Biology subjects

Kwon, J.

Publications and source records attributed to Kwon, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

B lymphocytes acquire myeloid and autoimmune phenotypes via the downregulation of lymphocyte-specific protein-1

Actin-binding proteins (ABPs) have been established as important mediators of immune homeostasis, but their effects on lymphocytes are poorly understood. Here, we demonstrated that LSP1, an ABP, is a master regulator for innate immune responses in B lymphocytes. Lsp1 deficiency in B cells upregulated the expression of myeloid genes, including CD11b, CD11c, and myeloperoxidase, and bestowed myeloid morphology. Strikingly, Lsp1-deficient B cells exhibited dual functions, namely, strong phagocytic activity and high antibody (Ab) production, like chimera. The PKC{beta}-CEBP{beta} pathway was found to be required for such functional chimerism. Moreover, Lsp1 deficiency induced the myeloid B cell phenotype and autoantibody production in B cells and consequently accelerated the progression of experimental lupus in mice. These changes were abrogated by retinoic acid, which upregulated LSP1 expression. In lupus patients, LSP1 expression in B cells was downregulated and inversely correlated with myeloperoxidase (MPO) expression. Overall, this study reveals a new role of the ABP LSP1 in B lymphocytes and emphasizes its critical involvement in promoting autoimmune responses, particularly by generating functionally chimeric B cells.

immunology↗

bioRxiv2024

Cerebellar tonic inhibition orchestrates the maturation of information processing and motor coordination

Tonic inhibition in cerebellar granule cells (GC) is crucial in information coding fidelity for motor coordination. It emerges in activity-dependent and-independent manners, and their interplay evolves with age. However, specific molecular and cellular mechanisms and how their change affects network-level computation and motor behavior remain unclear. Here we show that, while net tonic inhibitory current remains unchanged, the main source of tonic GABA switches from synaptic spillover (neuronal activity-dependent) to astrocytic Best1 (activity-independent) throughout adolescence (4-8 weeks) in mice. Computational modeling based on experimental data demonstrated that this switch down-regulates the internally generated network activity mediating mutual inhibition between GC clusters receiving different inputs, thereby enhancing their independence. Consistent with simulations, 3D-posture analysis revealed an age-dependent increase in independent limb movements during spontaneous motion, which was impaired in Best1 knockout mice. Our findings highlight the late-stage development of complex motor coordination driven by the emergence of astrocyte-mediated tonic inhibition. O_LI6 main figures, 58 references, 5,924 words in the manuscript (excluding the abstract, tables, figure legends and references). C_LIO_LISupplementary information: 1 text (supplementary methods), 9 figures, 4 movies, and 1 table. C_LI

neuroscience↗

bioRxiv2024

Predicting task-related brain activity from resting-state brain dynamics with fMRI Transformer

Accurate prediction of the brains task reactivity from resting-state functional magnetic resonance imaging (fMRI) data remains a significant challenge in neuroscience. Traditional statistical approaches often fail to capture the complex, nonlinear spatiotemporal patterns of brain function. This study introduces SwiFUN (Swin fMRI UNet Transformer), a novel deep-learning framework designed to predict 3D task activation maps directly from resting-state fMRI scans. SwiFUN leverages advanced techniques such as shifted window-based self-attention, which helps to understand complex patterns by focusing on varying parts of the data sequentially, and a contrastive learning strategy to better capture individual differences among subjects. When applied to predicting emotion-related task activation in adults (UK Biobank, n=7,038) and children (ABCD, n=4,944), SwiFUN consistently achieved higher overall prediction accuracy than existing methods across all contrasts; it demonstrated an improvement of up to 27% for the FACES-PLACES contrast in ABCD data. The resulting task activation maps revealed individual differences across cortical and subcortical regions associated with sex, age, and depressive symptoms. This scalable, transformer-based approach potentially reduces the need for task-based fMRI in clinical settings, marking a promising direction for future neuroscience and clinical research that enhances our ability to understand and predict brain function.

neuroscience↗

bioRxiv2023

Age-dependent RGS5 loss in pericytes induces cardiac dysfunction and fibrosis in the heart

