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Hada A, Xiao Z. Ligands for Intestinal Intraepithelial T Lymphocytes in Health and Disease. Pathogens 2025; 14:109. [PMID: 40005486 PMCID: PMC11858322 DOI: 10.3390/pathogens14020109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/27/2025] Open
Abstract
The intestinal tract is constantly exposed to a diverse mixture of luminal antigens, such as those derived from commensals, dietary substances, and potential pathogens. It also serves as a primary route of entry for pathogens. At the forefront of this intestinal defense is a single layer of epithelial cells that forms a critical barrier between the gastrointestinal (GI) lumen and the underlying host tissue. The intestinal intraepithelial T lymphocytes (T-IELs), one of the most abundant lymphocyte populations in the body, play a crucial role in actively surveilling and maintaining the integrity of this barrier by tolerating non-harmful factors such as commensal microbiota and dietary components, promoting epithelial turnover and renewal while also defending against pathogens. This immune balance is maintained through interactions between ligands in the GI microenvironment and receptors on T-IELs. This review provides a detailed examination of the ligands present in the intestinal epithelia and the corresponding receptors expressed on T-IELs, including T cell receptors (TCRs) and non-TCRs, as well as how these ligand-receptor interactions influence T-IEL functions under both steady-state and pathological conditions. By understanding these engagements, we aim to shed light on the mechanisms that govern T-IEL activities within the GI microenvironment. This knowledge may help in developing strategies to target GI ligands and modulate T-IEL receptor expression, offering precise approaches for treating intestinal disorders.
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Affiliation(s)
| | - Zhengguo Xiao
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA;
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Guo Y, He J, Li S, Zou S, Zhang H, Yang X, Wang J. Warm and humid environment induces gut microbiota dysbiosis and bacterial translocation leading to inflammatory state and promotes proliferation and biofilm formation of certain bacteria, potentially causing sticky stool. BMC Microbiol 2025; 25:24. [PMID: 39819481 PMCID: PMC11737230 DOI: 10.1186/s12866-024-03730-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/23/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND AND AIMS OF THE STUDY Fluctuations in environmental temperature and humidity significantly affect human physiology and disease manifestation. In the Lingnan region of China, high summer temperatures and humidity often cause symptoms like diminished appetite, sticky tongue coating, sticky stool, unsatisfactory defecation, lethargy, and joint heaviness. These are referred to as "Dampness Syndrome" in Traditional Chinese Medicine (TCM). Thick and greasy tongue fur and sticky feces are characteristic symptoms of "Dampness Syndrome" and serve as crucial diagnostic indicators in TCM for assessing health conditions. However, the specific mechanisms that lead to these symptoms, such as sticky feces and thick and greasy tongue fur, have not been fully elucidated. Understanding these external symptoms is essential, as they reflect internal health status. Warm, humid environments favor microorganism growth, potentially disrupting gut microbiota and bacterial translocation, which could induce an immune-inflammatory response. The primary objective of this study is to explore the potential significant role of immune response products in influencing the proliferation and biofilm formation of gut microbiota, which may subsequently lead to changes in fecal characteristics. METHODS In this study, mice were exposed to a controlled warm and humid environment (25 ± 3 °C with 95% humidity) for 16 days to simulate conditions associated with "Dampness Syndrome." After this period, Huoxiang Zhengqi Water, a traditional remedy, has been administrated for four days. On the one hand saliva and tongue coating samples were also taken from human subjects with "Dampness Syndrome" for microorganism culturing and to assess biofilm formation, on the other hand the co-culture products of a macrophage cell line RAW264.7 and Candida albicans and the effect of tumor necrosis factor-α (TNF-α) were evaluated for their impact on the proliferation and biofilm-forming abilities of different bacterial strains. RESULTS Compared to a control group, the treatment group exhibited significant changes in gut microbiota, including increased biofilm formation, which was mitigated by Huoxiang Zhengqi Water. In the model group, fungal translocation was observed, potentially triggering an inflammatory response. Intraperitoneal injections of various bacterial strains in mice reproduced the sticky stool characteristics. Both mice and human subjects with "Dampness Syndrome" displayed elevated serum levels of inflammatory cytokines TNF-α and interleukin-17 A (IL-17A). Interestingly, Saliva samples from individuals with "Dampness Syndrome" showed elevated TNF-α levels, accompanied by thick and greasy tongue fur. Culturing samples from the tongue coating of individuals in the "Dampness Syndrome" group revealed an increased biofilm formation capability. C. albicans co-cultured with RAW264.7 cells increased TNF-α secretion, and the supernatant promoted pathogenic bacterial proliferation and biofilm formation. TNF-α specifically enhanced biofilm formation in microorganism like C. albicans and Staphylococcus aureus, with minimal effect on beneficial bacteria like Lacticaseibacillus paracasei and Lactiplantibacillus plantarum in the tested conditions. CONCLUSIONS These findings provided new insights into the biological mechanisms of 'Dampness Syndrome' and support the therapeutic role of Huoxiang Zhengqi Water in treating symptoms associated with microbial dysbiosis and inflammation. Additionally, they indicate that TNF-α seems to have selective effects in promoting the proliferation and biofilm formation of different microbial species.
