Biology subjects

Zhu, C.

Publications and source records attributed to Zhu, C..

At least 163 records · Page 9Linked to original sources

bioRxiv2022

Genetic and histological correlation between the musk gland and skin of Chinese forest musk deer

Chinese forest musk deer (FMD, Moschus berezovskii) glands have the ability to secrete musk, which plays an important role in attracting females during the breeding season. Sebaceous glands (SGs) are exocrine skin glands associated with hair follicles that continuously release a mixture of sebum, lipids and cellular debris, by holocrine secretion. Both the musk glands and the skin tissues of the FMD contain abundant sebaceous glands, and Sox9, Caveolin1, and Androgen receptor (AR) are all involved in the regulation of sebum secretion by the sebaceous glands. However, there are fewer studies on the correlation between skin and musk glands and the expression of Sox9, Caveolin1, and AR in the musk glands and skin tissue of FMD. To address this gap, we analyzed biochemical data from FMD skin tissues and musk glands using transcriptomic data, hematoxylin-eosin (HE) staining, western blotting (WB), immunohistochemistry (IHC), tissue dissection, and RT-qPCR. Anatomical results show that only adult male FMD had complete glandular part and sachets, while 4-month-old FMD do not have well-developed sachets. Transcriptomic data showed that 88.24% of genes were co-expressed in the skin and musk glands tissues of FMD. The WB, IHC, and RT-qPCR results showed that the genes involved in regulating sebum secretion, Sox9, Caveolin1, and AR were expressed in the skin tissues and musk glands. In summary, skin tissues and musk glands tissue have a strong correlation, and Sox9, Caveolin1, and AR may play important roles in skin tissues and musk glands tissue.

biochemistry↗

bioRxiv2022

Memory in Repetitive Protein-Protein Interaction Series -- in Memory of the Late Professor Robert M. Nerem

Over the past three decades, the senior author had interacted with and been mentored by the late Professor Robert M. Nerem. In his memory, the authors summarized several observations made, ideas conceptualized, and mathematical models developed during this period for quantitatively analyzing memory effects in repetitive protein-protein interactions (PPI). Interactions between proteins in an organism coordinate its biological processes and may impact its responses to changing environment and diseases through feedback systems. Feedback systems function by using changes in the past to influence behaviors in the future, which we refer here as memory. Specifically, we consider how proteins on cell or in isolation retain information about prior interactions to impact current interactions. The micropipette, biomembrane force probe and atomic force microscopic techniques were used to repeatedly assay several PPIs. The resulting time series were analyzed by a previous and two new models to extract three memory indices of short (seconds), intermediate (minutes), and long (hours) timescales. We found that interactions of cell membrane, but not soluble, T cell receptor (TCR) with peptide-major histocompatibility complex (pMHC) exhibits short-term memory that impacts on-rate, but not off-rate of the binding kinetics. Peptide dissociation from MHC resulted in intermediate- and long-term memories in TCR-pMHC interactions. However, we observed no changes in kinetic parameters by repetitive measurements on living cells over intermediate timescale using stable pMHCs. Parameters quantifying memory effects in PPIs could provide additional information regarding biological mechanisms. The methods developed herein also provide tools for future research.

biophysics↗

bioRxiv2022

Tumor microenvironments impair T cell receptor affinity and function

CD8+ T cells underpin effective anti-tumor immune responses in melanoma; however, their functions are attenuated due to various immunosuppressive factors in the tumor microenvironment (TME), resulting in disease progression. T cell function is elicited by the T cell receptor (TCR), which recognizes antigen peptide-major histocompatibility complex (pMHC) expressed on tumor cells via direct physical contact, i.e., two-dimensional (2D) interaction. TCR-pMHC 2D affinity plays a central role in antigen recognition and discrimination, and is sensitive to both the conditions of the T cell and the microenvironment in which it resides. Herein, we demonstrate that CD8+ T cells residing in TME have lower 2D TCR-pMHC bimolecular affinity and TCR-pMHC-CD8 trimolecular avidity, pull fewer TCR-pMHC bonds by endogenous forces, flux lower level of intracellular calcium in response to antigen stimulation, exhibit impaired in vivo activation, and show diminished anti-tumor effector function. These detrimental effects are localized in the tumor and tumor draining lymph node (TdLN), and affect both antigen-inexperienced and antigen-experienced CD8+ T cells irrespective of their TCR specificities. These findings implicate impaired antigen recognition as a mechanism of T cell dysfunction in the TME.

