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa159 ◽

2020 ◽

Author(s):

Christin Weissleder ◽

Maree J Webster ◽

Guy Barry ◽

Cynthia Shannon Weickert

Keyword(s):

Bipolar Disorder ◽

Growth Factor ◽

Psychiatric Disorders ◽

Family Member ◽

Inhibitory Interneuron ◽

Trophic Factors ◽

Trophic Factor ◽

Insulin Like Growth Factor ◽

Neuronal Progenitor ◽

Subependymal Zone

Abstract The generation of inhibitory interneurons from neural stem cells in the subependymal zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the subependymal zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.

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The Toolbox for Untangling Chromosome Architecture in Immune Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.670884 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shuai Liu ◽

Keji Zhao

Keyword(s):

Gene Expression ◽

Immune Cells ◽

Spatial Organization ◽

Chromosome Structure ◽

Immune Cell ◽

Genome Structure ◽

Chromosome Architecture ◽

The Past ◽

Important Player ◽

The Way

The code of life is not only encrypted in the sequence of DNA but also in the way it is organized into chromosomes. Chromosome architecture is gradually being recognized as an important player in regulating cell activities (e.g., controlling spatiotemporal gene expression). In the past decade, the toolbox for elucidating genome structure has been expanding, providing an opportunity to explore this under charted territory. In this review, we will introduce the recent advancements in approaches for mapping spatial organization of the genome, emphasizing applications of these techniques to immune cells, and trying to bridge chromosome structure with immune cell activities.

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GJA1 Expression and Its Prognostic Value in Cervical Cancer

BioMed Research International ◽

10.1155/2020/8827920 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Silu Meng ◽

Xinran Fan ◽

Jianwei Zhang ◽

Ran An ◽

Shuang Li

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

Logistic Regression ◽

Gap Junction ◽

Signaling Pathway ◽

Immune Cells ◽

Immune Cell ◽

Normal Tissues ◽

Kaplan Meier ◽

Chi Squared

Gap Junction Protein Alpha 1 (GJA1) belongs to the gap junction family and has been widely studied in cancers. We evaluated the role of GJA1 in cervical cancer (CC) using public data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. The difference of GJA1 expression level between CC and normal tissues was analyzed by the Gene Expression Profiling Interactive Analysis (GEPIA), six GEO datasets, and the Human Protein Atlas (HPA). The relationship between clinicopathological features and GJA1 expression was analyzed by the chi-squared test and the logistic regression. Kaplan–Meier survival analysis and Cox proportional hazard regression analysis were used to assessing the effect of GJA1 expression on survival. Gene set enrichment analysis (GSEA) was used to screen the signaling pathways regulated by GJA1. Immune Cell Abundance Identifier (ImmuCellAI) was chosen to analyze the immune cells affected by GJA1. The expression of GJA1 in CC was significantly lower than that in normal tissues based on the GEPIA, GEO datasets, and HPA. Both the chi-squared test and the logistic regression showed that high-GJA1 expression was significantly correlated with keratinization, hormone use, tumor size, and FIGO stage. The Kaplan–Meier curves suggested that high-GJA1 expression could indicate poor prognosis ( p = 0.0058 ). Multivariate analysis showed that high-GJA1 expression was an independent predictor of poor overall survival (HR, 4.084; 95% CI, 1.354-12.320; p = 0.013 ). GSEA showed many cancer-related pathways, such as the p53 signaling pathway and the Wnt signaling pathway, were enriched in the high-GJA1-expression group. Immune cell abundance analysis revealed that the abundance of CD8 naive, DC, and neutrophil was significantly increased in the high-GJA1-expression group. In conclusion, GJA1 can be regarded as a potential prognostic marker of poor survival and therapeutic target in CC. Moreover, many cancer-related pathways may be the critical pathways regulated by GJA1. Furthermore, GJA1 can affect the abundance of immune cells.

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MMP1, MMP9, and COX2 Expressions in Promonocytes Are Induced by Breast Cancer Cells and Correlate with Collagen Degradation, Transformation-Like Morphological Changes in MCF-10A Acini, and Tumor Aggressiveness

BioMed Research International ◽

10.1155/2013/279505 ◽

2013 ◽

Vol 2013 ◽

pp. 1-15 ◽

Cited By ~ 15

Author(s):

