Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice

2004 ◽  
Vol 286 (6) ◽  
pp. G1050-G1058 ◽  
Author(s):  
Lane L. Clarke ◽  
Lara R. Gawenis ◽  
Emily M. Bradford ◽  
Louise M. Judd ◽  
Kathryn T. Boyle ◽  
...  
Keyword(s):  
Northern Blot Analysis ◽  
Clinical Symptoms ◽  
Bacterial Colonization ◽  
Paneth Cell ◽  
Light And Electron Microscopy ◽  
Paneth Cells ◽  
Real Time Quantitative Pcr ◽  
Granule Morphology ◽  
Mouse Intestine ◽  
Osmotic Laxative

Paneth cells of intestinal crypts contribute to host defense by producing antimicrobial peptides that are packaged as granules for secretion into the crypt lumen. Here, we provide evidence using light and electron microscopy that postsecretory Paneth cell granules undergo limited dissolution and accumulate within the intestinal crypts of cystic fibrosis (CF) mice. On the basis of this finding, we evaluated bacterial colonization and expression of two major constituents of Paneth cells, i.e., α-defensins (cryptdins) and lysozyme, in CF murine intestine. Paneth cell granules accumulated in intestinal crypt lumens in both untreated CF mice with impending intestinal obstruction and in CF mice treated with an osmotic laxative that prevented overt clinical symptoms and mucus accretion. Ultrastructure studies indicated little change in granule morphology within mucus casts, whereas granules in laxative-treated mice appear to undergo limited dissolution. Protein extracts from CF intestine had increased levels of processed cryptdins compared with those from wild-type (WT) littermates. Nonetheless, colonization with aerobic bacteria species was not diminished in the CF intestine and oral challenge with a cryptdin-sensitive enteric pathogen, Salmonella typhimurium, resulted in greater colonization of CF compared with WT intestine. Modest downregulation of cryptdin and lysozyme mRNA in CF intestine was shown by microarray analysis, real-time quantitative PCR, and Northern blot analysis. Based on these findings, we conclude that antimicrobial peptide activity in CF mouse intestine is compromised by inadequate dissolution of Paneth cell granules within the crypt lumens.

scholarly journals Detection of CD1 mRNA in Paneth cells of the mouse intestine by in situ hybridization.

1992 ◽  
Vol 40 (10) ◽  
pp. 1527-1534 ◽  
Author(s):  
J Lacasse ◽  
L H Martin
Keyword(s):  
In Situ Hybridization ◽  
Cell Biology ◽  
Paneth Cell ◽  
Intestinal Flora ◽  
Intraepithelial Lymphocytes ◽  
Paneth Cells ◽  
Peripheral T Cells ◽  
Mouse Intestine ◽  
Cluster Of Differentiation

Cluster of differentiation 1 (CD1) antigens are a family of non-MHC but Class I-like molecules that have been identified in humans and rodents. Although their function(s) remains unknown, it has been proposed that CD1 may present antigens to specific subsets of peripheral T-cells. We now provide evidence in support of this hypothesis through the demonstration by in situ hybridization that Paneth cells of the mouse intestine express CD1 mRNA. These cells are thought to be involved in the immunological regulation of intestinal flora and could accomplish this task through interactions with intestinal intraepithelial lymphocytes. The expression and localization of CD1 mRNA was confirmed by both autoradiographic and non-isotopic techniques. The relevance of these results to CD1 function as well as to Paneth cell biology is discussed.