BackgroundPericytes are capillary-associated mural cells involved in the maintenance and stability of the vascular network. Although ageing is one of the main risk factors for cardiovascular disease, the consequences of ageing on cardiac pericytes are unknown. MethodsIn this study, we have combined single-nucleus RNA sequencing and histological analysis to determine the effects of ageing on cardiac pericytes. Furthermore, we have conducted in vivo and in vitro analysis of Regulator of G protein signalling 5 (RGS5) loss of function and finally have performed pericytes-fibroblasts co-culture studies to understand the effect of RGS5 deletion in pericytes on the neighbouring fibroblasts. ResultsAgeing reduced the pericyte area and capillary coverage in the murine heart. Single nucleus RNA sequencing analysis further revealed that the expression of Rgs5 was reduced in cardiac pericytes from aged mice. In vivo and in vitro studies showed that the deletion of RGS5 impaired cardiac function, fibrosis, and induced morphological changes and a pro-fibrotic gene expression signature in pericytes characterized by the expression of different extracellular matrix components and growth factors e.g. TGFB2 and PDGFB. Indeed, culturing fibroblasts with the supernatant of RGS5 deficient pericytes induced their activation as evidenced by the increased expression of smooth muscle actin in a TGF{beta}2-dependent mechanism. ConclusionsOur results have identified RGS5 as a crucial regulator of pericyte function during cardiac ageing. The deletion of RGS5 causes cardiac dysfunction and induces myocardial fibrosis, one of the hallmarks of cardiac ageing.

physiology↗

bioRxiv2023

TREM2 Alteration Increases AD Biomarkers and is Associated with Key Genes with 5xFAD Mice Model Analysis on MODEL-AD Database

Alzheimer Disease is a multifactorial disorder characterized by cognitive decline and memory loss. A key gene associated with AD is the TREM2 gene which has been identified as a risk factor for AD. Studies show that TREM2 functions in microglia regulation that controls the amount of AB proteins by the mechanisms of clearance and degradation. However, the exact mechanism of how the TREM2 variations like TREM2 KO and TREM2 R47H contribute to the progression of Alzheimer is still debated. Moreover, research into the levels of gene expression and measurements of biomarkers that contribute to progression of AD is very limited. In this paper, we conduct a comprehensive analysis of the biomarker concentration and gene regulatory behavior in TREM2 KO and TREM2 R47H mutated mice models from the MODEL AD database in order to gain understanding of how these variations contribute to the formation of biomarkers and contribute to AD progression. Our research indicates a correlation between the mutated mice model and the different biomarker concentrations in the brain like insoluble AB40 and 42 proteins, soluble AB40 and 42 proteins, and NFL, which shows that TREM2 gene may be associated with multiple biomarkers. Moreover, we identified some key genes that were associated with the downregulation of the TREM2 gene with the TREM2 KO mice model gene analysis. Finally, we took the confocal images of the TREM2 KO mice model to analyze the effect that the lack of TREM2 extracellular receptor has on the neuritic dystrophy in the brain. Overall, we analyzed the biomarker concentration, gene regulatory activity, and the neuritic effects of the TREM2 KO and TREM2 R47H mutated variants of the TREM2 gene.

neuroscience↗

bioRxiv2023

The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix

Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphys Roth Large (MRL) strain has "super-healing" properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-{beta} signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized "myoscaffolds". Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-{beta}1 and TGF-{beta}3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg-/- MRL and Sgcg-/- DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief SummaryThe extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/547098v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@18543eborg.highwire.dtl.DTLVardef@2e3386org.highwire.dtl.DTLVardef@138d5ccorg.highwire.dtl.DTLVardef@5c4ef6_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and fermentation but decreased ATP levels and growth, suggesting that {Delta}agr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of {Delta}agr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected {Delta}agr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived "memory" of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2-/-) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

microbiology↗

bioRxiv2023

Measurement of Oxidative Stress in Huh-7 Cell Line to Determine the Effectiveness of PNPLA3 Targeted Gene Therapy for Mitigation of Lipid and Alcohol Induced Oxidative Stress in the Liver