immunology↗

bioRxiv2022

Systematic characterization of chromodomain proteins revealsan H3K9me1/2 reader regulating aging in C. elegans

The chromatin organization modifier domain (chromodomain) is an evolutionally conserved motif across eukaryotic species. The chromodomain mainly functions as a histone methyl-lysine reader to modulate gene expression, chromatin spatial conformation and genome stability. Mutations or aberrant expression of chromodomain proteins can result in cancer and other human diseases. Here, we systematically tagged chromodomain proteins with green fluorescent protein (GFP) using CRISPR/Cas9 technology in C. elegans. By combining ChIP-seq analysis and imaging, we delineated a comprehensive expression and functional map of chromodomain proteins. We then conducted a candidate-based RNAi screening and identified factors that regulate the expression and subcellular localization of the chromodomain proteins. Specifically, we revealed a new H3K9me1/2 reader, CEC-5, both by in vitro biochemistry and in vivo ChIP assays. MET-2, an H3K9me1/2 writer, is required for CEC-5 association with heterochromatin. Both MET-2 and CEC-5 are required for the normal lifespan of C. elegans. Furthermore, a forward genetic screening identified a conserved Arginine124 of CEC-5s chromodomain, which was essential for CEC-5s association with chromatin and life span regulation. Thus, our work will serve as a reference to explore chromodomain functions and regulation in C. elegans and allow potential applications in aging-related human diseases.

molecular biology↗

bioRxiv2022

SnapHiC-D: a computational pipeline to identify differential chromatin contacts from single cell Hi-C data

Single cell Hi-C (scHi-C) has been used to map genome organization in complex tissues. However, computational tools to detect dynamic chromatin contacts from scHi-C datasets in development and through disease pathogenesis are still lacking. Here, we present SnapHiC-D, a computational pipeline to identify differential chromatin contacts (DCCs) between two scHi-C datasets. Compared to methods designed for bulk Hi-C data, SnapHiC-D detects DCCs with high sensitivity and accuracy. We used SnapHiC-D to identify celltype-specific chromatin contacts at 10 kilobase resolution in mouse hippocampal and human prefrontal cortical tissues, and demonstrated that DCCs detected in the cortical and hippocampal cell types are generally correlated with cell-type-specific gene expression patterns and epigenomic features.

bioinformatics↗

bioRxiv2022

The guanine nucleotide exchange factor Rin-like acts as a gatekeeper for T follicular helper cell differentiation via regulating CD28 signaling

T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody producing B-cells in human and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Further, adoptive transfer experiments using WT and Rinl-KO naive CD4+ T cells unraveled T cell-intrinsic functions of Rinl. Mechanistically, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first-time the importance of endocytic processes for Tfh differentiation. HighlightsO_LIRinl-KO CD4+ T cells show increased Tfh differentiation in a context independent manner C_LIO_LIThe regulation of Tfh differentiation is T cell-intrinsic C_LIO_LIRinl controls CD28 endocytosis and shapes Tfh-specific CD28 signal transduction C_LIO_LIHuman Tfh differentiation is regulated by Rinl C_LI

immunology↗

bioRxiv2022

MLL3 regulates the CDKN2A tumor suppressor locus in liver cancer

Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3/KMT2C) histone methyltransferase occur in a range of solid tumors and heterozygous deletions encompassing MLL3 occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Mll3 cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded genes, Ink4a and Arf. Conversely, elevated MLL3 expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Mll3 restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in MLL3 and CDKN2A display mutual exclusivity in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network.

