Biology subjects

Oldenburg, B.

Publications and source records attributed to Oldenburg, B..

3 recordsLinked to original sources

bioRxiv2022

Compartment-driven imprinting of intestinal CD4 (regulatory) T cells in inflammatory bowel disease and homeostasis

ObjectiveThe mucosal immune system is implicated in the etiology and progression of inflammatory bowel diseases. The lamina propria and epithelium of the gut mucosa constitute two separate compartments, containing distinct T cell populations. Human CD4 T cell programming and regulation of lamina propria and epithelium CD4 T cells, especially during inflammation, remains incompletely understood. DesignWe performed imaging mass cytometry, flow cytometry, bulk and single-cell RNA-sequencing to profile ileal lamina propria and intraepithelial CD4 T cells (CD4CD8, regulatory T cells (Tregs), CD69- and CD69high Trm T cells) in controls and Crohns disease (CD) patients (paired non-inflamed and inflamed). ResultsInflammation results in alterations of the CD4 T cell population with a pronounced increase in Tregs and migrating/infiltrating cells. On a transcriptional level, inflammation within the epithelium induced T cell activation, increased IFN{gamma} responses and effector Treg differentiation. Conversely, few transcriptional changes within the lamina propria were observed. Key regulators including the chromatin remodelers ARID4B and SATB1 were found to drive compartment-specific transcriptional programming of CD4 T(reg) cells. ConclusionInflammation in CD patients primarily induces changes within the epithelium and not the lamina propria. Additionally, there is compartment-specific CD4 T cell imprinting, driven by shared regulators, upon translocation from the lamina propria to the epithelium. The main consequence of epithelial translocation, irrespective of inflammation, seems to be an overall dampening of broad (pro-inflammatory) responses and tight regulation of lifespan. These data suggest differential regulation of the lamina propria and epithelium, with a specific regulatory role in the inflamed epithelium.

immunology↗

bioRxiv2021

Catestatin regulates the colonic mucus layer in inflammatory bowel disease

BackgroundThe pro-hormone chromogranin A (CgA) and its bioactive cleavage product catestatin (CST) are both associated with inflammatory bowel disease (IBD) and dysregulated barrier functions, but their exact role has remained elusive. Here, we demonstrate that CST regulates the colonic mucus layer. MethodsCST levels were measured in feces of IBD patients. The mucus layer, goblet cells, and immune cell infiltration were analyzed by histology and electron microscopy in colon tissue from IBD patients and mice with selective deletion of the CST-coding region of the CgA gene. ResultsCST levels were elevated in feces of IBD patients compared to healthy controls. The thickness of the mucus layer was increased in non-affected, but not in inflamed, regions of the colon in IBD patients. The thickness of the mucus layer and concomitant mucus production were also increased in the CST-KO mouse. This mucus phenotype in CST-KO mice could be reversed by bone marrow transplantation from wildtype mice. ConclusionsCST produced by bone-marrow derived immune cells reduces production of the mucus layer in the intestine. This might contribute to the reduced mucus layer in inflamed colon regions of IBD patients. Additionally, CST feces levels might be a biomarker for IBD.

immunology↗

bioRxiv2020

Chromogranin A regulates gut permeability via the antagonistic actions of its proteolytic peptides

AimA leaky gut barrier has been implicated in the initiation and progression of a multitude of diseases, e.g., inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancers. Here we show how pro-hormone Chromogranin A (CgA), produced by the enteroendocrine cells, and Catestatin (CST: hCgA352-372), the most abundant CgA-derived proteolytic peptide, affect the gut barrier. MethodsColon tissues from region-specific CST-knockout (CST-KO) mice, CgA-knockout (CgA-KO) and WT mice were analyzed by immunohistochemistry, ultrastructural and flowcytometry studies. FITC-dextran assays were used to measure intestinal barrier function. Mice were supplemented with CST or CgA fragment pancreastatin (PST: CgA250-301). The microbial composition of cecum was determined. CgA and CST levels were measured in blood of IBD patients. ResultsCST-KO mice displayed (i) elongated tight, adherens junctions and desmosomes similar to IBD patients, and (ii) gut inflammation. Consistently, plasma FITC-dextran measurements showed increased intestinal paracellular permeability in the CST-knockout mice. This correlated with a higher ratio of Firmicutes to Bacteroidetes, a dysbiotic pattern commonly encountered in various diseases. Supplementation of CST-knockout mice with recombinant CST restored paracellular permeability and reversed inflammation, whereas CgA-knockout mice supplementation with CST and/or PST in CgA-KO mice showed that intestinal paracellular permeability is regulated by the antagonistic roles of these two peptides: CST reduces and PST increases permeability. ConclusionThe pro-hormone CgA regulates the intestinal paracellular permeability. CST is both necessary and sufficient to reduce permeability and primarily acts via antagonizing the effects of PST.

physiology↗