NAFLD is a condition of increased buildup of fat in the liver, causing lipotoxicity that can manifest to cirrhosis, steatosis and fibrosis, which can cause significant and eventually irreversible damage to the liver. A key gene associated is the PNPLA3 I148M variant, which has been shown to display lipogenesis functionality. However, the role of PNPLA3 in increased ROS formation is debated. Moreover, there are no studies determining correlation between the variant and alcohol-induced oxidative stress. This project determines the following mechanistic functions of the PNPLA I148M variant to test for the efficiency of PNPLA3 gene therapy for patients with fatty liver disease and alcohol liver disease. There is a strong correlation between lipid induced oxidative stress and PNPLA3 148M variant. DCFDA shows increased concentration of H2O2 for PNPLA3 148M overexpressed cell lines for both ethanol and FFA treatment groups. Moreover, there is a statistical correlation between PNPLA3 148M overexpressed cell lines and increased mitochondrial oxidative stress by MitoSOX cellular ROS analysis methods. This study confirmed the significant decrease in oxidative stress levels for 148I variant overexpressed cell lines and proved the efficiency of PNPLA3 targeted gene therapy to NAFLD patients and suggested the potential use of the therapeutic method to patients with ALD. To ensure gene therapeutic effectiveness for patients with NAFLD and alcoholic liver diseases, further experiments may be needed to verify molecular pathways of ROS formation by PNPLA3 with qPCR analysis.

biochemistry↗

bioRxiv2023

SUBTLE: An unsupervised platform with temporal link embedding that maps animal behavior

While huge strides have recently been made in language-based machine learning, the ability of artificial systems to comprehend the sequences that comprise animal behavior has been lagging behind. In contrast, humans instinctively recognize behaviors by finding similarities in behavioral sequences. Here, we develop an unsupervised behavior-mapping framework, SUBTLE (spectrogram-UMAP-based temporal-link embedding), to capture comparable behavioral repertoires from 3D action skeletons. To find the best embedding method, we devise a temporal proximity index as a metric to gauge temporal representation in the behavioral embedding space. The method achieves the best performance compared to current embedding strategies. Its spectrogram-based UMAP clustering not only identifies subtle inter-group differences but also matches human-annotated labels. SUBTLE framework automates the tasks of both identifying behavioral repertoires like walking, grooming, standing, and rearing, and profiling individual behavior signatures like subtle inter-group differences by age. SUBTLE highlights the importance of temporal representation in the behavioral embedding space for human-like behavioral categorization. One Sentence SummaryUnsupervised behavior-mapping from 3D action skeletons achieves superior performance, captures behavioral repertoires, and identifies inter-group differences, emphasizing how temporal representation is critical in the behavioral embedding space.

neuroscience↗

bioRxiv2023

Loss-of-SIRT7 sensitizes hepatocellular carcinoma to sorafenib through the regulation of ERK Phosphorylation

The FDA-approved oral multi-kinase inhibitor, sorafenib (BAY 43-9006, Nexavar), is the first approved systemic therapy for patients with unresectable hepatocellular carcinoma (HCC). Although it has been shown to significantly improve the overall survival of patients with HCC, drug resistance limits the response rate to this therapeutic. Here, we report that acquired sorafenib resistance is associated with overexpression of the deacetylase, SIRT7, and a high level of ERK phosphorylation. Further, we identify that the hyperactivation of ERK is controlled by SIRT7-mediated deacetylation of DDX3X. The inhibition of SIRT7 combined with sorafenib resulted in a marked reduction of cell viability in vitro and of tumor growth in vivo. It seems plausible that SIRT7 is responsible for the acquired sorafenib resistance and its inhibition is most likely beneficial together in conjunction with sorafenib by suppressing ERK signaling. HighlightsO_LISorafenib resistance in HCC is associated with SIRT7 and ERK hyperactivation. C_LIO_LISuppression of SIRT7 combined with sorafenib restores sensitivity to sorafenib. C_LIO_LISIRT7 controls sorafenib resistance through ERK activation by mediating DDX3X deacetylation. C_LI

cancer biology↗

bioRxiv2022

Bursting Translation on Single mRNAs in Live Cells

Stochasticity has emerged as a mechanism to control gene expression. Much of this so-called "noise" has been attributed to bursting transcription. However, the stochasticity of translation has not similarly been investigated due to a lack of enabling imaging technologies. We developed techniques to track single mRNAs and their translation in live cells for hours, allowing measurement of previously uncharacterized translation dynamics. We applied genetic and pharmacological perturbations to control translation kinetics. Like transcription, translation is not a constitutive process but instead cycles between inactive and active states or "bursts". But unlike transcription, which is largely frequency modulated, complex structure in the 5-untranslated region alters burst amplitude. Bursting frequency can be controlled through cap-proximal sequences and trans-acting factors such as eIF4F. We coupled single molecule imaging with stochastic modeling to deduce the fundamental kinetic parameters of translational bursting, a new dimension of translational control. HighlightsO_LILong-term tracking of single mRNAs reveals multi-state, bursting translation C_LIO_LIStructure in the 5-untranslated region modulates translational burst amplitude C_LIO_LI5-cap proximal sequences modulate translational burst frequency C_LIO_LImTOR signaling adjusts translation bursting to respond to environmental cues C_LI