cancer biology↗

bioRxiv2022

Senescence rewires microenvironment sensing to facilitate anti-tumor immunity

Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent tumor model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels cell surface proteome to alter how they sense environmental factors, as exemplified by Type II interferon gamma (IFN-{gamma}). Compared to proliferating cells, senescent cells upregulate IFN-{gamma} receptor, become hypersensitized to microenvironmental IFN-{gamma}, and more robustly induce antigen presenting machinery -effects also recapitulated in human tumor cells treated with senescence-inducing drugs. Disruption of the IFN-{gamma} sensing by senescent cells blunts their immune-mediated clearance without disabling their characteristic secretory program or immune cell recruitment. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance. SIGNIFICANCEOur work identifies a novel interplay between tissue remodeling and tissue sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance anti-tumor immunity.

cancer biology↗

bioRxiv2022

Spatiotemporal heterogeneity and the long-term impact of meteorological , environmental and socio-economic factors of scrub typhus in China from 2012 to 2018

Large-scale outbreaks of scrub typhus combined with the emergence of this vector-borne rickettsiosis in new areas indicate that this disease remains seriously neglected. This study aimed to explore the long-term changes and regional leading factors of scrub typhus in China, so as to provide fresh insights for the prevention and control of this disease. In this study, a Bayesian space-time hierarchical model (BSTHM) was used to identify the long-term spatiotemporal heterogeneity of scrub typhus and quantify the association between meteorological factors and scrub typhus in southern and northern China from 2012 to 2018. GeoDetector model was used to quantify the dominant forces of environmental and socioeconomic factors in the Northern and the Southern China. Scrub typhus often appeared in summer and autumn (June to November), and epidemically peaked in October, with obvious temporal seasonality. Spatially, the hot spots (high-risk regions) were concentrated in the south, on the contrary the cold spots (low-risk regions) in the north. In addition, the main meteorological factor, average temperature, gave a significant impact in both areas. The average temperature increased by 1 {degrees}C, resulting in a decrease of 1.10% in southern China and an increase of 0.96% in northern China in the risk of scrub typhus. The determinant environmental and socio-economic factors of scrub typhus in the two areas were altitude and per capita GDP, with q-values of 0.91 and 0.87, respectively. Meteorological, environmental and socio-economic factors had a significant impact on the distribution of scrub typhus, with obvious seasonality and spatial heterogeneity. This study provides helpful suggestions and basis for reasonably allocating resources and controlling the occurrence of scrub typhus. Author summaryScrub typhus is a natural-focus disease caused by the bite of chigger mite larval. In this study, we use BSTHM to capture the overall temporal trend and spatial hot spots of scrub typhus, and quantify the relationship between the disease and major meteorological factors. Meanwhile, Geodetector model was used to quantify the influence of other potential risk factors and estimate the spatio-temporal heterogeneity of scrub typhus. The results showed that scrub typhus had significant seasonality, with a q value of 0.52, and spatial heterogeneity, with a q-value of 0.64. Scrub typhus mainly occurred in summer and autumn, and high-risk areas were mainly distributed in southern China (Yunnan, Hainan and Guangdong). These heterogeneity were closely related to the vector and host. Whether in the South or the north, scrub typhus was closely related to risk factors such as temperature, per capita GDP, NDVI, altitude and the percentage of children aged 0-14. These results suggest that the relevant departments should strengthen the monitoring of the ecological environment, the host and vector of Orientia tsutsugamushi, and strengthen the risk awareness, so as to prevent and control the possible increased risk of scrub typhus under these meteorological, environmental and socio-economic conditions. Considering the differences in different regions, resources should be allocated reasonably.

ecology↗

bioRxiv2022

Privacy-preserving integration of multiple institutional data for single-cell type identification with scPrivacy

The rapid accumulation of large-scale single-cell RNA-seq datasets from multiple institutions presents remarkable opportunities for automatically cell annotations through integrative analyses. However, the privacy issue has existed but being ignored, since we are limited to access and utilize all the reference datasets distributed in different institutions globally due to the prohibited data transmission across institutions by data regulation laws. To this end, we present scPrivacy, which is the first and generalized automatically single-cell type identification prototype to facilitate single cell annotations in a data privacy-preserving collaboration manner. We evaluated scPrivacy on a comprehensive set of publicly available benchmark datasets for single-cell type identification to stimulate the scenario that the reference datasets are rapidly generated and distributed in multiple institutions, while they are prohibited to be integrated directly or exposed to each other due to the data privacy regulations, demonstrating its effectiveness, time efficiency and robustness for privacy-preserving integration of multiple institutional datasets in single cell annotations.

