scholarly journals Enteric Salmonella Infection Inhibits Paneth Cell Antimicrobial Peptide Expression

2003 ◽  
Vol 71 (3) ◽  
pp. 1109-1115 ◽  
Author(s):  
Nita H. Salzman ◽  
Margaret M. Chou ◽  
Hendrik de Jong ◽  
Lide Liu ◽  
Edith M. Porter ◽  
...  
Keyword(s):  
Type Iii Secretion ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Enteric Pathogens ◽  
Intestinal Lumen ◽  
Oral Inoculation ◽  
Serovar Typhimurium ◽  
Peptide Expression ◽  
Small Intestinal ◽  
Antimicrobial Peptide Expression

ABSTRACT Paneth cells, highly secretory epithelial cells found at the bases of small intestinal crypts, release a variety of microbicidal molecules, including α-defensins and lysozyme. The secretion of antimicrobials by Paneth cells is thought to be important in mucosal host defense against invasion by enteric pathogens. We explored whether enteric pathogens can interfere with this arm of defense. We found that oral inoculation of mice with wild-type Salmonella enterica serovar Typhimurium decreases the expression of α-defensins (called cryptdins in mice) and lysozyme. Oral inoculation with Salmonella serovar Typhimurium strains that are heat killed, lack the PhoP regulon, and lack the SPI1 type III secretion system or with Listeria monocytogenes does not have this effect. Salmonella may gain a specific survival advantage in the intestinal lumen by decreasing the expression of microbicidal peptides in Paneth cells through direct interactions between Salmonella and the small intestinal epithelium.

scholarly journals Expansion of Paneth Cell Population in Response to Enteric Salmonella enterica Serovar Typhimurium Infection

2011 ◽  
Vol 80 (1) ◽  
pp. 266-275 ◽  
Author(s):  
Nadine R. Martinez Rodriguez ◽  
Marjannie D. Eloi ◽  
Alexandria Huynh ◽  
Teresa Dominguez ◽  
Annie H. Cheung Lam ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Population ◽  
Salmonella Enterica ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Differentiation Markers ◽  
Gastrointestinal Infections ◽  
Content Type ◽  
Serovar Typhimurium ◽  
Small Intestinal

ABSTRACTPaneth cells residing at the base of the small intestinal crypts contribute to the mucosal intestinal first line defense by secreting granules filled with antimicrobial polypeptides including lysozyme. These cells derive from the columnar intestinal stem cell located at position 0 and the transit amplifying cell located at position +4 in the crypts. We have previously shown thatSalmonella entericaserovar Typhimurium (ST), a leading cause of gastrointestinal infections in humans, effects an overall reduction of lysozyme in the small intestine. To extend this work, we examined small-intestinal tissue sections at various time points after ST infection to quantify and localize expression of lysozyme and assess Paneth cell abundance, apoptosis, and the expression of Paneth cell differentiation markers. In response to infection with ST, the intestinal Paneth cell-specific lysozyme content, the number of lysozyme-positive Paneth cells, and the number of granules per Paneth cell decreased. However, this was accompanied by increases in the total number of Paneth cells and the frequency of mitotic events in crypts, by increased staining for the proliferation marker PCNA, primarily at the crypt side walls where the transit amplifying cell resides and not at the crypt base, and by apoptotic events in villi. Furthermore, we found a time-dependent upregulation of first β-catenin, followed by EphB3, and lastly Sox9 in response to ST, which was not observed after infection with aSalmonellapathogenicity island 1 mutant deficient in type III secretion. Our data strongly suggest that, in response to ST infection, a Paneth cell differentiation program is initiated that leads to an expansion of the Paneth cell population and that the transit amplifying cell is likely the main progenitor responder. Infection-induced expansion of the Paneth cell population may represent an acute intestinal inflammatory response similar to neutrophilia in systemic infection.

scholarly journals IL-22 receptor signaling in Paneth cells is critical for their maturation, microbiota colonization, Th17-related immune responses, and anti-Salmonella immunity

2020 ◽  
Author(s):  
Stephen J. Gaudino ◽  
Michael Beaupre ◽  
Xun Lin ◽  
Preet Joshi ◽  
Sonika Rathi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Host Defense ◽  
Knockout Mice ◽  
Paneth Cell ◽  
Cell Types ◽  
Paneth Cells ◽  
Lineage Tracing ◽  
Interleukin 22 ◽  
Serovar Typhimurium ◽  
Small Intestinal

Abstract Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1fl/fl;Lgr5-EGFP-creERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5+ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

scholarly journals Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn’s disease model mice

