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 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 STING Signaling Promotes Apoptosis, Necrosis, and Cell Death: An Overview and Update

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
Song Liu ◽  
Wenxian Guan
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Tumor Immunity ◽  
Host Defense ◽  
Cell Types ◽  
Immune Homeostasis ◽  
Induce Cell Death ◽  
Distinct Cell ◽  
Clinical Strategies ◽  
Apoptosis And Necrosis

STING is a newly identified intracellular sensor of foreign and endogenous DNA. STING has been recognized as an activator of immune responses by TBK1/IRF3 and NF-κB pathways, and it is suggested to play critical roles in host defense, autoimmune diseases, and tumor immunity. Recent studies have revealed that the outcome of STING activation could vary between distinct cell types and scenarios. STING activation in certain cell types triggered cell death including apoptosis and necrosis. This effect could be critical for preventing unnecessary or excessive inflammatory events and maintaining host immune homeostasis. This review is dedicated to summarize recent evidences in the field of STING-mediated cell death and to demonstrate dual outcomes of STING signaling. Besides canonical immune responses represented by IFN and TNF productions, STING signaling can also induce cell death events in a variety of cell types. The double-faced characteristics of STING signaling requires further exploration and precious regulation before tailoring clinical strategies for associated diseases.

scholarly journals Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells

2017 ◽  
Vol 312 (6) ◽  
pp. G592-G605 ◽  
Author(s):  
Kunihiro Kishida ◽  
Sarah C. Pearce ◽  
Shiyan Yu ◽  
Nan Gao ◽  
Ronaldo P. Ferraris
Keyword(s):  
Stem Cells ◽  
Cell Types ◽  
Paneth Cells ◽  
Nutrient Sensing ◽  
Intestinal Stem Cells ◽  
Intestinal Cell ◽  
Cell Type ◽  
Extended Lifespan ◽  
Small Intestinal ◽  
Single Cell Type

Nutrient sensing triggers responses by the gut-brain axis modulating hormone release, feeding behavior and metabolism that become dysregulated in metabolic syndrome and some cancers. Except for absorptive enterocytes and secretory enteroendocrine cells, the ability of many intestinal cell types to sense nutrients is still unknown; hence we hypothesized that progenitor stem cells (intestinal stem cells, ISC) possess nutrient sensing ability inherited by progenies during differentiation. We directed via modulators of Wnt and Notch signaling differentiation of precursor mouse intestinal crypts into specialized organoids each containing ISC, enterocyte, goblet, or Paneth cells at relative proportions much higher than in situ as determined by mRNA expression and immunocytochemistry of cell type biomarkers. We identified nutrient sensing cell type(s) by increased expression of fructolytic genes in response to a fructose challenge. Organoids comprised primarily of enterocytes, Paneth, or goblet, but not ISC, cells responded specifically to fructose without affecting nonfructolytic genes. Sensing was independent of Wnt and Notch modulators and of glucose concentrations in the medium but required fructose absorption and metabolism. More mature enterocyte- and goblet-enriched organoids exhibited stronger fructose responses. Remarkably, enterocyte organoids, upon forced dedifferentiation to reacquire ISC characteristics, exhibited a markedly extended lifespan and retained fructose sensing ability, mimicking responses of some dedifferentiated cancer cells. Using an innovative approach, we discovered that nutrient sensing is likely repressed in progenitor ISCs then irreversibly derepressed during specification into sensing-competent absorptive or secretory lineages, the surprising capacity of Paneth and goblet cells to detect fructose, and the important role of differentiation in modulating nutrient sensing. NEW & NOTEWORTHY Small intestinal stem cells differentiate into several cell types transiently populating the villi. We used specialized organoid cultures each comprised of a single cell type to demonstrate that 1) differentiation seems required for nutrient sensing, 2) secretory goblet and Paneth cells along with enterocytes sense fructose, suggesting that sensing is acquired after differentiation is triggered but before divergence between absorptive and secretory lineages, and 3) forcibly dedifferentiated enterocytes exhibit fructose sensing and lifespan extension.

scholarly journals Constitutive STAT5 activation regulates Paneth and Paneth-like cells to control Clostridium difficile colitis

2019 ◽  
Vol 2 (2) ◽  
pp. e201900296 ◽  
Author(s):  
Ruixue Liu ◽  
Richard Moriggl ◽  
Dongsheng Zhang ◽  
Haifeng Li ◽  
Rebekah Karns ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Cell Fate ◽  
Intestinal Inflammation ◽  
Paneth Cell ◽  
Cell Lineage ◽  
Niche Differentiation ◽  
Paneth Cells ◽  
Lineage Tracing ◽  
Intestinal Epithelial ◽  
Clostridium Difficile Colitis

Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile, Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5+Lgr5−CD24+Lyso+ or cKit+ niche cells, which imprinted Lgr5hiKi67+ IESCs. Mechanistically, pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration.

scholarly journals Entamoeba histolyticaAlters Ileal Paneth Cell Functions in Intact and Muc2 Mucin Deficiency

2018 ◽  
Vol 86 (7) ◽  
pp. e00208-18 ◽  
Author(s):  
Eduardo R. Cobo ◽  
Ravi Holani ◽  
France Moreau ◽  
Kiminori Nakamura ◽  
Tokiyoshi Ayabe ◽  
...  
Keyword(s):  
Entamoeba Histolytica ◽  
Host Defense ◽  
Cysteine Proteinase ◽  
Paneth Cell ◽  
Active Form ◽  
Paneth Cells ◽  
Content Type ◽  
Cell Functions ◽  
Pathogen Invasion ◽  
And Function