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Affiliation(s)
- Yinrui Guo
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Jianlang He
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Shaojie Li
- Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai, Guangdong, China
| | - Shiqi Zou
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Haiting Zhang
- The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Xin Yang
- Guangdong Engineering Research Center of Early Clinical Trials of Biotechnology Drugs, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Jian Wang
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
- Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
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Zheng S, Wang Z, Cao X, Wang L, Gao X, Shen Y, Du J, Liu P, Zhuang Y, Guo X. Insights into the effects of chronic combined chromium-nickel exposure on colon damage in mice through transcriptomic analysis and in vitro gastrointestinal digestion assay. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 279:116458. [PMID: 38759536 DOI: 10.1016/j.ecoenv.2024.116458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/25/2024] [Accepted: 05/09/2024] [Indexed: 05/19/2024]
Abstract
Heavy metals interact with each other in a coexisting manner to produce complex combined toxicity to organisms. At present, the toxic effects of chronic co-exposure to heavy metals hexavalent chromium [Cr(VI)] and divalent nickel [Ni(II)] on organisms are seldom studied and the related mechanisms are poorly understood. In this study, we explored the mechanism of the colon injury in mice caused by chronic exposure to Cr or/and Ni. The results showed that, compared with the control group, Cr or/and Ni chronic exposure affected the body weight of mice, and led to infiltration of inflammatory cells in the colon, decreased the number of goblet cells, fusion of intracellular mucus particles and damaged cell structure of intestinal epithelial. In the Cr or/and Ni exposure group, the activity of nitric oxide synthase (iNOS) increased, the expression levels of MUC2 were significantly down-regulated, and those of ZO-1 and Occludin were significantly up-regulated. Interestingly, factorial analysis revealed an interaction between Cr and Ni, which was manifested as antagonistic effects on iNOS activity, ZO-1 and MUC2 mRNA expression levels. Transcriptome sequencing further revealed that the expression of genes-related to inflammation, intestinal mucus and tight junctions changed obviously. Moreover, the relative contents of Cr(VI) and Ni(II) in the Cr, Ni and Cr+Ni groups all changed with in-vitro gastrointestinal （IVG）digestion, especially in the Cr+Ni group. Our results indicated that the chronic exposure to Cr or/and Ni can lead to damage to the mice colon, and the relative content changes of Cr(VI) and Ni(II) might be the main reason for the antagonistic effect of Cr+Ni exposure on the colon damage.
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Affiliation(s)
- Shuangyan Zheng
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China; Sino-German Joint Research Institute, Nanchang University, Nanchang 330047, China; School of Food Science and Technology, Nanchang University, Nanchang 330047, China
| | - Zilong Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xianhong Cao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Luqi Wang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiaona Gao
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yufan Shen
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Jun Du
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Ping Liu
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Yu Zhuang
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China
| | - Xiaoquan Guo
- Jiangxi Provincial Key Laboratory for Animal Health, Institute of Animal Population Health, College of Animal Science and Technology, Jiangxi Agricultural University, Nanchang 330045, China.
