scholarly journals P105 Glutathione S-transferase theta 1 protects against colitis through goblet cell differentiation via interleukin-22

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S188-S188
Author(s):  
J H Kim ◽  
J B Ahn ◽  
D H Kim ◽  
S Kim ◽  
H W Ma ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Immune Responses ◽  
Goblet Cell ◽  
Goblet Cells ◽  
Dependent Manner ◽  
Glutathione S Transferase ◽  
Host Immune Responses ◽  
Interleukin 22 ◽  
Gstt1 Gene ◽  
Goblet Cell Differentiation

Abstract Background The enzyme glutathione S-transferase theta 1 (GSTT1) is involved in detoxifying chemicals, including reactive oxygen species (ROS). Oxidative stress plays a key role in the pathogenesis of inflammatory bowel disease (IBD). Although mutation of the GSTT1 gene increases IBD susceptibility, the underlying mechanisms remain unexplained. Methods The Gstt1 gene was intrarectally or intraperitoneally delivered to mice with dextran sodium sulphate (DSS)-induced colitis. The GSTT1 gene was knocked down or knocked out using short interfering RNA or genome editing, respectively. Protein and mRNA expression and differentiation of goblet cells were evaluated. Results We identified decreased expression of GSTT1 in inflamed tissues from IBD patients and mice compared with their control counterparts, respectively. We also noted attenuation of colitis through gene transfer of Gstt1 to DSS-treated mice via the interleukin-22 (IL-22) pathway. GSTT1 was differently regulated by pathogens and host immune responses. Down-regulation of GSTT1 reduced innate defence responses and goblet cell differentiation. The GSTT1 mutation in intestinal epithelial cells as well as IBD patients diminished its dimerisation, which was connected to insufficient phosphorylation of signal transducer and activator of transcription 3 and p38/mitogen-activated protein kinase by their common activator, IL-22. Conclusion GSTT1 ameliorated IL-22 in colitis in a dependent manner and contributed as a modulator of goblet cells through sensing pathogens and host immune responses. Its mutations are linked to chronic intestinal inflammation due to its insufficient dimerisation. Our results provide new insights into GSTT1 mutations and their functional consequences in IBDs.

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

2020 ◽  
Vol 34 (2) ◽  
pp. 3289-3304
Author(s):  
Jae Hyeon Kim ◽  
Jae Bum Ahn ◽  
Da Hye Kim ◽  
Soochan Kim ◽  
Hyun Woo Ma ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Glutathione S Transferase ◽  
Interleukin 22 ◽  
Goblet Cell Differentiation

scholarly journals Indoles from the commensal microbiota act via the AHR and IL-10 to tune the cellular composition of the colonic epithelium during aging

2020 ◽  
Vol 117 (35) ◽  
pp. 21519-21526 ◽  
Author(s):  
Domonica N. Powell ◽  
Alyson Swimm ◽  
Robert Sonowal ◽  
Alexis Bretin ◽  
Andrew T. Gewirtz ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Intestinal Epithelium ◽  
Dynamic Structure ◽  
Goblet Cells ◽  
Type I ◽  
Cellular Composition ◽  
Type I Ifn ◽  
Commensal Microbiota ◽  
Goblet Cell Differentiation

The intestinal epithelium is a highly dynamic structure that rejuvenates in response to acute stressors and can undergo alterations in cellular composition as animals age. The microbiota, acting via secreted factors related to indole, appear to regulate the sensitivity of the epithelium to stressors and promote epithelial repair via IL-22 and type I IFN signaling. As animals age, the cellular composition of the intestinal epithelium changes, resulting in a decreased proportion of goblet cells in the colon. We show that colonization of young or geriatric mice with bacteria that secrete indoles and various derivatives or administration of the indole derivative indole-3 aldehyde increases proliferation of epithelial cells and promotes goblet cell differentiation, reversing an effect of aging. To induce goblet cell differentiation, indole acts via the xenobiotic aryl hydrocarbon receptor to increase expression of the cytokine IL-10. However, the effects of indoles on goblet cells do not depend on type I IFN or on IL-22 signaling, pathways responsible for protection against acute stressors. Thus, indoles derived from the commensal microbiota regulate intestinal homeostasis, especially during aging, via mechanisms distinct from those used during responses to acute stressors. Indoles may have utility as an intervention to limit the decline of barrier integrity and the resulting systemic inflammation that occurs with aging.

Thyroid hormones regulate goblet cell differentiation and Fgf19-Fgfr4 signaling

Endocrinology ◽  
2021 ◽  
Author(s):  
Einat Blitz ◽  
Hiroki Matsuda ◽  
Stefan Guenther ◽  
Takuto Morikawa ◽  
Yukihiko Kubota ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Thyroid Hormones ◽  
Goblet Cell ◽  
Pathological Condition ◽  
Goblet Cells ◽  
Gastrointestinal Diseases ◽  
Dominant Negative ◽  
Whole Body ◽  
Zebrafish Model ◽  
Goblet Cell Differentiation

