Single cell sequencing of the effects of blocking lymphotoxin alpha in the mesenteric lymph node and spleen
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE296503 | GEO | 2025/08/01
REPOSITORIES: GEO
Similar Datasets
Project description:B lymphocytes may facilitate chronic inflammation through antibody production or secretion of cytokines, including lymphotoxin (LT)-a and -b associated with development of lymphoid tissue. Tertiary lymphoid structures (TLS) characterize human and murine ileitis by suppressing outflow from the ileum. Here, we unraveled disparate roles for B cells in chronic ileitis driven by the cytokine TNF. B cell-derived secretory IgA protected against ileal inflammation, whereas B cell-derived LTa guarded against ileitis-associated loss of body mass. This protection was not due to formation of TLS, as we initially hypothesized, because enhanced weight loss did not emerge when TLS were eliminated during ileitis due to B cell-selective deletion of LTb. Instead, weight loss driven by the cachectic cytokine TNF was exacerbated when LTa3, another ligand for TNF receptors, was selectively neutralized. Thus, B cells’ multi-faceted impact on ileitis includes generating secretory IgA, expressing LTa1b2 to drive formation of TLS, and producing LTa3 to protect against weight loss in the presence of TNF.
2025-07-31 | GSE255722 | GEO
Project description:CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn’s disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn’s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
2020-01-10 | GSE143404 | GEO
Project description:CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn’s disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn’s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
2020-01-10 | GSE143403 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below. CD4+ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4+ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn?s disease-like ileitis following transfer into Rag1-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn?s disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.
2020-01-10 | GSE143405 | GEO
Project description:Roundworm infections result in morbidity, causing significant health and economic concerns in humans and pigs, respectively. We investigated the humoral responses of A. suum infected pigs before and after transition from larval to adult stage and confirmed our previous report on the diagnostic value of human Ascaris-specific antibodies. We evaluated the systemic and mucosal humoral responses in Ascaris infected pigs at 14- and 35-days post-infection (dpi). Ascaris-specific antibodies against larval and adult worm antigens and adult excretory/secretory (ES) products in serum, broncho-alveolar lavage fluid and intestinal mucus were quantified by ELISA. IgA+ B cells in jejunal/ileal mesenteric lymph nodes (mLNs) were investigated using flow cytometry.
2025-06-20 | MSV000098272 | MassIVE
Project description:Objectives: Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+ regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis. Methods: RNA-sequencing (RNA-seq) and flow cytometry were performed on inflamed gut and joint samples and tissue-derived Tregs from TNF∆ARE mice. In situ hybridization of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble(s) TNFR levels were measured in serum of mice and SpA patients and controls. Treg function was explored by in vitro co-cultures and in vivo by conditional Treg depletion. Results: Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 mRNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in SpA patients with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue restricted TNFSF receptor and p38MAPK gene expression. Conclusions: These data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.
2023-05-22 | GSE232406 | GEO
Project description:Objectives: Gut and joint inflammation commonly co-occur in spondyloarthritis (SpA) which strongly restricts therapeutic modalities. The immunobiology underlying differences between gut and joint immune regulation, however, is poorly understood. We therefore assessed the immunoregulatory role of CD4+FOXP3+ regulatory T (Treg) cells in a model of Crohn’s-like ileitis and concomitant arthritis. Methods: RNA-sequencing (RNA-seq) and flow cytometry were performed on inflamed gut and joint samples and tissue-derived Tregs from TNF∆ARE mice. In situ hybridization of TNF and its receptors (TNFR) was applied to human SpA gut biopsies. Soluble(s) TNFR levels were measured in serum of mice and SpA patients and controls. Treg function was explored by in vitro co-cultures and in vivo by conditional Treg depletion. Results: Chronic TNF exposure induced several TNF superfamily (TNFSF) members (4-1BBL, TWEAK and TRAIL) in synovium and ileum in a site-specific manner. Elevated TNFR2 mRNA levels were noted in TNF∆ARE/+ mice leading to increased sTNFR2 release. Likewise, sTNFR2 levels were higher in SpA patients with gut inflammation and distinct from inflammatory and healthy controls. Tregs accumulated at both gut and joints of TNF∆ARE mice, yet their TNFR2 expression and suppressive function was significantly lower in synovium versus ileum. In line herewith, synovial and intestinal Tregs displayed a distinct transcriptional profile with tissue restricted TNFSF receptor and p38MAPK gene expression. Conclusions: These data point to profound differences in immune-regulation between Crohn’s ileitis and peripheral arthritis. Whereas Tregs control ileitis they fail to dampen joint inflammation. Synovial resident Tregs are particularly maladapted to chronic TNF exposure.
