The Role of the Intestinal Epithelium in the “Weep and Sweep” Response during Gastro—Intestinal Helminth Infections

Helminths are metazoan parasites infecting around 1.5 billion people all over the world. During coevolution with hosts, worms have developed numerous ways to trick and evade the host immune response, and because of their size, they cannot be internalized and killed by immune cells in the same way as bacteria or viruses. During infection, a substantial Th2 component to the immune response is evoked which helps restrain Th1-mediated tissue damage. Although an enhanced Th2 response is often not enough to kill the parasite and terminate an infection in itself, when tightly coordinated with the nervous, endocrine, and motor systems it can dislodge parasites from tissues and expel them from the gut. A significant role in this “weep and seep” response is attributed to intestinal epithelial cells (IEC). This review highlights the role of various IEC lineages (enterocytes, tuft cells, Paneth cells, microfold cells, goblet cells, and intestine stem cells) during the course of helminth infections and summarizes their roles in regulating gut architecture and permeability, and muscle contractions and interactions with the immune and nervous system.

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Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses

Parasites & Vectors ◽

10.1186/s13071-020-04467-7 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

María Álvarez-Izquierdo ◽

Miguel Pérez-Crespo ◽

J. Guillermo Esteban ◽

Carla Muñoz-Antoli ◽

Rafael Toledo

Keyword(s):

Immune Response ◽

Secondary Infection ◽

Alternative Activation ◽

Intestinal Helminth ◽

Th2 Response ◽

Th2 Responses ◽

Resistance To Infection ◽

Interleukin 25

Abstract Background The cytokine interleukin-25 (IL-25) is recognized as the most relevant initiator of protective T helper 2 (Th2) responses in intestinal helminth infections. This cytokine induces resistance against several species of intestinal helminths, including the trematode Echinostoma caproni. E. caproni has been extensively used as an experimental model to study the factors determining resistance to intestinal infections. In the study reported here, we assessed the role of IL-25 in the generation of resistance in mice infected with E. caproni. Methods The factors that determine the production of IL-25 in mice experimentally infected with E. caproni were determined, as were the consequences of IL-25 production in terms of polarization of the immune response and resistance to infection. Results Our results show that the role of IL-25 in the polarization of the immune response differs between the primary and secondary immune responses. IL-25 is required for the development of a Th2 phenotype in primary E. caproni infections, but it can also promote the differentiation to Th2 memory cell subsets that enhance type-2 immunity in memory responses. However, the development of Th2 responses does not induce resistance to infection. The Th2 phenotype does not elicit resistance, and IL-25 is responsible for the resistance regardless of its type-2 cytokine activity and activation of signal transducer and activator of transcription (STAT6). Alternative activation of macrophages induced by IL-25 can be implicated in the resistance to infection. Conclusions In contrast to primary infection, secondary infection elicits a type-2 immune response even in the absence of IL-25 expression. Despite the development of a type-2 response, mice are susceptible to secondary infection associated with the lack of IL-25. Resistance to infection is due to the production of IL-25, which acts autonomously from Th2 response in terms of parasite clearance.

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Protective Effects of Lactoferrin against SARS-CoV-2 Infection In Vitro

Nutrients ◽

10.3390/nu13020328 ◽

2021 ◽

Vol 13 (2) ◽

pp. 328 ◽

Cited By ~ 1

Author(s):

Claudio Salaris ◽

Melania Scarpa ◽

Marina Elli ◽

Alice Bertolini ◽

Simone Guglielmetti ◽

...

Keyword(s):

Immune Response ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Plaque Assay ◽

Immune Response Gene ◽

Intestinal Epithelial ◽

Antiviral Immune Response ◽

Qrt Pcr ◽

Anti Inflammatory

SARS-CoV-2 is a newly emerging virus that currently lacks curative treatments. Lactoferrin (LF) is a naturally occurring non-toxic glycoprotein with broad-spectrum antiviral, immunomodulatory and anti-inflammatory effects. In this study, we assessed the potential of LF in the prevention of SARS-CoV-2 infection in vitro. Antiviral immune response gene expression was analyzed by qRT-PCR in uninfected Caco-2 intestinal epithelial cells treated with LF. An infection assay for SARS-CoV-2 was performed in Caco-2 cells treated or not with LF. SARS-CoV-2 titer was determined by qRT-PCR, plaque assay and immunostaining. Inflammatory and anti-inflammatory cytokine production was determined by qRT-PCR. LF significantly induced the expression of IFNA1, IFNB1, TLR3, TLR7, IRF3, IRF7 and MAVS genes. Furthermore, LF partially inhibited SARS-CoV-2 infection and replication in Caco-2 intestinal epithelial cells. Our in vitro data support LF as an immune modulator of the antiviral immune response with moderate effects against SARS-CoV-2 infection.