ABSTRACTEnteric α-defensins, termed cryptdins (Crps) in mice, and lysozymes secreted by Paneth cells contribute to innate host defense in the ileum. Antimicrobial factors, including lysozymes and β-defensins, are often embedded in luminal glycosylated colonic Muc2 mucin secreted by goblet cells that form the protective mucus layer critical for gut homeostasis and pathogen invasion. In this study, we investigated ileal innate immunity againstEntamoeba histolytica, the causative agent of intestinal amebiasis, by inoculating parasites in closed ileal loops inMuc2+/+andMuc2−/−littermates and quantifying Paneth cell localization (lysozyme expression) and function (Crp secretion). Relative toMuc2+/+littermates,Muc2−/−littermates showed a disorganized mislocalization of Paneth cells that was diffusely distributed, with elevated lysozyme secretion in the crypts and on villi in response toE. histolytica. Inhibition ofE. histolyticaGal/GalNAc lectin (Gal-lectin) binding with exogenous galactose andEntamoeba histolyticacysteine proteinase 5 (EhCP5)-negativeE. histolyticahad no effect on parasite-induced erratic Paneth cell lysozyme synthesis. Although the basal ileal expression ofCrpgenes was unaffected inMuc2−/−mice in response toE. histolytica, there was a robust release of proinflammatory cytokines and Crp peptide secretions in luminal exudates that was also present in the colon. Interestingly,E. histolytica-secreted cysteine proteinases cleaved the proregion of Crp4 but not the active form. These findings define Muc2 mucin as an essential component of ileal barrier function that regulates the localization and function of Paneth cells critical for host defense against microbes.

scholarly journals Multi-omic analysis defines the first microRNA atlas across all small intestinal epithelial lineages and reveals novel markers of almost all major cell types

2021 ◽  
Author(s):  
Michael Shanahan ◽  
Matt Kanke ◽  
Oyebola O. Oyesola ◽  
Yu-Han Hung ◽  
Kieran Koch-Laskowski ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Paneth Cell ◽  
Cell Types ◽  
Small Rna Sequencing ◽  
Cell Type ◽  
Cell Type Specificity ◽  
In Vivo Models ◽  
Small Intestinal ◽  
Host Genes

MicroRNA-mediated regulation is critical for the proper development and function of the small intestinal (SI) epithelium. However, it is not known which microRNAs are expressed in each of the cell types of the SI epithelium. To bridge this important knowledge gap, we performed comprehensive microRNA profiling in all major cell types of the mouse SI epithelium. We used flow cytometry and fluorescence-activated cell sorting with multiple reporter mouse models to isolate intestinal stem cells, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, tuft cells and secretory progenitors. We then subjected these cell populations to small RNA-sequencing. The resulting atlas revealed highly enriched microRNA markers for almost every major cell type (https://sethupathy-lab.shinyapps.io/SI_miRNA/). Several of these lineage-enriched microRNAs (LEMs) were observed to be embedded in annotated host genes. We used chromatin-run-on sequencing to determine which of these LEMs are likely co-transcribed with their host genes. We then performed single-cell RNA-sequencing to define the cell type specificity of the host genes and embedded LEMs. We observed that the two most-enriched microRNAs in secretory progenitors are miR-1224 and miR-672, the latter of which we found is deleted in hominin species. Finally, using several in vivo models, we established that miR-152 is a Paneth cell-specific microRNA.

scholarly journals Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches

2019 ◽  
Author(s):  
A Treveil ◽  
P Sudhakar ◽  
Z J Matthews ◽  
T Wrzesinski ◽  
E J Jones ◽  
...  
Keyword(s):  
Network Analysis ◽  
Goblet Cell ◽  
Paneth Cell ◽  
Cell Types ◽  
Goblet Cells ◽  
Paneth Cells ◽  
Future Application ◽  
Gut Health ◽  
Cell Type ◽  
Cell Type Specific

AbstractThe epithelial lining of the small intestine consists of multiple cell types, including Paneth cells and goblet cells, that work in cohort to maintain gut health. 3D in vitro cultures of human primary epithelial cells, called organoids, have become a key model to study the functions of Paneth cells and goblet cells in normal and diseased conditions. Advances in these models include the ability to skew differentiation to particular lineages, providing a useful tool to study cell type specific function/dysfunction in the context of the epithelium. Here, we use comprehensive profiling of mRNA, microRNA and long non-coding RNA expression to confirm that Paneth cell and goblet cell enrichment of murine small intestinal organoids (enteroids) establishes a physiologically accurate model. We employ network analysis to infer the regulatory landscape altered by skewing differentiation, and using knowledge of cell type specific markers, we predict key regulators of cell type specific functions: Cebpa, Jun, Nr1d1 and Rxra specific to Paneth cells, Gfi1b and Myc specific for goblet cells and Ets1, Nr3c1 and Vdr shared between them. Links identified between these regulators and cellular phenotypes of inflammatory bowel disease (IBD) suggest that global regulatory rewiring during or after differentiation of Paneth cells and goblet cells could contribute to IBD aetiology. Future application of cell type enriched enteroids combined with the presented computational workflow can be used to disentangle multifactorial mechanisms of these cell types and propose regulators whose pharmacological targeting could be advantageous in treating IBD patients with Crohn’s disease or ulcerative colitis.Table of contentsWe demonstrate the application of network biology techniques to increase understanding of intestinal dysbiosis through studying transcriptomics data from Paneth and goblet cell enriched enteroids.

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.

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