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Abo H, Sultana MF, Kawashima H. Dual function of angiogenin-4 inducing intestinal stem cells and apoptosis. Front Cell Dev Biol 2023; 11:1181145. [PMID: 38020881 PMCID: PMC10651741 DOI: 10.3389/fcell.2023.1181145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 10/17/2023] [Indexed: 12/01/2023] Open
Abstract
The intestinal epithelium is the first line of host defense, and its homeostasis is dependent on soluble factors that comprise the crypt niche. Antimicrobial proteins are one of the mediators to maintain gut homeostasis. Angiogenin-4 (Ang4) is a member of the ribonuclease A superfamily and plays a pivotal role in antimicrobial activity against gut microbiota. However, the functions of Ang4 within the intestinal crypt niche, particularly its involvement in the development of intestinal epithelial cells (IECs), remain unknown. Here, we demonstrate that Ang4 plays a significant role in maintaining Lgr5+ intestinal stem cells (ISCs) and induces apoptosis of IECs in a concentration-dependent manner. We revealed that Ang4 is highly expressed by Paneth cells in the small intestine, as well as regenerating islet-derived family member-4 (Reg4) expressing goblet cells in the colon, and both cell subsets highly contribute to ISC maintenance. Functional analysis using intestinal organoids revealed that Ang4 induces Wnt and Notch signaling, increases Lgr5+ stem cell expansion, and promotes organoid growth. Furthermore, high concentrations of Ang4 induced apoptosis in the IEC cell line and organoids. Collectively, we propose that Ang4 is a dual functional protein and is a novel member of the crypt niche factor that promotes the expansion of ISCs and induces apoptosis.
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Affiliation(s)
- Hirohito Abo
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Mst. Farzana Sultana
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Department of Pharmacy, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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Ni S, Yuan X, Cao Q, Chen Y, Peng X, Lin J, Li Y, Ma W, Gao S, Chen D. Gut microbiota regulate migration of lymphocytes from gut to lung. Microb Pathog 2023; 183:106311. [PMID: 37625662 DOI: 10.1016/j.micpath.2023.106311] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/10/2023] [Accepted: 08/18/2023] [Indexed: 08/27/2023]
Abstract
The community of microorganisms known as gut microbiota that lives in the intestine confers significant health benefits on its host, primarily in the form of immunological homeostasis regulation. Gut microbiota not only can shape immune responses in the gut but also in other organs. This review focus on the gut-lung axis. Aberrant gut microbiota development is associated with greater lung disease susceptibility and respiratory disease induced by a variety of pathogenic bacteria. They are known to cause changes in gut microbiota. Recent research has found that immune cells in the intestine migrate to distant lung to exert anti-infective effects. Moreover, evidence indicates that the gut microbiota and their metabolites influence intestinal immune cells. Therefore, we suspect that intestine-derived immune cells may play a significant role against pulmonary pathogenic infections by receiving instructions from gut microbiota.
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Affiliation(s)
- Silu Ni
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Xiulei Yuan
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Qihang Cao
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Yiming Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Xingyu Peng
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Jingyi Lin
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Yanyan Li
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Wentao Ma
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
| | - Shikong Gao
- Shenmu Animal Husbandry Development Center, Shenmu, 719399, Shaanxi, China.
| | - Dekun Chen
- College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, Shaanxi, China.
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Alonso S, Edelblum K. Metabolic regulation of γδ intraepithelial lymphocytes. DISCOVERY IMMUNOLOGY 2023; 2:kyad011. [PMID: 38179241 PMCID: PMC10766425 DOI: 10.1093/discim/kyad011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2024]
Abstract
Elucidating the relationship between cellular metabolism and T cell function has substantially advanced our understanding of how T cells are regulated in response to activation. The metabolic profiles of circulating or peripheral T cells have been well-described, yet less is known regarding how complex local microenvironments shape or modulate the bioenergetic profile of tissue-resident T lymphocytes. Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide immunosurveillance of the intestinal epithelium to limit tissue injury and microbial invasion; however, their activation and effector responses occur independently of antigen recognition. In this review, we will summarize the current knowledge regarding γδ T cell and IEL metabolic profiles and how this informs our understanding of γδ IEL metabolism. We will also discuss the role of the gut microbiota in shaping the metabolic profile of these sentinel lymphocytes, and in turn, how these bioenergetics contribute to regulation of γδ IEL surveillance behavior and effector function. Improved understanding of the metabolic processes involved in γδ IEL homeostasis and function may yield novel strategies to amplify the protective functions of these cells in the context of intestinal health and disease.