molecular biology↗

bioRxiv2022

Myoscaffolds demonstrate differential matrix components across muscular dystrophies

Extracellular matrix (ECM) pathologic remodeling underlies many fibrotic disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin-and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Adeno-associated viral expression of annexin A6 specifically in muscle resulted in annexin A6 deposition throughout the ECM, indicating muscle as a source of this ECM protein. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility. Dystrophin-deficient decellularized matrices inhibited myoblast mobility while dysferlin-deficient decellularized matrices enhanced myoblast movement. Myoblasts treated with recombinant annexin A6 increased mobillity similar to that seen on dysferlin-deficient decellularized matrix. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity. TEASERFibrosis in muscular dystrophy has differential effects on myoblasts HIGHLIGHTSO_LISpatial architecture and composition of the ECM differ across genetically distinct forms of muscular dystrophy, especially with respect to Annexin A6 protein deposition C_LIO_LIMatrix from dystrophin-mediated muscular dystrophy inhibits myoblast movement C_LIO_LIMatrix from dysferlin-deficient muscular dystrophy promotes myoblast motility C_LIO_LIAnnexin A6 was sufficient to enhance myoblast motility C_LI

molecular biology↗

bioRxiv2022

All-optical observation on activity-dependent nanoscale dynamics of myelinated axons

In the mammalian brain, rapid conduction of neural information is supported by the myelin, whose functional efficacy shows steep dependence on its nanoscale cytoarchitecture. Although previous in vitro studies suggested that neural activity accompanies nanometer-scale cellular deformations, it has remained unexplored whether neural activity can dynamically remodel the myelinated axon due to the technical challenge in observing its nanostructural dynamics in living tissues. To this end, we introduced a novel all-optical approach combining a nanoscale dynamic readout based on spectral interferometry and optogenetic control of neural excitation on a living brain slice preparation. In response to optogenetically evoked neuronal burst firing, the myelinated axons exhibited progressive and reversible spectral redshifts, corresponding to the transient swelling at a subnanometer scale. We further revealed that the activity-dependent nanostructural dynamics was localized to the paranode. In summary, our novel all-optical studies substantiate that myelinated axon exhibits activity-dependent nanoscale swelling, which potentially serves to dynamically tune the transmission speed of neural information. RESEARCH SUMMARIESAs neural activity involves rapid ion flux across the cell membrane, researchers have long been tried to detect the accompanying nanoscale morphological dynamics. However, measuring the activity-dependent nanostructural dynamics in the living mammalian brain has been an enigma due to the technical limitations. By combining excitatory optogenetics and in situ nanoscale metrology based on spectral interference, we demonstrate the first direct observation that the mammalian axons exhibit transient activity-dependent swelling at subnanometer-scale.

neuroscience↗

bioRxiv2021

VRK1 is required in VRK2-methylated cancers of the nervous system

Collateral lethality occurs when loss of one paralog renders cancer cells dependent on the remaining paralog. Combining genome scale CRISPR/Cas9 screens coupled with RNA-sequencing in over 900 cancer cell lines, we found that cancers of nervous system lineage, including adult and pediatric gliomas and neuroblastomas, required the nuclear kinase Vaccinia-Related Kinase 1 (VRK1) for their survival. VRK1 dependency was inversely correlated with expression of its paralog VRK2. VRK2 knockout (KO) sensitized cells to VRK1 suppression, and conversely, VRK2 overexpression increased cell fitness in the setting of VRK1 suppression. DNA methylation of the VRK2 promoter was associated with low VRK2 expression in human neuroblastomas, and adult and pediatric gliomas. Mechanistically, depletion of VRK1 reduced Barrier-to-Autointegration Factor (BAF) phosphorylation during mitosis, resulting in DNA damage and apoptosis. Together, these studies identify VRK1 as a synthetic lethal target in VRK2 promoter-methylated adult and pediatric gliomas and neuroblastomas. Statement of SignificanceWe credential VRK1 as a target in adult and pediatric gliomas, and neuroblastomas with VRK2 promoter methylation. This demonstrates the utility of paralog-driven synthetic lethal interactions for biomarker-linked, targeted therapeutics.