Abstract Hypothyroidism is a common pathological condition that is characterized by insufficient activity of the thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), in the whole body or in specific tissues. Hypothyroidism is associated with inadequate development of the intestine as well as gastrointestinal diseases. We utilized a zebrafish model of hypothyroidism in order to identify and characterize TH-modulated genes and cellular pathways controlling intestine development. In the intestine of hypothyroid juveniles and adults, the number of mucus-secreting goblet cells was reduced, and this phenotype could be rescued by T3 treatment. Transcriptome profiling revealed dozens of differentially expressed genes in the intestine of hypothyroid adults compared to controls. Notably, the expression of genes encoding to Fgf19 and its receptor Fgfr4 was markedly increased in the intestine of hypothyroid adults, and treatment with T3 normalized it. Blocking FGF signaling, using an inducible dominant negative Fgfr transgenic line, rescued the number of goblet cells in hypothyroid adults. These results show that THs inhibit the Fgf19-Fgfr4 signaling pathway, which is associated with inhibition of goblet cell differentiation in hypothyroidism. Both the TH and Fgf19-Fgfr4 signaling pathways can be pharmaceutical targets for the treatment of TH-related gastrointestinal diseases.

scholarly journals Cigarette Smoke Activates NOTCH3 to Promote Goblet Cell Differentiation in Human Airway Epithelial Cells

2020 ◽  
Author(s):  
Manish Bodas ◽  
Andrew R. Moore ◽  
Bharathiraja Subramaniyan ◽  
Constantin Georgescu ◽  
Jonathan D. Wren ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Notch Signaling ◽  
Cigarette Smoke ◽  
Goblet Cell ◽  
Airway Epithelium ◽  
The United States ◽  
Dependent Manner ◽  
Over Expression ◽  
Goblet Cell Differentiation

AbstractChronic obstructive pulmonary disease (COPD) is the 3rd leading cause of death in the United States and is primarily caused by cigarette smoking. Increased numbers of mucus-producing secretory (“goblet”) cells defined as goblet cell metaplasia or hyperplasia (GCMH), contributes significantly to COPD pathophysiology. The objective of this study was to determine whether NOTCH signaling regulates goblet cell differentiation in response to cigarette smoke. Primary human bronchial epithelial cells (HBECs) from nonsmokers and COPD smokers were differentiated in vitro on air-liquid interface and exposed to cigarette smoke extract (CSE) for 7 days. NOTCH signaling activity was modulated using (1) the NOTCH/γ-secretase inhibitor Dibenzazepine (DBZ), (2) lentiviral over-expression of the NOTCH3-intracellular domain (NICD3) or (3) NOTCH3-specific siRNA. Cell differentiation and response to CSE were evaluated by qPCR, Western blotting, immunostaining and RNA-Seq. We found that CSE exposure of nonsmoker airway epithelium induced goblet cell differentiation characteristic of GCMH. Treatment with DBZ suppressed CSE-dependent induction of goblet cell differentiation. Furthermore, CSE induced NOTCH3 activation, as revealed by increased NOTCH3 nuclear localization and elevated NICD3 protein levels. Over-expression of NICD3 increased the expression of goblet cell associated genes SPDEF and MUC5AC, whereas NOTCH3 knockdown suppressed CSE-mediated induction of SPDEF and MUC5AC. Finally, CSE exposure of COPD airway epithelium induced goblet cell differentiation in a NOTCH3-dependent manner. These results identify NOTCH3 activation as one of the important mechanisms by which cigarette smoke induces goblet cell differentiation, thus providing a novel potential strategy to control GCMH-related pathologies in smokers and patients with COPD.

Goblet Cell Hyperplasia is not Epithelial-Autonomous in the Cftr Knockout Intestine

2021 ◽  
Author(s):  
Nancy M Walker ◽  
Jinghua Liu ◽  
Sarah M Young ◽  
Rowena A Woode ◽  
Lane L. Clarke
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Ex Vivo ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Cell Numbers ◽  
Markers Of Inflammation ◽  
Tlr4 Agonist ◽  
Goblet Cell Differentiation ◽  
Mucosal Morphology

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2, Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum as compared to wild-type (WT). IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2 and Tlr4 protein expression was increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4 and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.

scholarly journals IL-33 Induces Murine Intestinal Goblet Cell Differentiation Indirectly via Innate Lymphoid Cell IL-13 Secretion

2018 ◽  
Vol 202 (2) ◽  
pp. 598-607 ◽  
Author(s):  
Amanda Waddell ◽  
Jefferson E. Vallance ◽  
Amy Hummel ◽  
Theresa Alenghat ◽  
Michael J. Rosen
Keyword(s):  
Cell Differentiation ◽  
Goblet Cell ◽  
Lymphoid Cell ◽  
Innate Lymphoid Cell ◽  
Goblet Cell Differentiation

scholarly journals WNT/RYK signaling restricts goblet cell differentiation during lung development and repair

2019 ◽  
Vol 116 (51) ◽  
pp. 25697-25706 ◽  
Author(s):  
Hyun-Taek Kim ◽  
Wenguang Yin ◽  
Yuko Nakamichi ◽  
Paolo Panza ◽  
Beate Grohmann ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cells ◽  
Goblet Cell ◽  
Lung Development ◽  
Alveolar Epithelial Cells ◽  
Airway Epithelial ◽  
Cell Hyperplasia ◽  
Mucus Hypersecretion ◽  
Goblet Cell Hyperplasia ◽  
Goblet Cell Differentiation

Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in anN-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development;Rykmutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specificRykdeletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specificRykdeletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.

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