G. K. Chimal-Ramírez ◽

N. A. Espinoza-Sánchez ◽

D. Utrera-Barillas ◽

L. Benítez-Bribiesca ◽

J. R. Velázquez ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Immune Cells ◽

Immune Cell ◽

Morphological Changes ◽

Tumor Stroma ◽

Collagen Degradation ◽

Tumor Aggressiveness ◽

Soluble Factors ◽

Immune Effector

Tumor-associated immune cells often lack immune effector activities, and instead they present protumoral functions. To understand how tumors promote this immunological switch, invasive and noninvasive breast cancer cell (BRC) lines were cocultured with a promonocytic cell line in a Matrigel-based 3D system. We hypothesized that if communication exists between tumor and immune cells, coculturing would result in augmented expression of genes associated with tumor malignancy. Upregulation of proteasesMMP1andMMP9and inflammatoryCOX2genes was found likely in response to soluble factors. Interestingly, changes were more apparent in promonocytes and correlated with the aggressiveness of the BRC line. Increased gene expression was confirmed by collagen degradation assays and immunocytochemistry of prostaglandin 2, a product of COX2 activity. Untransformed MCF-10A cells were then used as a sensor of soluble factors with transformation-like capabilities, finding that acini formed in the presence of supernatants of the highly aggressive BRC/promonocyte cocultures often exhibited total loss of the normal architecture. These data support that tumor cells can modify immune cell gene expression and tumor aggressiveness may importantly reside in this capacity. Modeling interactions in the tumor stroma will allow the identification of genes useful as cancer prognostic markers and therapy targets.

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289 COOPERATIVE EXPRESSION OF PLURIPOTENCY-RELATED GENES AND NEURAL CREST MARKER GENES IN PORCINE GFP-TRANSGENIC SKIN-DERIVED PROGENITORS

Reproduction Fertility and Development ◽

10.1071/rdv21n1ab289 ◽

2009 ◽

Vol 21 (1) ◽

pp. 241

Author(s):

M. T. Zhao ◽

C. S. Isom ◽

J. G. Zhao ◽

Y. H. Hao ◽

J. Ross ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Neural Crest ◽

Therapeutic Potential ◽

Marker Gene ◽

Stem Cell Marker ◽

Marker Genes ◽

Specific Marker ◽

Marker Gene Expression ◽

Neural Crest Origin

Recently neural crest derived multipotent progenitors from skin have attracted much attention as the skin may provide an accessible, autologous source of stem cells available with therapeutic potential (Toma JG et al. 2001 Nat. Cell Biol. 3, 778–784). The multipotent property of stem cells could be tracked back to the expression of specific marker genes that are exclusively expressed in multipotent stem cells rather than any other types of differentiated cells. Here we demonstrate the property of multipotency and neural crest origin of porcine GFP-transgenic skin derived progenitors (termed pSKP) in vitro by marker gene expression analysis. The pSKP cells were isolated from the back skin of GFP transgenic fetuses by serum-free selection culture in the presence of EGF (20 ng mL–1) and bFGF (40 ng mL–1), and developed into spheres in 1–2 weeks (Dyce PW et al. 2004 Biochem. Biophy. Res. Commun. 316, 651–658). Three groups of RT-PCR primers were used on total RNA from purified pSKP cells: pluripotency related genes (Oct4, Sox2, Nanog, Stat3), neural crest marker genes (p75NGFR, Slug, Twist, Pax3, Sox9, Sox10) and lineage specific genes (GFAP, tubulin β-III, leptin). Expression of both pluripotency related genes and neural crest marker genes were detected in undifferentiated pSKP cells. In addition, transcripts for fibronectin, vimentin and nestin (neural stem cell marker) were also present. The percentage of positive cells for Oct4, fibronection and vimentin were 12.3%, 67.9% and 53.7% respectively. Differentiation assays showed the appearance of tubulin β-III positive (39.4%) and GFAP-positive (42.6%) cells in cultures by immunocytochemistry, which share the characteristics of neurons and glial cells, respectively. Thus, we confirm the multiple lineage potentials and neural crest origin of pSKP cells in the level of marker gene expression. This work was funded by National Institutes of Health National Center for Research Resources RR013438.

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Calculation of immune cell proportion from batch tumor gene expression profile based on support vector regression

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720020500304 ◽

2020 ◽

Vol 18 (05) ◽

pp. 2050030

Author(s):

Dongmei Ai ◽

Gang Liu ◽

Xiaoxin Li ◽

Yuduo Wang ◽

Man Guo

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Support Vector Regression ◽

Gene Expression Profile ◽

Immune Cells ◽

Immune Cell ◽

Relative Proportion ◽

Support Vector ◽

Cancer Tissues ◽

Cell Proportion

In addition to tumor cells, a large number of immune cells are found in the tumor microenvironment (TME) of cancer patients. Tumor-infiltrating immune cells play an important role in tumor progression and patient outcome. We improved the relative proportion estimation algorithm of immune cells based on RNA-seq gene expression profiling and solved the multiple linear regression model by support vector regression ([Formula: see text]-SVR). These steps resulted in increased robustness of the algorithm and more accurate calculation of the relative proportion of different immune cells in cancer tissues. This method was applied to the analysis of infiltrating immune cells based on 41 pairs of colorectal cancer tissues and normal solid tissues. Specifically, we compared the relative fractions of six types of immune cells in colorectal cancer tissues to those found in normal solid tissue samples. We found that tumor tissues contained a higher proportion of CD8 T cells and neutrophils, while B cells and monocytes were relatively low. Our pipeline for calculating immune cell proportion using gene expression profile data can be freely accessed from GitHub at https://github.com/gutmicrobes/EICS.git.