2020 ◽  
Vol 3 (6) ◽  
pp. e201900592
Author(s):  
Yu Shimizu ◽  
Kiminori Nakamura ◽  
Aki Yoshii ◽  
Yuki Yokoi ◽  
Mani Kikuchi ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Er Stress ◽  
Disease Progression ◽  
Intestinal Microbiota ◽  
Disulfide Bonds ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Intestinal Lumen ◽  
Reduced Form

Crohn’s disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

scholarly journals Paneth Cell Cryptdins Actin Vitroas Apical Paracrine Regulators of the Innate Inflammatory Response

2004 ◽  
Vol 279 (19) ◽  
pp. 19902-19907 ◽  
Author(s):  
Patricia W. Lin ◽  
Peter O. Simon ◽  
Andrew T. Gewirtz ◽  
Andrew S. Neish ◽  
Andre J. Ouellette ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Cell Membranes ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Mitogen Activated Protein Kinase ◽  
Microbial Pathogens ◽  
Intestinal Lumen ◽  
Intestinal Cell ◽  
Cell Physiology ◽  
Dependent Manner

Intestinal-specific antimicrobial α-defensins, termed cryptdins, are secreted into the intestinal lumen by mouse Paneth cells in response to microbial pathogens. Cryptdins kill microbes by forming pores in their limiting membranes. The cryptdin isoforms 2 and 3 also can form anion-conductive pores in eukaryotic cell membranes, thus affecting cell physiology. Here, we find that when applied to apical membranes of the human intestinal cell line T84, cryptdin 3 (Cr3) induces secretion of the proinflammatory cytokine interleukin 8 (IL-8) in a dose-dependent manner. The induction of IL-8 secretion is specific to the cryptdins that form channels in mammalian cell membranes because cryptdin 4, which does not form pores in T84 cells, does not induce IL-8 secretion. Cr3 induces inflammatory cytokine secretion by activating NF-κB and p38 mitogen-activated protein kinase in a Ca2+-dependent manner, but influx by extra-cellular Ca2+is not involved. Unlike other known inflammatory agonists, signal transduction by Cr3 occurs slowly, suggesting a novel mechanism of action. These results show that selective cryptdins may amplify their roles in innate immunity by acting as novel paracrine agonists to coordinate an inflammatory response with the antimicrobial secretions of Paneth cells.

scholarly journals Regional variations in Paneth cell antimicrobial peptide expression along the mouse intestinal tract

2008 ◽  
Vol 9 (1) ◽  
pp. 37 ◽  
Author(s):  
Jenny Karlsson ◽  
Katrin Pütsep ◽  
Hiutung Chu ◽  
Robert J Kays ◽  
Charles L Bevins ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Intestinal Tract ◽  
Paneth Cell ◽  
Regional Variations ◽  
Peptide Expression ◽  
Antimicrobial Peptide Expression

scholarly journals Norepinephrine released by intestinal Paneth cells exacerbates ischemic AKI

2020 ◽  
Vol 318 (1) ◽  
pp. F260-F272 ◽  
Author(s):  
Sang Jun Han ◽  
Mihwa Kim ◽  
Vivette Denise D’Agati ◽  
H. Thomas Lee
Keyword(s):  
Tyrosine Hydroxylase ◽  
Systemic Inflammation ◽  
Critical Role ◽  
Paneth Cell ◽  
Protein A ◽  
Kidney Injury ◽  
Paneth Cells ◽  
Plasma Norepinephrine ◽  
Norepinephrine Release ◽  
Small Intestinal

Small intestinal Paneth cells play a critical role in acute kidney injury (AKI) and remote organ dysfunction by synthesizing and releasing IL-17A. In addition, intestine-derived norepinephrine is a major mediator of hepatic injury and systemic inflammation in sepsis. We tested the hypothesis that small intestinal Paneth cells synthesize and release norepinephrine to exacerbate ischemic AKI. After ischemic AKI, we demonstrated larger increases in portal venous norepinephrine levels compared with plasma norepinephrine in mice, consistent with an intestinal source of norepinephrine release after renal ischemia and reperfusion. We demonstrated that murine small intestinal Paneth cells express tyrosine hydroxylase mRNA and protein, a critical rate-limiting enzyme for the synthesis of norepinephrine. We also demonstrated mRNA expression for tyrosine hydroxylase in human small intestinal Paneth cells. Moreover, freshly isolated small intestinal crypts expressed significantly higher norepinephrine levels after ischemic AKI compared with sham-operated mice. Suggesting a critical role of IL-17A in Paneth cell-mediated release of norepinephrine, recombinant IL-17A induced norepinephrine release in the small intestine of mice. Furthermore, mice deficient in Paneth cells (SOX9 villin Cre mice) have reduced plasma norepinephrine levels after ischemic AKI. Finally, supporting a critical role for norepinephrine in generating ischemic AKI, treatment with the selective α-adrenergic antagonists yohimbine and phentolamine protected against murine ischemic AKI with significantly reduced renal tubular necrosis, inflammation, and apoptosis and less hepatic dysfunction. Taken together, we identify Paneth cells as a critical source of norepinephrine release that may lead to intestinal and liver injury and systemic inflammation after AKI.

