Biology subjects

Rice, T.

Publications and source records attributed to Rice, T..

8 recordsLinked to original sources

bioRxiv2026

Inhibition of p65 NF-κB enhances production of galactose-deficient IgA1 through suppression of C1GALT1 and SP1 in plasmablast-like cell subpopulations

IgA nephropathy (IgAN) is a common primary glomerulonephritis characterized by glomerular immune-complex deposits with (co)dominant IgA. These deposits are enriched for IgA1 glycoforms with some O-glycans deficient in galactose (Gd-IgA1). Circulating Gd-IgA1 is bound by IgG autoantibodies to form immune complexes, some of which deposit in glomeruli. Genomic and immunologic studies indicate involvement of pro-inflammatory signaling pathways in the production of Gd-IgA1 in IgAN. Genomic studies identified multiple genetic loci associated with IgAN and suggested a convergence on the NF-{kappa}B pathway, including RELA, the gene encoding the NF-{kappa}B subunit p65. However, the mechanisms by which NF-{kappa}B pathways may affect O-glycosylation in IgA1-producing cells are unknown. Using EBV-immortalized B cells derived from peripheral-blood mononuclear cells of IgAN patients and healthy controls that have constitutively activated NF-{kappa}B, we report that inhibition of NF-{kappa}B/p65 by a selective IKK{beta} inhibitor TPCA-1 reduced phosphorylation of NF-{kappa}B/p65 at S536 and decreased production of IgA1 and, conversely, increased Gd-IgA1 production. This was likely related to reduced expression of C1GALT1 gene that encodes the enzyme responsible for galactosylation of IgA1 O-glycans. Flow-cytometry imaging revealed changes in nuclear translocation and co-localization of the NF-{kappa}B/p65 with co-transcriptional factor SP1, a transcriptional activator of C1GALT1, suggesting that NF-{kappa}B pathway affects IgA1 O-glycosylation via SP1 transcriptional control of C1GALT1 expression. Furthermore, prolonged IKK{beta} inhibition altered B cell subpopulations, enhancing generation of cells with a plasmablast-like phenotype, characterized by high SSC MFI and CD138 expression. Together, these findings provide functional evidence for involvement of NF-{kappa}B/p65 and its transcriptional partners in IgA1 O-glycosylation. HighlightsO_LIIKK{beta} inhibition reduced C1GALT1 expression and thereby increased galactose-deficient IgA1 (Gd-IgA1) production in immortalized human B cells. C_LIO_LISP1+ subpopulations, a transcriptional activator of C1GALT1, declined after sustained NF-{kappa}B inhibition. C_LIO_LINF-{kappa}B inhibition shifted a subpopulation of B cells into a plasmablast-like phenotype. C_LIO_LIThis study links NF-{kappa}B signaling with the GWAS-identified RELA susceptibility locus and IgA1 O-glycosylation. C_LI

immunology↗

bioRxiv2023

Microbiota epigenetically direct tuft cell differentiation to control type 2 immunity

Allergy and anti-helminth immunity are driven by type 2 responses in mucosal tissues. Tuft cells are key regulators of type 2 immunity, however the factors that control these cells remain poorly understood. Here we find that butyrate-producing commensal bacteria decrease tuft cells in the intestine. Butyrate suppression of tuft cells required the epigenetic modifying enzyme histone deacetylase 3 (HDAC3), suggesting that HDAC3 may promote tuft cell-dependent immunity. Consistent with this, epithelial-intrinsic HDAC3 actively regulated tuft cell expansion in vivo and was required to induce type 2 immune responses during helminth infection. Interestingly, butyrate epigenetically restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids was sufficient to block tuft cell expansion. Collectively, these data reveal an epigenetic pathway in stem cells that directs tuft cell differentiation, and highlight a new level of regulation through which commensal bacteria calibrate intestinal immunity.

immunology↗

bioRxiv2022

Epithelial MHC class II directs microbiota-specific intestinal immune homeostasis

Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we find that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibit increased accumulation of commensal-specific CD4+ T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific CD4+ T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelial-intrinsic ablation of HDAC3 promoted T cell driven-colitis and primed development of pathogenic commensal-specific Th17 cells. Mechanistically, HDAC3 was essential for MHC class II (MHCII) expression by the intestinal epithelium, and epithelial-intrinsic MHCII actively limited commensal-specific Th17 cells and prevented microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in controlling development of tissue-intrinsic T cells that recognize commensal microbes and drive pathologic inflammation.

immunology↗

bioRxiv2021

Commensal bacterial-derived retinoic acid primes host defense to intestinal infection