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ImmuSort, a database on gene plasticity and electronic sorting for immune cells

Scientific Reports ◽

10.1038/srep10370 ◽

2015 ◽

Vol 5 (1) ◽

Cited By ~ 19

Author(s):

Pingzhang Wang ◽

Yehong Yang ◽

Wenling Han ◽

Dalong Ma

Keyword(s):

Gene Expression ◽

Immune Cells ◽

Immune Cell ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Experimental Conditions ◽

Evaluation Scores ◽

Cell Groups ◽

Differential Gene ◽

Disease Associated Genes

Abstract Gene expression is highly dynamic and plastic. We present a new immunological database, ImmuSort. Unlike other gene expression databases, ImmuSort provides a convenient way to view global differential gene expression data across thousands of experimental conditions in immune cells. It enables electronic sorting, which is a bioinformatics process to retrieve cell states associated with specific experimental conditions that are mainly based on gene expression intensity. A comparison of gene expression profiles reveals other applications, such as the evaluation of immune cell biomarkers and cell subsets, identification of cell specific and/or disease-associated genes or transcripts, comparison of gene expression in different transcript variants and probe set quality evaluation. A plasticity score is introduced to measure gene plasticity. Average rank and marker evaluation scores are used to evaluate biomarkers. The current version includes 31 human and 17 mouse immune cell groups, comprising 10,422 and 3,929 microarrays derived from public databases, respectively. A total of 20,283 human and 20,963 mouse genes are available to query in the database. Examples show the distinct advantages of the database. The database URL is http://immusort.bjmu.edu.cn/.

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Novel Prognostic Biomarkers in Gastric Cancer: CGB5, MKNK2, and PAPPA2

Frontiers in Oncology ◽

10.3389/fonc.2021.683582 ◽

2021 ◽

Vol 11 ◽

Author(s):

Min Qin ◽

Zhihai Liang ◽

Heping Qin ◽

Yifang Huo ◽

Qing Wu ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Regression Analysis ◽

Immune Cells ◽

Prognostic Model ◽

Prognostic Markers ◽

Immune Cell ◽

Risk Group ◽

P Value ◽

Expression Data

IntroductionGastric cancer is one of the most common malignant tumors of the digestive tract. However, there are no adequate prognostic markers available for this disease. The present study used bioinformatics to identify prognostic markers for gastric cancer that would guide the clinical diagnosis and treatment of this disease.Materials and MethodsGene expression data and clinical information of gastric cancer patients along with the gene expression data of 30 healthy samples were downloaded from the TCGA database. The initial screening was performed using the WGCNA method combined with the analysis of differentially expressed genes, which was followed by univariate analysis, multivariate COX regression analysis, and Lasso regression analysis for screening the candidate genes and constructing a prognostic model for gastric cancer. Subsequently, immune cell typing was performed using CIBERSORT to analyze the expression of immune cells in each sample. Finally, we performed laboratory validation of the results of our analyses using immunohistochemical analysis.ResultsAfter five screenings, it was revealed that only three genes fulfilled all the screening requirements. The survival curves generated by the prognostic model revealed that the survival rate of the patients in the high-risk group was significantly lower compared to the patients in the low-risk group (P-value < 0.001). The immune cell component analysis revealed that the three genes were differentially associated with the corresponding immune cells (P-value < 0.05). The results of immunohistochemistry also support our analysis.ConclusionCGB5, MKNK2, and PAPPA2 may be used as novel prognostic biomarkers for gastric cancer.

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Recent advances in psychoneuroimmunology: Inflammation in psychiatric disorders

Translational Neuroscience ◽

10.2478/s13380-011-0019-0 ◽

2011 ◽

Vol 2 (2) ◽

Cited By ~ 12

Author(s):

Monojit Debnath ◽

Karen Doyle ◽

Camilla Langan ◽

Colm McDonald ◽

Brian Leonard ◽

...

Keyword(s):

Gene Expression ◽

Bipolar Disorder ◽

Psychiatric Disorders ◽

Molecular Mechanisms ◽

Molecular Genetic ◽

Major Depressive ◽

Immune System Dysfunction ◽

Expression Studies ◽

Gene Expression Studies

AbstractPsychiatric disorders are common and complex and their precise biological underpinnings remain elusive. Multiple epidemiological, molecular, genetic and gene expression studies suggest that immune system dysfunction may contribute to the risk for developing psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder. However, the precise mechanisms by which inflammation-related events confer such risk are unclear. In this review, we examine the peripheral and central evidence for inflammation in psychiatric disorders and the potential molecular mechanisms implicated including inhibition of neurogenesis, apoptosis, the HPA-axis, the role of brain-derived neurotrophic factor and the interplay between the glutamatergic, dopaminergic and serotonergic neurotransmitter systems.

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