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Affiliation(s)
- Sara Alonso
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Karen Edelblum
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Richard N, Savoye G, Leboutte M, Amamou A, Ghosh S, Marion-Letellier R. Crohn’s disease: Why the ileum? World J Gastroenterol 2023; 29:3222-3240. [PMID: 37377591 PMCID: PMC10292140 DOI: 10.3748/wjg.v29.i21.3222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Crohn’s disease (CD) is an inflammatory bowel disease characterized by immune-mediated flares affecting any region of the intestine alternating with remission periods. In CD, the ileum is frequently affected and about one third of patients presents with a pure ileal type. Moreover, the ileal type of CD presents epidemiological specificities like a younger age at onset and often a strong link with smoking and genetic susceptibility genes. Most of these genes are associated with Paneth cell dysfunction, a cell type found in the intestinal crypts of the ileum. Besides, a Western-type diet is associated in epidemiological studies with CD onset and increasing evidence shows that diet can modulate the composition of bile acids and gut microbiota, which in turn modulates the susceptibility of the ileum to inflammation. Thus, the interplay between environmental factors and the histological and anatomical features of the ileum is thought to explain the specific transcriptome profile observed in CD ileitis. Indeed, both immune response and cellular healing processes harbour differences between ileal and non-ileal CD. Taken together, these findings advocate for a dedicated therapeutic approach to managing ileal CD. Currently, interventional pharmacological studies have failed to clearly demonstrate distinct response profiles according to disease site. However, the high rate of stricturing disease in ileal CD requires the identification of new therapeutic targets to significantly change the natural history of this debilitating disease.
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Affiliation(s)
- Nicolas Richard
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Guillaume Savoye
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- CHU Rouen, Department of Gastroenterology, Rouen University Hospital-Charles Nicolle, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Mathilde Leboutte
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
| | - Asma Amamou
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Subrata Ghosh
- APC Microbiome Ireland, Biosciences Building, University College Cork, Cork T12 YT20, Ireland
| | - Rachel Marion-Letellier
- University of Rouen Normandie, INSERM, ADEN UMR 1073, Nutrition, Inflammation and Microbiota-Gut-Brain Axis, Rouen F-76000, France
- Institute for Research and Innovation in Biomedicine, University of Rouen Normandie, Rouen F-76000, France
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Zhang C, Liu H, Sun L, Wang Y, Chen X, Du J, Sjöling Å, Yao J, Wu S. An overview of host-derived molecules that interact with gut microbiota. IMETA 2023; 2:e88. [PMID: 38868433 PMCID: PMC10989792 DOI: 10.1002/imt2.88] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 01/17/2023] [Accepted: 01/21/2023] [Indexed: 06/14/2024]
Abstract
The gut microbiota comprises bacteria, archaea, fungi, protists, and viruses that live together and interact with each other and with host cells. A stable gut microbiota is vital for regulating host metabolism and maintaining body health, while a disturbed microbiota may induce different kinds of disease. In addition, diet is also considered to be the main factor that influences the gut microbiota. The host could shape the gut microbiota through other factors. Here, we reviewed the mechanisms that mediate host regulation on gut microbiota, involved in gut-derived molecules, including gut-derived immune system molecules (secretory immunoglobulin A, antimicrobial peptides, cytokines, cluster of differentiation 4+ effector T cell, and innate lymphoid cells), sources related to gut-derived mucosal molecules (carbon sources, nitrogen sources, oxygen sources, and electron respiratory acceptors), gut-derived exosomal noncoding RNA (ncRNAs) (microRNAs, circular RNA, and long ncRNA), and molecules derived from organs other than the gut (estrogen, androgen, neurohormones, bile acid, and lactic acid). This study provides a systemic overview for understanding the interplay between gut microbiota and host, a comprehensive source for potential ways to manipulate gut microbiota, and a solid foundation for future personalized treatment that utilizes gut microbiota.
