Biology subjects

Elliott, E.

Publications and source records attributed to Elliott, E..

10 recordsLinked to original sources

bioRxiv2026

Damaged glomeruli in proliferative pediatric lupus nephritis exhibit a C5a-C5aR1 induced fibrotic transcriptional program

Lupus nephritis (LN) is a leading cause of morbidity in pediatric systemic lupus erythematosus (pSLE) due to suboptimal kidney remission rates and the sequelae of prolonged intensive immunosuppressive therapy. LN is patchy, with some glomeruli severely damaged while others remain histologically unaffected in the same kidney. Using spatial transcriptomic technology, we interrogated microanatomic transcriptional differences between histologically damaged and unaffected glomeruli in pSLE LN to understand local drivers of renal injury. Despite SLE being a disease of Type I interferon (IFN), IFN gene response does not associate with local glomerular damage. Rather, damage associates with a transcriptional module of higher expression of myeloid cell markers, C5AR1 (encoding the receptor for complement component 5a [C5a]), early complement components, and fibrosis genes. Bulk RNA-sequencing of C5a stimulated human monocyte-derived-macrophages revealed upregulation of tissue-remodeling and fibrosis-related pathways reversible by the C5aR1 inhibiting drug avacopan. These same C5a-inducible fibrosis genes were significantly upregulated in histologically damaged versus unaffected LN glomeruli providing a mechanistic link between C5a-C5aR1 signaling and early fibrosis in proliferative lupus nephritis. Our data provide insight into an understudied connection between complement activation and fibrosis relevant in SLE and likely other inflammatory diseases of complement activation.

immunology↗

bioRxiv2024

CHD8 adulthood microglial knockout induces behavioral, morphological, and transcriptional changes in a sex-dependent manner

AbstractMutations in CHD8 (chromodomain-helicase-DNA binding protein 8) are highly associated with autism spectrum disorders. It has been well established that CHD8 has a prominent role in the development of neurons. However, there is little knowledge of its specific roles in microglia, and its possible roles in cellular functions after development, i.e. adulthood. In addition, while microglial dysfunction has been characterized in autism, the roles of autism-associated genes in microglial function have not been well characterized. Using conditional transgenic mouse models, we determined that adulthood deletion of CHD8 in microglia induces robust changes in behavior, including anxiety, social deficits, and depression-like behavior, in association with changes in microglial activation and robust microglial gene expression changes, including expression of cytokines. Of great interest, many of these changes were seen specifically in male deletion mice, and not female deletion mice. In contrast, adulthood neuron knockout had more subtle effects on behavior, mainly on depression-like behavior, and induced subtle changes in gene transcription related to the Wnt/Beta-Catenin pathway. These changes were also only present in male neuron knockout mice. In summary, CHD8 is particularly important for microglial function in adulthood and has cellular effects that are specific to males.

neuroscience↗

bioRxiv2024

Forebrain neuronal SMC3 regulates body weight and metabolic health partially through regulation of hypothalamic Melanocortin 4 receptor

SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Excitatory conditional neuron-specific SMC3 knockout (cKO) mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus displayed dysregulated neuronal morphology and associated transcriptional abnormalities in RNA-seq analysis across various cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level, a pivotal regulator of appetite and metabolism. Correspondingly, ChIP-seq analysis revealed genome-wide alterations in the binding dynamics of SMC3 of the cKO animals, including Mc4r associated regions. Notably, a significant correlation emerged between multiple sites exhibiting a marked decrease in binding and downregulated genes. The administration of Setmelanotide, an MC4r agonist, to cKO group resulted in a notable reduction in both weight and food consumption in these mice. Therefore, we have identified specific and reversable metabolic parameters that are regulated by neuronal Smc3 in adulthood.

neuroscience↗

bioRxiv2024

Reduction of chemokine CXCL9 expression by omega-3 fatty acids via ADP-ribosylhydrolase ARH3 in MIN6 insulin-producing cells

Type 1 diabetes (T1D) results from the autoimmune destruction of the insulin producing {beta} cells of the pancreas. Omega-3 fatty acids protect {beta} cells and reduce the incident of T1D. However, how omega-3 fatty acids act on {beta} cells is not well understood. We have shown that omega-3 fatty acids reduce pro-inflammatory cytokine-mediated {beta}-cell apoptosis by upregulating the expression of the ADP-ribosylhydrolase ARH3. Here, we further investigate the {beta}-cell protection mechanism by ARH3 by performing siRNA of its gene Adprhl2 in MIN6 insulin-producing cells followed by treatment with a cocktail of the pro-inflammatory cytokines IL-1{beta} + IFN-{gamma} + TNF-, and proteomics analysis. ARH3 regulated proteins from several pathways related to the nucleus (splicing, RNA surveillance and nucleocytoplasmic transport), mitochondria (metabolic pathways) and endoplasmic reticulum (protein folding). ARH3 also regulated the levels of cytokine-signaling proteins related to the antigen processing and presentation, and chemokine-signaling pathway. We further studied the role of ARH in regulating the chemokine CXCL9. We confirmed that ARH3 reduces the cytokine-induced expression of CXCL9 by ELISA. We also found that CXCL9 expression is regulated by omega-3 fatty acids. In conclusion, we showed that omega-3 fatty acids regulate CXCL9 expression via ARH3, which might have a role in protecting {beta} cells from immune attack and preventing T1D development.

cell biology↗

bioRxiv2023

Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease

Hyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress - including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology - namely IL-12, IFN gamma (IFNg), and IL-10. In vitro we demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/571271v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a2330corg.highwire.dtl.DTLVardef@1c59944org.highwire.dtl.DTLVardef@1d151b5org.highwire.dtl.DTLVardef@14b4301_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender

immunology↗

bioRxiv2023

CTCF regulates anxiety and depression like behavior and maintenance of neuronal identity in the adult mouse brain