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Prevention of Dextran Sulfate Sodium-induced Mouse Colitis by a Fungal Protein Ling Zhi-8 via Promoting the Barrier Function of Intestinal Epithelial Cells

Food & Function ◽

10.1039/d0fo02604b ◽

2021 ◽

Author(s):

Yu-Huan Chen ◽

Jenn-Yeu Shin ◽

Hsiu-Mei Wei ◽

Chi-Chen Lin ◽

Linda Chia-Hui Yu ◽

...

Keyword(s):

Epithelial Cells ◽

Immune Cells ◽

Ganoderma Lucidum ◽

Dextran Sulfate ◽

Dextran Sulfate Sodium ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Fungal Protein ◽

Fungal Immunomodulatory Protein

A fungal immunomodulatory protein Ling Zhi-8 (LZ-8) isolated from Ganoderma lucidum (GL) regulates immune cells and inhibits tumor growth; however, the role of LZ-8 in intestinal epithelial cells (IECs) is...

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Rspo3 regulates the abnormal differentiation of small intestinal epithelial cells in diabetic state

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02385-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ti-Dong Shan ◽

Han Yue ◽

Xue-Guo Sun ◽

Yue-Ping Jiang ◽

Li Chen

Keyword(s):

Epithelial Cells ◽

Bioinformatics Analysis ◽

Intestinal Epithelial Cells ◽

Underlying Mechanism ◽

Luciferase Reporter ◽

Intestinal Epithelial ◽

Epithelial Stem Cells ◽

Diabetic State ◽

Definitive Evidence

Abstract Background The complications caused by diabetes mellitus (DM) are the focus of clinical treatment. However, little is known about diabetic enteropathy (DE) and its potential underlying mechanism. Methods Intestinal epithelial cells (IECs) and intestinal epithelial stem cells (IESCs) were harvested from BKS.Cg-Dock7m+/+Leprdb/JNju (DM) mice, and the expression of R-Spondin 3 (Rspo3) was detected by RT-qPCR, Western blotting, immunohistochemistry, and immunofluorescence. The role of Rspo3 in the abnormal differentiation of IECs during DM was confirmed by knockdown experiments. Through miRNA expression profiling, bioinformatics analysis, and RT-qPCR, we further analyzed the differentiation-related miRNAs in the IECs from mice with DM. Results Abnormal differentiation of IECs was observed in the mice with DM. The expression of Rspo3 was upregulated in the IECs from the mice with DM. This phenomenon was associated with Rspo3 overexpression. Additionally, Rspo3 is a major determinant of Lgr5+ stem cell identity in the diabetic state. Microarray analysis, bioinformatics analysis, and luciferase reporter assays revealed that microRNA (miR)-380-5p directly targeted Rspo3. Moreover, miR-380-5p upregulation was observed to attenuate the abnormal differentiation of IECs by regulating Rspo3 expression. Conclusions Together, our results provide definitive evidence of the essential role of Rspo3 in the differentiation of IECs in DM.

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Protective role of berberine on ulcerative colitis through modulating enteric glial cells–intestinal epithelial cells–immune cells interactions

Acta Pharmaceutica Sinica B ◽

10.1016/j.apsb.2019.08.006 ◽

2020 ◽

Vol 10 (3) ◽

pp. 447-461 ◽

Cited By ~ 10

Author(s):

Heng Li ◽

Chen Fan ◽

Huimin Lu ◽

Chunlan Feng ◽

Peilan He ◽

...

Keyword(s):

Ulcerative Colitis ◽

Epithelial Cells ◽

Glial Cells ◽

Immune Cells ◽

Intestinal Epithelial Cells ◽

Protective Role ◽

Intestinal Epithelial ◽

Enteric Glial Cells

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Cholera Toxin Destabilizes Retromer to Inhibit NA + /H + Exchanger3 Activity in Intestinal Epithelial Cells- Possible Therapeutic Role of a Retromer Stabilizer in Treating Diarrhea

Gastroenterology ◽

10.1016/s0016-5085(17)30577-2 ◽

2017 ◽

Vol 152 (5) ◽

pp. S67

Author(s):

Varsha Singh ◽

Jianbo Yang ◽

Jianyi Yin ◽

Ming Tse ◽

Nicholas C. Zachos ◽

...