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Affiliation(s)
- Chenguang Zhang
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Huifeng Liu
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Lei Sun
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Yue Wang
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Xiaodong Chen
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Juan Du
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Åsa Sjöling
- Centre for Translational Microbiome Research, Department of Microbiology, Tumor and Cell BiologyKarolinska InstitutetStockholmSweden
| | - Junhu Yao
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
| | - Shengru Wu
- College of Animal Science and TechnologyNorthwest A&F UniversityYanglingChina
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Ang1 and Ang4 differentially affect colitis and carcinogenesis in an AOM-DSS mouse model. PLoS One 2023; 18:e0281529. [PMID: 36881568 PMCID: PMC9990929 DOI: 10.1371/journal.pone.0281529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 01/25/2023] [Indexed: 03/08/2023] Open
Abstract
INTRODUCTION Angiogenin-1 (Ang1) and angiogenin-4 (Ang4) are 14-kDa ribonucleases with potent angiogenic and antimicrobial properties. The role of Ang1 and Ang4 in chronic colitis and colitis-associated cancer has not been previously studied. METHODS Wild-type (WT) and angiogenin-1 knock-out (Ang1-KO) C57BL/6 mice were given azoxymethane, a colon carcinogen, 2 days in advance of three cycles of 3.5% dextran sodium sulfate (DSS). Disease activity index (DAI) was recorded, a colonoscopy was performed after each DSS treatment, and mice were euthanized (colitis, recovery, cancer) with tissue evaluated by histopathology. Ang1, Ang4, TNF-α, Il-1F062, IL-6, IL-10, IL-23, IL-33 mRNA levels were analyzed by RT-PCR. RESULTS Ang1-KO mice exhibited more severe colitis compared to WT mice during both the acute (P<0.05) and recovery (P<0.05) phases of each DSS cycle. Consistent with these results, colonic TNF-α, IL1-β, IL-6, IL-10, and IL-33 mRNA levels were significantly upregulated in Ang1-KO mice (P<0.05). While Ang4 increased to similar levels in both WT and Ang1-KO mice during colitis and recovery phases, WT mice were distinguished by a significant upregulation of Ang1. Interestingly, despite the reduced colitis, WT mice developed significantly more tumors compared to Ang1-KO mice (P<0.05). 134 tumors formed in WT mice (4.6 tumors/mouse) while only 46 tumors formed (1.5 tumors/mice) in Ang1-KO mice, which were also characterized by a 34-fold decrease in Ang4 compared to WT mice and the complete absence of Ang1. CONCLUSIONS In a mouse model of colitis-associated cancer, Ang1-KO mice develop more severe colitis, but fewer tumors compared to WT mice. Ang1 levels correlate with the severity of colitis and the development of colitis-associated cancer, while Ang4 was upregulated during both colitis and cancer. Ang1 and Ang4 play important regulatory roles in the response to chronic colitis and the development of colitis-associated cancer and may serve as novel therapeutic targets.
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10
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Sultana MF, Abo H, Kawashima H. Human and mouse angiogenins: Emerging insights and potential opportunities. Front Microbiol 2022; 13:1022945. [PMID: 36466652 PMCID: PMC9714274 DOI: 10.3389/fmicb.2022.1022945] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 11/01/2022] [Indexed: 12/27/2023] Open
Abstract
Angiogenin, a well-known angiogenic factor, is crucial to the angiogenesis in gastrointestinal tumors. Human angiogenin has only one gene, whereas the murine angiogenin family has extended to incorporate six genes. Evolutionary studies have suggested functional variations among murine angiogenin paralogs, even though the three-dimensional structures of angiogenin proteins are remarkably similar. In addition to angiogenesis, the ubiquitous pattern of angiogenin expression suggests a variety of functions, such as tumorigenesis, neuroprotective, antimicrobial activity, and innate immunity. Here, we comprehensively reviewed studies on the structures and functions of human and mouse angiogenins. Understanding the structure and function of angiogenins from a broader perspective could facilitate future research related to development of novel therapeutics on its biological processes, especially in gastrointestinal cancers.
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Affiliation(s)
- Mst. Farzana Sultana
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Department of Pharmacy, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Hirohito Abo
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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Abstract
The ribonuclease A (RNase A) family is one of the best-characterized vertebrate-specific proteins. In humans, eight catalytically active RNases (numbered 1–8) have been identified and have unique tissue distributions. Apart from the digestion of dietary RNA, a broad range of biological actions, including the regulation of intra- or extra-cellular RNA metabolism as well as antiviral, antibacterial, and antifungal activities, neurotoxicity, promotion of cell proliferation, anti-apoptosis, and immunomodulatory abilities, have been recently reported for the members of this family. Based on multiple biological roles, RNases are found to participate in the pathogenic processes of many diseases, such as infection, immune dysfunction, neurodegeneration, cancer, and cardiovascular disorders. This review summarizes the available data on the human RNase A family and illustrates the significant roles of the eight canonical RNases in health and disease, for stimulating further basic research and development of ideas on the potential solutions for disease diagnosis and treatment.