cancer biology↗

bioRxiv2021

Gabra5LHA Mediate Astrocytic GABA-induced Obesity via Decreasing Energy Expenditure

The lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

neuroscience↗

bioRxiv2021

Astrocytic urea cycle detoxifies Aβ-derived ammonia while impairing memory in Alzheimers Disease

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (A{beta}) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear A{beta} plaques. However, how A{beta} induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas A{beta}-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic by-products ammonia, H2O2, and GABA to recover from reactive astrogliosis and memory impairment in AD model. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial A{beta} detoxification and detrimental memory impairment in AD. We propose ODC1-inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.

neuroscience↗

bioRxiv2021

Global Plant Extinction Risk Assessment Informs Novel Biodiversity Hotspots

Curbing biodiversity loss and its impact on ecosystem services, resilience and Natures Contributions to People is one of the main challenges of our generation (IPBES, 2019b, 2019a; Secretariat of the United Nations Convention on Biological Diversity, 2020). A global baseline assessment of the threat status of all of biodiversity is crucial to monitor the progress of conservation policies worldwide (Mace & al., 2000; Secretariat of the United Nations Convention on Biological Diversity, 2021) and target priority areas for conservation (Walker & al., 2021). However, the magnitude of the task seems insurmountable, as even listing the organisms already known to science is a challenge (Nic Lughadha & al., 2016; Borsch & al., 2020; Govaerts & al., 2021). A new approach is needed to overcome this stumbling block and scale-up the assessment of extinction risk. Here we show that analyses of natural history mega-datasets using artificial intelligence allows us to predict a baseline conservation status for all vascular plants and identify target areas for conservation corresponding to hotspots optimally capturing different aspects of biodiversity. We illustrate the strong potential of AI-based methods to reliably predict extinction risk on a global scale. Our approach not only retrieved recognized biodiversity hotspots but identified new areas that may guide future global conservation action (Myers & al., 2000; Brooks & al., 2006). To further work in this area and guide the targets of the post-2020 biodiversity framework (Diaz & al., 2020a; Secretariat of the United Nations Convention on Biological Diversity, 2020; Mair & al., 2021), it will be necessary to accelerate the acquisition of fundamental data and allow inclusion of social and economic factors (Possingham & Wilson, 2005).

plant biology↗

bioRxiv2021

Distinct trans-placental effects of maternal immune activation by TLR3 and TLR7 agonists: implications for schizophrenia risk

Exposure to infection in utero predisposes towards psychiatric diseases such as autism, depression and schizophrenia in later life. The mechanisms involved are typically studied by administering mimetics of double-stranded (ds) RNA viral or bacterial infection to pregnant rats or mice. The effect of single-stranded (ss) virus mimetics has been largely ignored, despite evidence linking prenatal ss virus exposure specifically with psychiatric disease. Understanding the effects of gestational ss virus exposure has become even more important with the current SARS-CoV-2 pandemic. In this study, in pregnant mice, we compare directly the effects, on the maternal blood, placenta and the embryonic brain, of maternal administration of ds-virus mimetic poly I:C (to activate toll-like receptor 3, TLR3) and ss-virus mimetic resiquimod (to activate TLR7/8). We find that, 4h after the administration, both poly I:C and resiquimod elevated the levels of IL-6, TNF, and chemokines including CCL2 and CCL5, in maternal plasma. Both agents also increased placental mRNA levels of IL-6 and IL-10, but only resiquimod increased placental TNF mRNA. In foetal brain, poly I:C produced no detectable immune-response-related increases, whereas pronounced increases in cytokine (e.g. Il-6, Tnf) and chemokine (e.g. Ccl2, Ccl5) expression were observed with maternal resiquimod administration. The data show substantial differences between the effect of maternal exposure to a TLR7/8 activator as compared to a TLR3 activator. There are significant implications for future modelling of diseases where maternal ss virus exposure contributes to environmental disease risk in offspring.

neuroscience↗