bioinformatics↗

bioRxiv2022

RNA Methylome Reveals the m6A-Mediated Regulation of Flavor Metabolites in Tea Leaves under Solar-Withering

Epitranscriptomic mark N6-methyladenosine (m6A) is the most predominant internal modification in RNAs, which plays pivotal roles in response to diverse stresses. Multiple environmental stresses caused by withering process can greatly influence the accumulation of specialized metabolites and the formation of tea flavor. However, little is known about the effects of m6A-mediated regulatory mechanism on flavor-related metabolisms in tea leaves. Here, we explored m6A-mediated regulatory mechanism and its impacts on flavonoid and terpenoid metabolisms under solar-withering using integrated RNA methylome and transcriptome. Dynamic changes in global m6A levels of tea leaves are mainly controlled by two m6A erasers (CsALKBH4A and CsALKBH4B) under solar-withering. Differentially methylated peak (DMP)-associated genes under different shading rates of solar-withering were identified and found to be enriched in terpenoid biosynthesis and spliceosome pathways. Further analyses indicated that CsALKBH4-driven RNA demethylation can not only directly affect the accumulation of volatile terpenoids by mediating the stability and abundance of terpenoid biosynthesis-related genes, but also indirectly influence the contents of flavonoids, catechins, and theaflavins via triggering the alternative splicing (AS)-mediated regulation. Our findings underscored a novel layer of epitranscriptomic gene regulation in tea flavor-related metabolic pathways and established a compelling link between m6A-mediated regulatory mechanism and the formation of high-quality flavor in tea leaves under solar-withering.

plant biology↗

bioRxiv2022

Amplification is the Primary Mode of Gene-by-Sex Interaction in Complex Human Traits

Sex differences in complex traits are suspected to be in part due to widespread gene-by-sex interactions (GxSex), but empirical evidence has been elusive. Here, we infer the mixture of ways polygenic effects on physiological traits covary between males and females. We find that GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects ("amplification"), rather than in the identity of causal variants. Amplification patterns account for sex differences in trait variance. In some cases, testosterone may mediate amplification. Finally, we develop a population-genetic test linking GxSex to contemporary natural selection and find evidence for sexually antagonistic selection on variants affecting testosterone levels. Taken together, our results suggest that the amplification of polygenic effects is a common mode of GxSex that may contribute to sex differences and fuel their evolution. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/490973v3_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@19c267eorg.highwire.dtl.DTLVardef@a32233org.highwire.dtl.DTLVardef@1a6daeorg.highwire.dtl.DTLVardef@116cbff_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2022

Cooperative ectodomain interaction among TCRαβ, CD3γε, and CD3δε enhances TCR mechanotransduction

TCR signaling poses a mechanical problem: pMHC binding occurs at the TCR{beta} ectodomain (ECD) head, whereas ITAM phosphorylation occurs on CD3 cytoplasmic tails. Chemistry cannot bridge this >10 nm gap, requiring the two events to be coupled through the TCR-CD3 interface, thus involving conformational allostery and being regulatable by force. Although weak ECD cis-interactions between TCR{beta} and CD3 have been proposed to contribute to this coupling, their kinetics and mechanical competence remain elusive. Here, we quantify TCR{beta}-CD3 ECD cis-interactions in a pseudo-cis configuration using two-dimensional binding and single-bond force spectroscopy, finding that TCR{beta}-CD3{gamma}{varepsilon} and TCR{beta}-CD3{delta}{varepsilon} interactions have low affinity and rapid kinetics, yet form catch bonds. Critically, concurrent engagement of CD3{gamma}{varepsilon} and CD3{delta}{varepsilon} produces high cis-cooperativity, yielding a stronger and longer-lasting CD3{gamma}{varepsilon}-TCR{beta}-CD3{delta}{varepsilon} trimolecular catch bond than the sum of the two dimeric bonds, with force-stabilized lifetimes matching those of agonist TCR-pMHC trans-interaction. Molecular dynamics simulations reveal an expanded, cooperative, and asymmetric contact network, making CD3{delta}{varepsilon} more force-responsive and susceptible to conformational change than CD3{gamma}{varepsilon}. Interface mutations do not alter force-free affinities but remodel cooperative cis-bond profiles, leading to an inverse correlation with trans-bond profiles and T cell signaling. These results identify cooperative ECD cis-interaction as a mechanically regulatable allosteric coupling element at the TCR-CD3 junction important to antigen recognition and signal initiation.