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Affiliation(s)
- Desen Sun
- Department of Gastroenterology, The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang 315020, China,Department of Biochemistry and Molecular Biology, and Zhejiang Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Chenjie Han
- Institute of Environmental Medicine and Affiliated Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China,Undergraduate Program in Public Health, School of Public Health, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Jinghao Sheng
- Institute of Environmental Medicine and Affiliated Hangzhou First People’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China,Corresponding author
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Valdes J, Gagné-Sansfaçon J, Reyes V, Armas A, Marrero G, Moyo-Muamba M, Ramanathan S, Perreault N, Ilangumaran S, Rivard N, Fortier LC, Menendez A. Defects in the expression of colonic host defense factors associate with barrier dysfunction induced by a high-fat/high-cholesterol diet. Anat Rec (Hoboken) 2022; 306:1165-1183. [PMID: 36196983 DOI: 10.1002/ar.25083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 08/25/2022] [Accepted: 09/11/2022] [Indexed: 11/07/2022]
Abstract
The effect of Western diets in the gastrointestinal system is largely mediated by their ability to promote alterations in the immunity and physiology of the intestinal epithelium, and to affect the composition of the commensal microbiota. To investigate the response of the colonic epithelium to high-fat/high-cholesterol diets (HFHCDs), we evaluated the synthesis of host defense factors involved in the maintenance of the colonic homeostasis. C57BL/6 mice were fed an HFHCD for 3 weeks and their colons were evaluated for histopathology, gene expression, and microbiota composition. In addition, intestinal permeability and susceptibility to Citrobacter rodentium were also studied. HFHCD caused colonic hyperplasia, loss of goblet cells, thinning of the mucus layer, moderate changes in the composition of the intestinal microbiota, and an increase in intestinal permeability. Gene expression analyses revealed significant drops in the transcript levels of Muc1, Muc2, Agr2, Atoh1, Spdef, Ang4, Camp, Tff3, Dmbt1, Fcgbp, Saa3, and Retnlb. The goblet cell granules of HFHCD-fed mice were devoid of Relmβ and Tff3, indicating defective production of those two factors critical for intestinal epithelial defense and homeostasis. In correspondence with these defects, colonic bacteria were in close contact with, and invading the epithelium. Fecal shedding of C. rodentium showed an increased bacterial burden in HFHCD-fed animals accompanied by increased epithelial damage. Collectively, our results show that HFHCD perturbs the synthesis of colonic host defense factors, which associate with alterations in the commensal microbiota, the integrity of the intestinal barrier, and the host's susceptibility to enteric infections.
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Affiliation(s)
- Jennifer Valdes
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Jessica Gagné-Sansfaçon
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Vilcy Reyes
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Anny Armas
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Gisela Marrero
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Mitterrand Moyo-Muamba
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Sheela Ramanathan
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Nathalie Perreault
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Subburaj Ilangumaran
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Nathalie Rivard
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Louis-Charles Fortier
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
| | - Alfredo Menendez
- Department of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, Quebec, Canada
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13
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Lei X, Ketelut-Carneiro N, Shmuel-Galia L, Xu W, Wilson R, Vierbuchen T, Chen Y, Reboldi A, Kang J, Edelblum KL, Ward D, Fitzgerald KA. Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules. J Exp Med 2022; 219:e20212563. [PMID: 35792863 PMCID: PMC9263552 DOI: 10.1084/jem.20212563] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 04/11/2022] [Accepted: 06/09/2022] [Indexed: 08/29/2023] Open
Abstract
Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC-IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαβ+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A-BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC-IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.