Keyword(s):

Epithelial Cells ◽

Cholera Toxin ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Therapeutic Role

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Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance

Journal of Leukocyte Biology ◽

10.1189/jlb.1ru0716-327r ◽

2016 ◽

Vol 101 (2) ◽

pp. 377-394 ◽

Cited By ~ 20

Author(s):

Neeraja Kulkarni ◽

Manisha Pathak ◽

Girdhari Lal

Keyword(s):

Epithelial Cells ◽

Chemokine Receptors ◽

Intestinal Epithelial Cells ◽

Mucosal Inflammation ◽

Intestinal Epithelial

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Expression of lysophosphatidic acid receptor 5 is necessary for the regulation of intestinal Na+/H+ exchanger 3 by lysophosphatidic acid in vivo

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00130.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G433-G442 ◽

Cited By ~ 3

Author(s):

Kayte A. Jenkin ◽

Peijian He ◽

C. Chris Yun

Keyword(s):

Epithelial Cells ◽

Lysophosphatidic Acid ◽

Direct Evidence ◽

Intestinal Epithelial Cells ◽

Regulatory Role ◽

Intestinal Epithelial ◽

Fluid Absorption ◽

Wild Type

Lysophosphatidic acid (LPA) is a bioactive lipid molecule, which regulates a broad range of pathophysiological processes. Recent studies have demonstrated that LPA modulates electrolyte flux in the intestine, and its potential as an antidiarrheal agent has been suggested. Of six LPA receptors, LPA5 is highly expressed in the intestine. Recent studies by our group have demonstrated activation of Na+/H+ exchanger 3 (NHE3) by LPA5. However, much of what has been elucidated was achieved using colonic cell lines that were transfected to express LPA5. In the current study, we engineered a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC, and investigated the role of LPA5 in NHE3 regulation and fluid absorption in vivo. The intestine of Lpar5ΔIEC mice appeared morphologically normal, and the stool frequency and fecal water content were unchanged compared with wild-type mice. Basal rates of NHE3 activity and fluid absorption and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5. NHE3 activation involves trafficking of NHE3 from the terminal web to microvilli, and this mobilization of NHE3 by LPA was abolished in Lpar5ΔIEC mice. Dysregulation of NHE3 was specific to LPA, and insulin and cholera toxin were able to stimulate and inhibit NHE3, respectively, in both wild-type and Lpar5ΔIEC mice. The current study for the first time demonstrates the necessity of LPA5 in LPA-mediated stimulation of NHE3 in vivo. NEW & NOTEWORTHY This study is the first to assess the role of LPA5 in NHE3 regulation and fluid absorption in vivo using a mouse that lacks LPA5 in intestinal epithelial cells, Lpar5ΔIEC. Basal rates of NHE3 activity and fluid absorption, and total NHE3 expression were not changed in Lpar5ΔIEC mice. However, LPA did not activate NHE3 activity or fluid absorption in Lpar5ΔIEC mice, providing direct evidence for the regulatory role of LPA5.

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Functional coupling of the downregulated in adenoma Cl−/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.90350.2008 ◽

2009 ◽

Vol 296 (2) ◽

pp. G202-G210 ◽

Cited By ~ 44

Author(s):

Mark W. Musch ◽

Donna L. Arvans ◽

Gary D. Wu ◽

Eugene B. Chang

Keyword(s):

Carbonic Anhydrase ◽

Brush Border ◽

Brush Border Membrane ◽

Intestinal Epithelial Cells ◽

Functional Coupling ◽

Intestinal Epithelial ◽

Colon Cells ◽

Base Exchange ◽

Synaptotagmin I

Non-nutrient-dependent salt absorption across the brush-border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na+/H+ (aNHE) and anion exchange transport, with the latter suspected of being mediated by DRA (downregulated in adenoma; SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine whether DRA and NHE activities can be coupled, we measured 22Na+ and 36Cl− uptake in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms NHE2 and NHE3, increased 36Cl− uptake was observed. Inhibition of DRA activity by niflumic acid was greater than that by DIDS as well as by the NHE inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl−/base exchange and apical NHE.

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