Cryptdin gene expression in developing mouse small intestine

1997 ◽  
Vol 272 (1) ◽  
pp. G197-G206 ◽  
Author(s):  
D. Darmoul ◽  
D. Brown ◽  
M. E. Selsted ◽  
A. J. Ouellette
Keyword(s):  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Lumen ◽  
Intestinal Epithelial ◽  
Rt Pcr ◽  
Adult Mice ◽  
Mucosal Surfaces ◽  
Mouse Small Intestine ◽  
Pcr Products ◽  
Mouse Intestine

In rodents, the four intestinal epithelial cell lineages differentiate and become morphologically distinct during the first 2-3 postnatal wk. In studies reported here, reverse transcriptase-polymerase chain reaction (RT-PCR)-based assays detected Paneth cell defensin mRNAs in intestinal RNA from 1-day-old (P1) mice before crypt formation and maturation of the epithelium. Analysis of these defensin-coding RT-PCR products from P1 mice showed that 69% of clones sequenced coded for cryptdin-6, suggesting that it is the most abundant enteric defensin mRNA in the newborn. Paneth cell mRNAs, including cryptdins-4 and -5, lysozyme, matrilysin, and defensin-related sequences, also were detected in RNA from P1 mouse intestine. Unlike adult mice, where only Paneth cells are immunopositive for cryptdin, cryptdin-containing cells were distributed throughout the newborn intestinal epithelium and not in association with rudimentary crypts. Cryptdin immunoreactivity in the P1 mouse intestine was specific for intracellular granule contents, and immunofluorescent detection of cryptdins on mucosal surfaces suggested that the peptides are released into the intestinal lumen in P1 mice Defensin secretion may contribute to innate immunity of the neonatal intestine before the presence of distinguishable Paneth cells.

scholarly journals Targeting Mitochondrial Damage as a Therapeutic for Ileal Crohn’s Disease

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1349
Author(s):  
Kibrom M. Alula ◽  
Dakota N. Jackson ◽  
Andrew D. Smith ◽  
Daniel S. Kim ◽  
Kevin Turner ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Lipid Metabolism ◽  
Crohn's Disease ◽  
Paneth Cell ◽  
Mitochondrial Damage ◽  
Paneth Cells ◽  
Cell Phenotype ◽  
Type I ◽  
Targeted Therapeutics ◽  
Gene Signatures

Paneth cell defects in Crohn’s disease (CD) patients (called the Type I phenotype) are associated with worse clinical outcomes. Recent studies have implicated mitochondrial dysfunction in Paneth cells as a mediator of ileitis in mice. We hypothesized that CD Paneth cells exhibit impaired mitochondrial health and that mitochondrial-targeted therapeutics may provide a novel strategy for ileal CD. Terminal ileal mucosal biopsies from adult CD and non-IBD patients were characterized for Paneth cell phenotyping and mitochondrial damage. To demonstrate the response of mitochondrial-targeted therapeutics in CD, biopsies were treated with vehicle or Mito-Tempo, a mitochondrial-targeted antioxidant, and RNA transcriptome was analyzed. During active CD inflammation, the epithelium exhibited mitochondrial damage evident in Paneth cells, goblet cells, and enterocytes. Independent of inflammation, Paneth cells in Type I CD patients exhibited mitochondrial damage. Mito-Tempo normalized the expression of interleukin (IL)-17/IL-23, lipid metabolism, and apoptotic gene signatures in CD patients to non-IBD levels. When stratified by Paneth cell phenotype, the global tissue response to Mito-Tempo in Type I patients was associated with innate immune, lipid metabolism, and G protein-coupled receptor (GPCR) gene signatures. Targeting impaired mitochondria as an underlying contributor to inflammation provides a novel treatment approach for CD.

scholarly journals Emc3 maintains intestinal homeostasis by preserving secretory lineages

2021 ◽  
Author(s):  
Meina Huang ◽  
Li Yang ◽  
Ning Jiang ◽  
Quanhui Dai ◽  
Runsheng Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Dominant Role ◽  
Paneth Cell ◽  
Intestinal Barrier ◽  
Goblet Cells ◽  
Paneth Cells ◽  
Intestinal Barrier Function ◽  
Endoplasmic Reticulum Membrane ◽  
Mucus Production