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Affiliation(s)
- Xuqiu Lei
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Natalia Ketelut-Carneiro
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Liraz Shmuel-Galia
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Weili Xu
- Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ
| | - Ruth Wilson
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Tim Vierbuchen
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Yongzhi Chen
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
| | - Andrea Reboldi
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA
| | - Joonsoo Kang
- Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA
| | - Karen L. Edelblum
- Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ
| | - Doyle Ward
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA
- Center for Microbiome Research, University of Massachusetts Chan Medical School, Worcester, MA
| | - Katherine A. Fitzgerald
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA
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14
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Sultana MF, Suzuki M, Yamasaki F, Kubota W, Takahashi K, Abo H, Kawashima H. Identification of Crucial Amino Acid Residues for Antimicrobial Activity of Angiogenin 4 and Its Modulation of Gut Microbiota in Mice. Front Microbiol 2022; 13:900948. [PMID: 35733962 PMCID: PMC9207454 DOI: 10.3389/fmicb.2022.900948] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/09/2022] [Indexed: 01/15/2023] Open
Abstract
Angiogenin 4 bearing ribonuclease activity is an endogenous antimicrobial protein expressed in small and large intestine. However, the crucial amino acid residues responsible for the antibacterial activity of Ang4 and its impact on gut microbiota remain unknown. Here, we report the contribution of critical amino acid residues in the functional regions of Ang4 to its activity against Salmonella typhimurium LT2 and the effect of Ang4 on gut microbiota in mice. We found that Ang4 binds S. typhimurium LT2 through two consecutive basic amino acid residues, K58 and K59, in the cell-binding segment and disrupts the bacterial membrane integrity at the N-terminal α-helix containing residues K7 and K30, as evidenced by the specific mutations of cationic residues of Ang4. We also found that the RNase activity of Ang4 was not involved in its bactericidal activity, as shown by the H12 mutant, which lacks RNase activity. In vivo administration of Ang4 through the mouse rectum and subsequent bacterial 16S rRNA gene sequencing analyses demonstrated that administration of Ang4 not only increased beneficial bacteria such as Lactobacillus, Akkermansia, Dubosiella, Coriobacteriaceae UCG-002, and Adlercreutzia, but also decreased certain pathogenic bacteria, including Alistipes and Enterohabdus, indicating that Ang4 regulates the shape of gut microbiota composition. We conclude that Ang4 kills bacteria by disrupting bacterial membrane integrity through critical basic amino acid residues with different functionalities rather than overall electrostatic interactions and potentially maintains gut microflora in vivo under physiological and pathophysiological conditions.
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Affiliation(s)
- Mst. Farzana Sultana
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
- Department of Pharmacy, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Maki Suzuki
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Fumiya Yamasaki
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Wataru Kubota
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Kohta Takahashi
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hirohito Abo
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroto Kawashima
- Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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15
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A potent HNF4α agonist reveals that HNF4α controls genes important in inflammatory bowel disease and Paneth cells. PLoS One 2022; 17:e0266066. [PMID: 35385524 PMCID: PMC8985954 DOI: 10.1371/journal.pone.0266066] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 03/11/2022] [Indexed: 11/19/2022] Open
Abstract
HNF4α has been implicated in IBD through a number of genome-wide association studies. Recently, we developed potent HNF4α agonists, including N-trans caffeoyltyramine (NCT). NCT was identified by structural similarity to previously the previously identified but weak HNF4α agonists alverine and benfluorex. Here, we administered NCT to mice fed a high fat diet, with the goal of studying the role of HNF4α in obesity-related diseases. Intestines from NCT-treated mice were examined by RNA-seq to determine the role of HNF4α in that organ. Surprisingly, the major classes of genes altered by HNF4α were involved in IBD and Paneth cell biology. Multiple genes downregulated in IBD were induced by NCT. Paneth cells identified by lysozyme expression were reduced in high fat fed mice. NCT reversed the effect of high fat diet on Paneth cells, with multiple markers being induced, including a number of defensins, which are critical for Paneth cell function and intestinal barrier integrity. NCT upregulated genes that play important role in IBD and that are downregulated in that disease. It reversed the loss of Paneth cell markers that occurred in high fat diet fed mice. These data suggest that HNF4α could be a therapeutic target for IBD and that the agonists that we have identified could be candidate therapeutics.