Interactions between the microbiota and mammalian host are essential for effective defense against pathogenic infection; however, the microbial-derived cues that mediate this beneficial relationship remain unclear. Here, we find that the intestinal epithelial cell (IEC)-associated commensal bacteria, Segmented Filamentous Bacteria (SFB), promotes early protection against the bacterial pathogen, Citrobacter rodentium, independently of CD4+ T cells. Global analyses demonstrated that SFB induced histone modifications in IECs at sites enriched for the retinoic acid receptor (RAR) motif. Interestingly, SFB-colonized mice exhibited greater expression of RAR targets during infection relative to germ-free mice, suggesting SFB may enhance defense through retinoic acid (RA) signaling. Consistent with this, supplementing germ-free mice with RA decreased pathogen levels. Further, mice with impaired RA-responsiveness in IECs displayed increased susceptibility to C. rodentium infection. RA was elevated in the intestine of mice colonized with SFB, indicating that the presence of commensal bacteria can modulate intestinal RA levels. However, this regulation by SFB was not dependent on mammalian RA production. Sequence analyses suggested that RA-generating enzymes are expressed by a subset of commensal bacteria. Remarkably, RA was produced by intestinal bacteria including SFB, and inhibiting RA signaling blocked SFB-induced protection against C. rodentium infection. These data collectively reveal RA as an unexpected microbiota-derived metabolite that primes innate intestinal defense and suggests that pre- and probiotic approaches to elevate RA could prevent or combat pathogenic infection.

microbiology↗

bioRxiv2020

The relationship between microbiomes and selective regimes in the sponge genus Ircinia.

Sponges are often densely populated by microbes that benefit their hosts through nutrition and bioactive secondary metabolites; however, sponges must simultaneously contend with the toxicity of microbes and thwart microbial overgrowth. Despite these fundamental tenets of sponge biology, the patterns of selection in the host sponges genomes that underlie tolerance and control of their microbiomes are still poorly understood. To elucidate these patterns of selection, we performed a population genetic analysis on multiple species of Ircinia from Belize, Florida, and Panama using an FST-outlier approach on transcriptome-annotated RADseq loci. As part of the analysis, we delimited species boundaries among seven growth forms of Ircinia. Our analyses identified balancing selection in immunity genes that have implications for the hosts tolerance of high densities of microbes. Additionally, our results support the hypothesis that each of the seven growth forms constitutes a distinct Ircinia species that is characterized by a unique microbiome. These results illuminate the evolutionary pathways that promote stable associations between host sponges and their microbiomes, and that potentially facilitate ecological divergence among Ircinia species.

evolutionary biology↗

bioRxiv2020

A novel synthetic peptide provides neuroprotection and rescues rat cortical neurons from anesthetic-induced cell death and modulation of growth and synaptic assembly

Anesthetics, although necessary for many modern procedures, exert neurotoxic effects in various experimental models; the underlying mechanisms, however, remain unknown. In the absence of this information, any in vivo mitigation strategy would be challenging. To help address these gaps, we sought to determine whether preserving mitochondrial network integrity with a non-toxic, short-life synthetic peptide, P110, could protect cortical neurons against both inhalational and intravenous anesthetic-induced neurotoxicity. This study provides the first direct comparative account of three key general anesthetics (desflurane, propofol, and ketamine) under identical conditions and demonstrates their impact on cellular viability, neurite outgrowth, and synaptic network assembly on neonatal rat cortical neurons. Further, we discovered that the inhibition of Fis1 receptor-mediated fission reverses anesthetic-induced aberrations in an agent-specific manner. Our data thus underscore the importance of a reductionist approach, offering unique opportunities to explore non-toxic, mitochondria-based therapeutic tools for mitigating anesthetic-induced harm to the developing brain.

neuroscience↗

bioRxiv2017

Sex-specific genome-wide association study in glioma identifies new risk locus at 3p21.31 in females, and finds sex-differences in risk at 8q24.21

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

epidemiology↗

bioRxiv2017

Sex-specific gene and pathway modeling of inherited glioma risk

BackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.\n\nMethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p<0.01) in a previous meta-analysis and X chromosome SNPs with nominally significant association (p<0.01), three algorithms (Pascal, BimBam, and GATES) were used to generate gene-scores, and Pascal was used to generate pathway scores. Results were considered significant when p<3.3x10-6 in [2/3] algorithms.\n\nResults25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively. EGFR and RTEL1-TNFRSF6B were significantly associated with all glioma and glioblastoma in males only, and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.\n\nConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.

epidemiology↗