AbstractIntestinal exocrine secretory lineages, including goblet cells and Paneth cells, provide vital innate host defense to pathogens. However, how these cells are specified and maintained to ensure intestinal barrier function remains poorly defined. Here we show that endoplasmic reticulum membrane protein complex subunit 3 (Emc3) is essential for differentiation and function of exocrine secretory lineages. Deletion of Emc3 in intestinal epithelium decreases mucus production by goblet cells and Paneth cell population, along with gut microbial dysbiosis, which result in spontaneous inflammation and increased susceptibility to DSS-induced colitis. Moreover, Emc3 deletion impairs stem cell niche function of Paneth cells, thus resulting in intestinal organoid culture failure. Mechanistically, Emc3 deficiency leads to increased endoplasmic reticulum (ER) stress. Mitigating ER stress with tauroursodeoxycholate acid alleviates secretory dysfunction and restores organoid formation. Our study identifies a dominant role of Emc3 in maintaining intestinal mucosal homeostasis.

scholarly journals Developmental switch of intestinal antimicrobial peptide expression

2008 ◽  
Vol 205 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Sandrine Ménard ◽  
Valentina Förster ◽  
Michael Lotz ◽  
Dominique Gütle ◽  
Claudia U. Duerr ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
High Performance ◽  
Bacterial Colonization ◽  
Paneth Cell ◽  
Active Form ◽  
Constitutive Expression ◽  
Postnatal Period ◽  
Enteric Infection ◽  
Immune Effector ◽  
Developmental Switch

Paneth cell–derived enteric antimicrobial peptides provide protection from intestinal infection and maintenance of enteric homeostasis. Paneth cells, however, evolve only after the neonatal period, and the antimicrobial mechanisms that protect the newborn intestine are ill defined. Using quantitative reverse transcription–polymerase chain reaction, immunohistology, reverse-phase high-performance liquid chromatography, and mass spectrometry, we analyzed the antimicrobial repertoire in intestinal epithelial cells during postnatal development. Surprisingly, constitutive expression of the cathelin-related antimicrobial peptide (CRAMP) was observed, and the processed, antimicrobially active form was identified in neonatal epithelium. Peptide synthesis was limited to the first two weeks after birth and gradually disappeared with the onset of increased stem cell proliferation and epithelial cell migration along the crypt–villus axis. CRAMP conferred significant protection from intestinal bacterial growth of the newborn enteric pathogen Listeria monocytogenes. Thus, we describe the first example of a complete developmental switch in innate immune effector expression and anatomical distribution. Epithelial CRAMP expression might contribute to bacterial colonization and the establishment of gut homeostasis, and provide protection from enteric infection during the postnatal period.

IV. Paneth cell antimicrobial peptides and the biology of the mucosal barrier

1999 ◽  
Vol 277 (2) ◽  
pp. G257-G261 ◽  
Author(s):  
Andre J. Ouellette
Keyword(s):  
Innate Immunity ◽  
Epithelial Cells ◽  
Antimicrobial Peptides ◽  
Paneth Cell ◽  
Chloride Ion ◽  
Paneth Cells ◽  
In Vitro Assays ◽  
Mucosal Barrier ◽  
Intermediate Cells

The hypothesis that epithelial cells release preformed antibiotic peptides as components of mucosal innate immunity has gained experimental support in recent years. In the mammalian small intestine, Paneth cells secrete granules that are rich in α-defensins and additional antimicrobial peptides into the lumen of the crypt. The α-defensins are homologues of peptides that function as mediators of nonoxidative microbial cell killing in phagocytic leukocytes, and they are potent microbicidal agents in in vitro assays. Because certain mouse α-defensins stimulate cultured epithelial cells to secrete chloride ion, those peptides appear to be capable of interacting directly with the apical membranes of neighboring cells and perhaps influencing crypt physiology. In instances of crypt disruption or induced Paneth cell deficiency, crypt intermediate cells appear to compensate by accumulating and secreting Paneth cell antimicrobial peptides. Challenges for the future will be to understand the mechanisms of this epithelial plasticity and to show that Paneth cells contribute directly to innate immunity in the crypt microenvironment.

scholarly journals PANETH CELL GRANULE OF MOUSE INTESTINE

1962 ◽  
Vol 15 (1) ◽  
pp. 136-139 ◽  
Author(s):  
H. M. Selzman ◽  
Robert A. Liebelt
Keyword(s):  
Paneth Cell ◽  
Cell Granule ◽  
Mouse Intestine