immunology↗

bioRxiv2022

Parallel lipid-carried epitope pillars enhance stimulation of chimeric antigen receptor T cells

Chimeric antigen receptor T cells are genetically engineered to express a specific T cell receptor of interest, such as to target a cancer-specific antigen. Signaling events in chimeric antigen receptor T cells are essential for their proliferation, survival, and function. To achieve optimal antitumor efficacy, signaling motifs as well as the structure of the transmembrane domain of the chimeric antigen receptor have to be carefully designed. However, it remains unclear whether the arrangement, and therefore the movement and elasticity, of tumor antigens influence their stimulation of chimeric antigen receptor T cells. Here we show that MUC1 molecules tethered to a glycosylphosphatidylinositol anchor drastically increased its stimulation of chimeric antigen receptor T cells. In particular, MUC1 molecules containing one tandem repeat sequence showed significantly greater stimulatory activity than five tandem repeat sequences. Thus glycosylphosphatidylinositol-anchored, tumor antigen epitope pillars in parallel are attractive targets for the design of chimeric antigen receptor T cells. These novel findings, which we propose as the parallel lipid-carried epitope model, emphasize the importance of epitope arrangement in selecting highly effective chimeric antigen receptor T cells, potentially revolutionizing the applicability of this therapy. Furthermore, our data have implications for the necessity of methodologies to measure the elasticity, movement, and density of antigen pillars in parallel, as key tools to guide future chimeric antigen receptor T cell therapy.

immunology↗

bioRxiv2022

A multiplexed in vivo approach to identify driver genes in small cell lung cancer

Small cell lung cancer (SCLC) is a highly lethal form of lung cancer. The high mutation burden in SCLC cells makes it challenging to predict key drivers of SCLC from genome sequencing data, thereby hindering the identification of possible therapeutic targets. Here we develop a quantitative multiplexed approach based on lentiviral barcoding with somatic CRISPR/Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. Lentiviral vector-mediated SCLC initiation was greatly enhanced by naphthalene pre-treatment, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Based on a meta-analysis across multiple human SCLC genomic datasets, we quantified the impact of inactivating 39 genes across many candidate pathways and captured both positive and detrimental effects on SCLC initiation and progression upon gene inactivation. This analysis and subsequent validation in human SCLC cells identified TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This new approach should illuminate novel drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify new therapeutic targets.

cancer biology↗

bioRxiv2022

Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function

FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naive and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naive NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naive Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXR{beta} in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naive and effector Treg cell subset composition independent from its ability to repress LXR{beta}-induced gene expression. Thus, our study reveals that NCOR1 maintains naive and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.

immunology↗

bioRxiv2022

Anti-phasic oscillatory development for speech and noise processing in cochlear implanted toddlers

Human brain demonstrates amazing readiness for speech and language learning at birth, but the auditory development preceding such readiness remains unknown. Cochlear implanted (CI) children with prelingual deafness provide a unique opportunity to study this developmental stage. Using functional near-infrared spectroscopy, we revealed that the brain of CI children was nearly irresponsive to sounds at CI hearing onset. With increasing CI experiences up to 32 months, the brain demonstrated function, region and hemisphere specific development. Most strikingly, the left anterior temporal lobe showed an oscillatory trajectory, changing in opposite phases for speech and noise. In addition, speech responses increased linearly in left sylvian parieto-temporal area and right inferior frontal gyrus, and noise responses changed in U shape in right supramarginal gyrus. Such cortical development predicted behavioral improvement. The study provides the first longitudinal brain imaging evidence for early auditory development preceding speech acquisition in the human brain. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/483211v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@d84974org.highwire.dtl.DTLVardef@1be9ba0org.highwire.dtl.DTLVardef@db5fb7org.highwire.dtl.DTLVardef@68f420_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe brain of cochlear implanted toddlers is functionally inferior to neonates C_LIO_LIHearing experiences drive functional development in auditory related cortical areas C_LIO_LISpeech and noise processing develop in anti-phasic oscillatory trajectories C_LIO_LIAuditory cortical development predicts post-implantation behavioral improvement C_LI

neuroscience↗

bioRxiv2022

24-Nor-ursodeoxycholic acid counteracts TH17/Treg imbalance and ameliorates intestinal inflammation by restricting glutaminolysis in differentiating TH17 cells