CCCTC-binding factor (CTCF) is a chromatin binding factor that binds to DNA sequence specific sites and, together with cohesin complex, establishes chromatin loops and regulates gene expression. CTCF was previously implicated as a major contributor in neural development. Genetic aberrations in CTCF are associated with intellectual disability, aggression, attention deficit, and autistic behavior. Previous mice-model studies have identified a necessary role for CTCF during development of CaMKIIa expressing excitatory neurons in the ability of learning and memory. However, it is not clear if CTCF is only necessary for development in the brain, or also in maintenance of neuronal functions and behavior in the adulthood. In the current study, adulthood-specific knockout of CTCF in excitatory neurons induced an elevation in anxiety and depression related behavior and a decrease in seeking social novelty. Depression and apathy-like behavior was reversed by treatment with serotonin specific reuptake inhibitor sertraline. Golgi staining analysis reveals major regression of dendritic complexity in the hippocampus and prefrontal cortex. In parallel, there is increased DNA compaction and decreased global H3K9 acetylation. Single nuclei RNA sequencing confirms a retreat in neuronal subtype identity in excitatory neurons after knockout. Gene ontology analysis display upregulation of genes that related regulation of cell population, neuronal development and neuronal differentiation and migration. These findings determine that CTCF is required for a propriate function of the mature excitatory neurons, independent of roles during development. Significance StatementThe gene CTCF is an important regulator of gene expression. Mutations in CTCF have been identified in individuals with a range of neurodevelopmental disorders, including intellectual disability and autism. However, it is unknown if CTCF is important only for neuronal development, or plays functional roles in the brain during adulthood. The current study finds that CTCF deletion during adulthood in excitatory neurons induces a behavioral phenotype that that includes increase in anxiety and depression-like behavior and changes in social behavior. In addition, CTCF depletion in adulthood affects the morphology, identity and gene expression of these specific types of neurons. Therefore, CTCF is not only important in brain development, but also in maintenance of proper neuronal function and behavior during adulthood.

neuroscience↗

bioRxiv2023

Aggression: A gut reaction? The effects of gut microbiome on aggression

Recent research has unveiled conflicting evidence regarding the link between aggression and the gut microbiome. In our investigation, we meticulously examined the behavioral patterns of four groups of mice - wild-type, germ-free (GF), mice treated with antibiotics, and recolonized GF mice - to gain mechanistic insights into the impact of the gut microbiome on aggression. We discovered a significant correlation between diminished microbiome and increased aggression. Importantly, this behavioral shift could be restored when a WT microbiota was reinstated. Microbiota manipulation also significantly altered brain function, particularly in aggression-associated genes, and urine metabolite profiles. Notably, our study extends beyond the murine model, shedding light on clinical implications of early-life antibiotic exposure. We found that fecal microbiome transplants from 1mo old infants prescribed antibiotics during their first days of life led to a marked increase in aggression in recipient mice. This research demonstrates that the microbiota modulates aggression and underscores its importance in the realm of behavioral science. One-Sentence SummaryThe antibiotic-altered gut microbiome is implicated in increased aggression. It also leads to altered brain function, particularly in genes linked to aggression, and urine metabolite profiles showing a multi-system response to microbiota disruption.

animal behavior and cognition↗

bioRxiv2023

Bacteroides is increased in an autism cohort and induces autism-relevant behavioral changes in mice in a sex-dependent manner

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition which is defined by decreased social communication and the presence of repetitive or stereotypic behaviors. Recent evidence has suggested that the gut-brain axis may be important in neurodevelopment in general and may play a role in ASD in particular. Here, we present a study of the gut microbiome in 96 individuals diagnosed with ASD in Israel, compared to 42 neurotypical individuals. We determined differences in alpha and beta diversity in the microbiome of individuals with ASD and demonstrated that the phylum Bacteroidetes and genus Bacteroides were the most significantly over-represented in individuals with ASD. To understand the possible functional significance of these changes, we treated newborn mice with Bacteroides fragilis at birth. B. fragilis-treated male mice displayed social behavior dysfunction, increased repetitive behaviors and gene expression dysregulation in the prefrontal cortex, while female mice did not display behavioral deficits. These findings suggest that overabundance of Bacteroides, particularly in early life, may have functional consequences for individuals with ASD.

neuroscience↗

bioRxiv2021

CHD8 regulates gut epithelial cell function and affects autism-related behaviours through the gut-brain axis

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by early onset deficits in social behavior and repetitive behavior. Chromodomain helicase DNA binding protein (CHD8) is one of the genes with the strongest association to autism. Alongside with the core symptoms of ASD, individuals with ASD are reported to have gastrointestinal (GI) problems, and a majority of individuals with CHD8 mutations display GI problems. However, the relationship between autism related genes, such as CHD8, gastrointestinal function, and autism related behaviours are yet very unclear. In the current study, we found that mice haploinsufficient for CHD8 have leaky gut, a dysregulated transcriptome in gut epithelial cells, decreased gut tuft cells and goblet cells, and an increase in microbial load. Specific deletion of CHD8 in gut epithelial cells induced an increase in anxiety-related behaviours in, a phenotype that is often observed in autism and full body knockdown of CHD8, in addition to decreased tuft cells. In addition, antibiotic treatment of CHD8 haploinsufficient mice attenuates sociability deficits. Therefore, the current study determines a pathway for autism-related GI deficits, and how these deficits may play a direct role in the development of autism-related behaviours.

neuroscience↗

bioRxiv2018

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

The urea cycle plays a role in the pathogenesis of Alzheimers disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

neuroscience↗