2023-05-22 | GSE232405 | GEO
Project description:Background: Although a number of intestinal inflammatory conditions pertain to the ileum, whole-genome gene expression analyses on ileal inflammation in animal models are lacking to date. Therefore, we aimed to identify and characterize alterations in gene expression in the acutely inflamed ileum of two murine models of intestinal inflammation, namely intestinal schistosomiasis and TNBS-induced ileitis, using Agilent whole-genome microarrays followed by bioinformatics analysis to detect enrichment of Kyoto Encyclopedia of Genes and Genomes pathways and Gene Ontology categories. Results: When compared with healthy control mice, of almost all known mouse genes and transcripts represented on the array, intestinal schistosomiasis and TNBS-induced ileitis yielded 207 and 1417 differential genes respectively, with 48 overlapping genes (adj.p.value<0.1 and log2FC>1 or <1). Complement and coagulation cascades, extracellular matrix-receptor interaction, Fc epsilon receptor I signaling pathways and protein activation cascade, cell adhesion categories were enriched for differential genes in intestinal schistosomiasis. Antigen processing and presentation, cell adhesion molecules, ABC transporters, Toll-like receptor signaling pathways and response to chemical stimulus categories were enriched for differential genes in TNBS-induced ileitis. Although cytokine-cytokine receptor interaction, intestinal immune network for immunoglobulin A production, focal adhesion pathways and immune, inflammatory and defense response categories were enriched for differential genes in both inflammation models, the vast majority of the associated differential genes were unique to each model. Conclusions: This study characterized the two diverse models of ileal inflammation at a whole-genome level and outlined their underlying molecular heterogeneity. The results indicate that intestinal schistosomiasis involves Th2 responses, enhanced tissue repair and complement activation, while TNBS-induced ileitis involves Th17 responses, defective antigen processing and presentation and altered Toll-like receptor-mediated responses. Epithelial barrier impairment seems to occur in both inflammation models. Moreover, the comprehensive differential gene-list provided by this study would be helpful as a starting point to explore a specific novel pathway in more detail dealing with small bowel inflammation. A total of 9 biological samples containing 3 each of Control, S.mansoni-infected and TNBS-treated were included in the study. A reference design was used including a reference sample containing a pool of equimolar amounts of all Control samples. The design consisted totally of 11 arrays which included 3 biological replicates each of Control (labeled in Cy5), S.mansoni-infected (labeled in Cy3) and TNBS-treated tissue samples(labeled in Cy5) as well as two dye flipped technical replicates of a Control and a S.mansoni-infected tissue sample. The reference was labeled with either Cy5 or Cy3, depending on the labeling of the test sample.
2012-10-05 | E-GEOD-31265 | biostudies-arrayexpress
Project description:Crohn’s disease is characterized by transmural inflammation and therefore the mesenteric immune compartment has gained interest. However, its significance in Crohn’s disease is largely unclear. Macrophages are plastic cells that adapt their phenotype to environmental stimuli resulting in inflammatory and regulatory macrophage subsets. Hence, their distribution can reflect the overall nature of an immune infiltrate. We show that mesenteric macrophages contain two populations, characterized as CD11b-high and CD11b-dim. The CD11b-dim population is characterized by expression of regulatory markers CD206, CD200R, CD163, PD-L2, CD32. CD11b-high macrophages display an IFNγ induced signature and produce high levels of calprotectin. CD11b-dim and CD11b-high populations were comparable between Crohn’s disease and other indications in expression pattern, but the CD11b-high population was strongly overrepresented in this patient group.
2021-04-07 | GSE148233 | GEO
Project description:Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer’s patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.
2022-07-13 | GSE160732 | GEO