Objective24-Nor-ursodeoxycholic acid (NorUDCA) is a novel therapeutic bile acid for treating primary sclerosing cholangitis (PSC), an immune-mediated cholestatic liver disease. Since PSC strongly associates with inflammatory bowel diseases (IBD) driven by TH17/Treg imbalance, we aimed to explore NorUDCAs immunomodulatory potential on intestinal TH17/Treg balance. DesignNorUDCAs impact on TH17/Treg tissue distribution was first assessed in Mdr2-/- mouse model of PSC. We specifically investigated NorUDCAs effect on modulating TH17/Treg balance in a CD4+ T cell driven colitis model induced by adoptive transfer of CD25-CD44lowCD45RBhighCD4+ TNaive cells into Rag2-/- mice, mimicking human IBD. Mechanistic studies were performed using molecular approaches, flow cytometry and metabolic assays in murine TH17 cells in vitro. NorUDCAs signaling effects observed in murine system were further validated in circulating CD4+ T cells from PSC patients with co-existing IBD. ResultsNorUDCA promoted Treg generation in both liver and intestine in the Mdr2-/- model. In the experimental IBD model, NorUDCA attenuated intestinal immunopathology. Mechanistically, NorUDCA demonstrated strong immunomodulatory efficacy in counteracting TH17/Treg imbalance by restricting glutaminolysis in differentiating TH17 cells, thus suppressed -Ketoglutarate-dependent mTORC1 activation, glycolysis and enhanced FOXP3 expression. NorUDCAs impact on mTORC1 signaling was further confirmed in circulating CD4+ T-cells from PSC patients with IBD. ConclusionNorUDCA possesses direct immunometabolic modulatory potency to counteract TH17/Treg imbalance and ameliorate excessive TH17 cell driven intestinal immunopathology. These findings extend future clinical applications of NorUDCA for treatment of TH17 cell-mediated disorders along the gut-liver axis and beyond. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIPSC is an immune-mediated cholestatic liver disease highly associated with IBD where TH17/Treg imbalance drives immunopathogenesis; seeking effective therapeutics covering both liver and intestinal disease in PSC is of high clinical relevance. C_LIO_LIIndependent of anti-cholestatic effects, NorUDCA has recently been shown to possess direct immunomodulatory properties on CD8+ T cell metabolism, lymphoblastogenesis and clonal expansion through targeting mTORC1 signaling. C_LIO_LISince mTORC1 serves as critical metabolic checkpoint orchestrating TH17/Treg axis, inhibiting mTORC1 activity represents a potential treatment avenue counteracting TH17/Treg imbalance under intestinal inflammatory conditions. C_LI What are the new findings?O_LINorUDCA enriches FOXP3+ Treg population in both liver and intestinal tissue in the cholestatic Mdr2-/- mouse model of PSC. C_LIO_LINorUDCA exhibits direct immunomodulatory efficacies in suppressing excess TH17 cell-mediated intestinal immunopathology and promotes FOXP3+ Treg generation in an experimental IBD model. C_LIO_LIMechanistically, NorUDCA counteracts TH17/Treg imbalance by restricting glutaminolysis in differentiating TH17 cells, thus suppresses -Ketoglutarate-dependent mTORC1 activation, glycolysis and enhances FOXP3 expression. C_LIO_LINorUDCAs impact on mTORC1 signaling was further confirmed in circulating CD4+ T cells from patients with PSC and IBD. C_LI How might it impact on clinical practice in the foreseeable future?These findings advance our current understanding of therapeutic potentials of NorUDCA, which might represent a novel therapeutic strategy in the treatment of PSC and concomitant IBD and other TH17-mediated intestinal diseases.

molecular biology↗