Paneth Cell Carcinoma of the Ampulla of Vater

2004 ◽  
Vol 128 (8) ◽  
pp. 908-910
Author(s):  
Jorge I. Mora ◽  
Julieta E. Barroeta ◽  
David A. Bernstein ◽  
Juan Lechago
Keyword(s):  
Cell Carcinoma ◽  
Paneth Cell ◽  
Ampulla Of Vater ◽  
Paneth Cells ◽  
Biological Behavior ◽  
Neoplastic Cells ◽  
Poorly Differentiated Adenocarcinoma ◽  
Ca 19.9 ◽  
Positive Immunostaining ◽  
Poorly Differentiated

Abstract We describe a Paneth cell carcinoma arising within the ampulla of Vater in a 64-year-old man. The phenotype of virtually all neoplastic cells was consistent with that of Paneth cells, based on routine morphology and their strong positive immunostaining for lysozyme. Additional widespread positive immunostaining for carcinoembryonic antigen and CA 19.9 supports a totipotential cell as the origin of such neoplastic cells. This case, therefore, represents a true Paneth cell carcinoma, as opposed to inclusion of occasional neoplastic Paneth cells into a poorly differentiated adenocarcinoma. This pattern of differentiation is rare, and predictions regarding its ultimate biological behavior and malignant potential must be guarded.

scholarly journals LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

2020 ◽  
Vol 6 (37) ◽  
pp. eabc0367 ◽  
Author(s):  
Rosalie T. Zwiggelaar ◽  
Håvard T. Lindholm ◽  
Madeleine Fosslie ◽  
Marianne Terndrup Pedersen ◽  
Yuki Ohta ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Epithelial ◽  
Intestinal Development ◽  
Gene Profile ◽  
Epithelial Homeostasis ◽  
Lysine Specific Demethylase ◽  
Epithelial Development ◽  
Important Regulator

Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside Paneth cells, appear after birth in the neonatal period. We aimed to identify regulators of neonatal intestinal epithelial development by testing a small library of epigenetic modifier inhibitors in Paneth cell–skewed organoid cultures. We found that lysine-specific demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 enzymatically represses genes that are normally expressed only in fetal and neonatal epithelium. This gene profile is similar to what is seen in repairing epithelium, and we find that Lsd1-deficient epithelium has superior regenerative capacities after irradiation injury. In summary, we found an important regulator of neonatal intestinal development and identified a druggable target to reprogram intestinal epithelium toward a reparative state.

scholarly journals Enteroendocrine and tuft cells support Lgr5 stem cells on Paneth cell depletion

2019 ◽  
Vol 116 (52) ◽  
pp. 26599-26605 ◽  
Author(s):  
Johan H. van Es ◽  
Kay Wiebrands ◽  
Carmen López-Iglesias ◽  
Marc van de Wetering ◽  
Laura Zeinstra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Receptor Gene ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Alternative Source ◽  
Stem Cell Maintenance ◽  
Diphtheria Toxin Receptor ◽  
Tuft Cells ◽  
Toxin Receptor

Cycling intestinal Lgr5+stem cells are intermingled with their terminally differentiated Paneth cell daughters at crypt bottoms. Paneth cells provide multiple secreted (e.g., Wnt, EGF) as well as surface-bound (Notch ligand) niche signals. Here we show that ablation of Paneth cells in mice, using a diphtheria toxin receptor gene inserted into the P-lysozyme locus, does not affect the maintenance of Lgr5+stem cells. Flow cytometry, single-cell sequencing, and histological analysis showed that the ablated Paneth cells are replaced by enteroendocrine and tuft cells. As these cells physically occupy Paneth cell positions between Lgr5 stem cells, they serve as an alternative source of Notch signals, which are essential for Lgr5+stem cell maintenance. Our combined in vivo results underscore the adaptive flexibility of the intestine in maintaining normal tissue homeostasis.

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