scholarly journals Butyric Acid and Leucine Induce α-Defensin Secretion from Small Intestinal Paneth Cells

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2817 ◽  
Author(s):  
Akiko Takakuwa ◽  
Kiminori Nakamura ◽  
Mani Kikuchi ◽  
Rina Sugimoto ◽  
Shuya Ohira ◽  
...  
Keyword(s):  
Butyric Acid ◽  
Pathogenic Bacteria ◽  
Ex Vivo ◽  
Paneth Cell ◽  
Paneth Cells ◽  
Short Chain ◽  
Immune Functions ◽  
Cell Secretion ◽  
Small Intestinal ◽  
Granule Secretion

The intestine not only plays a role in fundamental processes in digestion and nutrient absorption, but it also has a role in eliminating ingested pathogenic bacteria and viruses. Paneth cells, which reside at the base of small intestinal crypts, secrete α-defensins and contribute to enteric innate immunity through potent microbicidal activities. However, the relationship between food factors and the innate immune functions of Paneth cells remains unknown. Here, we examined whether short-chain fatty acids and amino acids induce α-defensin secretion from Paneth cells in the isolated crypts of small intestine. Butyric acid and leucine elicit α-defensin secretion by Paneth cells, which kills Salmonella typhimurium. We further measured Paneth cell secretion in response to butyric acid and leucine using enteroids, a three-dimensional ex vivo culture system of small intestinal epithelial cells. Paneth cells expressed short-chain fatty acid receptors, Gpr41, Gpr43, and Gpr109a mRNAs for butyric acid, and amino acid transporter Slc7a8 mRNA for leucine. Antagonists of Gpr41 and Slc7a8 inhibited granule secretion by Paneth cells, indicating that these receptor and transporter on Paneth cells induce granule secretion. Our findings suggest that Paneth cells may contribute to intestinal homeostasis by secreting α-defensins in response to certain nutrients or metabolites.

scholarly journals Acetylcholine-producing T cells in the intestine regulate antimicrobial peptide expression and microbial diversity

2016 ◽  
Vol 311 (5) ◽  
pp. G920-G933 ◽  
Author(s):  
Shobhit Dhawan ◽  
Giada De Palma ◽  
Rose A. Willemze ◽  
Francisca W. Hilbers ◽  
Caroline Verseijden ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Adrenergic Receptor ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Receptor Activation ◽  
Intestinal Lumen ◽  
Peptide Expression ◽  
Green Fluorescent ◽  
Antimicrobial Peptide Expression

The cholinergic anti-inflammatory pathway reduces systemic tumor necrosis factor (TNF) via acetylcholine-producing memory T cells in the spleen. These choline acetyltransferase (ChAT)-expressing T cells are also found in the intestine, where their function is unclear. We aimed to characterize these cells in mouse and human intestine and delineate their function. We made use of the ChAT-enhanced green fluorescent protein (eGFP) reporter mice. CD4Cremice were crossed to ChATfl/flmice to achieve specific deletion of ChAT in CD4+T cells. We observed that the majority of ChAT-expressing T cells in the human and mouse intestine have characteristics of Th17 cells and coexpress IL17A, IL22, and RORC. The generation of ChAT-expressing T cells was skewed by dendritic cells after activation of their adrenergic receptor β2. To evaluate ChAT T cell function, we generated CD4-specific ChAT-deficient mice. CD4ChAT−/−mice showed a reduced level of epithelial antimicrobial peptides lysozyme, defensin A, and ang4, which was associated with an enhanced bacterial diversity and richness in the small intestinal lumen in CD4ChAT−/−mice. We conclude that ChAT-expressing T cells in the gut are stimulated by adrenergic receptor activation on dendritic cells. ChAT-expressing T cells may function to mediate the host AMP secretion, microbial growth and expansion.

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