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16
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Chiang HY, Lu HH, Sudhakar JN, Chen YW, Shih NS, Weng YT, Shui JW. IL-22 initiates an IL-18-dependent epithelial response circuit to enforce intestinal host defence. Nat Commun 2022; 13:874. [PMID: 35169117 PMCID: PMC8847568 DOI: 10.1038/s41467-022-28478-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 01/26/2022] [Indexed: 12/19/2022] Open
Abstract
IL-18 is emerging as an IL-22-induced and epithelium-derived cytokine which contributes to host defence against intestinal infection and inflammation. In contrast to its known role in Goblet cells, regulation of barrier function at the molecular level by IL-18 is much less explored. Here we show that IL-18 is a bona fide IL-22-regulated gate keeper for intestinal epithelial barrier. IL-22 promotes crypt immunity both via induction of phospho-Stat3 binding to the Il-18 gene promoter and via Il-18 independent mechanisms. In organoid culture, while IL-22 primarily increases organoid size and inhibits expression of stem cell genes, IL-18 preferentially promotes organoid budding and induces signature genes of Lgr5+ stem cells via Akt-Tcf4 signalling. During adherent-invasive E. coli (AIEC) infection, systemic administration of IL-18 corrects compromised T-cell IFNγ production and restores Lysozyme+ Paneth cells in Il-22-/- mice, but IL-22 administration fails to restore these parameters in Il-18-/- mice, thereby placing IL-22-Stat3 signalling upstream of the IL-18-mediated barrier defence function. IL-18 in return regulates Stat3-mediated anti-microbial response in Paneth cells, Akt-Tcf4-triggered expansion of Lgr5+ stem cells to facilitate tissue repair, and AIEC clearance by promoting IFNγ+ T cells.
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Affiliation(s)
- Hung-Yu Chiang
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Hsueh-Han Lu
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | | | - Yu-Wen Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
- Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
| | - Nien-Shin Shih
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-Ting Weng
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Jr-Wen Shui
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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17
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Thangamani S, Monasky R, Lee JK, Antharam V, HogenEsch H, Hazbun TR, Jin Y, Gu H, Guo GL. Bile Acid Regulates the Colonization and Dissemination of Candida albicans from the Gastrointestinal Tract by Controlling Host Defense System and Microbiota. J Fungi (Basel) 2021; 7:jof7121030. [PMID: 34947012 PMCID: PMC8708873 DOI: 10.3390/jof7121030] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 11/23/2021] [Accepted: 11/24/2021] [Indexed: 12/12/2022] Open
Abstract
Candida albicans (CA), a commensal and opportunistic eukaryotic organism, frequently inhabits the gastrointestinal (GI) tract and causes life-threatening infections. Antibiotic-induced gut dysbiosis is a major risk factor for increased CA colonization and dissemination from the GI tract. We identified a significant increase of taurocholic acid (TCA), a major bile acid in antibiotic-treated mice susceptible to CA infection. In vivo findings indicate that administration of TCA through drinking water is sufficient to induce colonization and dissemination of CA in wild-type and immunosuppressed mice. Treatment with TCA significantly reduced mRNA expression of immune genes ang4 and Cxcr3 in the colon. In addition, TCA significantly decreased the relative abundance of three culturable species of commensal bacteria, Turicibacter sanguinis, Lactobacillus johnsonii, and Clostridium celatum, in both cecal contents and mucosal scrapings from the colon. Taken together, our results indicate that TCA promotes fungal colonization and dissemination of CA from the GI tract by controlling the host defense system and intestinal microbiota that play a critical role in regulating CA in the intestine.
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Affiliation(s)
- Shankar Thangamani
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA;
- Purdue Institute for Immunology, Inflammation and Infectious Diseases (PI4D), West Lafayette, IN 47906, USA
- College of Veterinary Medicine, Midwestern University, Glendale, AZ 85308, USA; (R.M.); (J.K.L.)
- Correspondence: ; Tel.: +1-765-494-0763
| | - Ross Monasky
- College of Veterinary Medicine, Midwestern University, Glendale, AZ 85308, USA; (R.M.); (J.K.L.)
| | - Jung Keun Lee
- College of Veterinary Medicine, Midwestern University, Glendale, AZ 85308, USA; (R.M.); (J.K.L.)
| | - Vijay Antharam
- Department of Chemistry, College of Arts, Humanities and Sciences, Methodist University, Fayetteville, NC 28311, USA;
| | - Harm HogenEsch
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA;
- Purdue Institute for Immunology, Inflammation and Infectious Diseases (PI4D), West Lafayette, IN 47906, USA
| | - Tony R. Hazbun
- Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47906, USA;
| | - Yan Jin
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA; (Y.J.); (H.G.)
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA; (Y.J.); (H.G.)
- Center for Translational Science, Department of Environmental Health Sciences, Robert Stempel College of Public Health and Social Work, Florida International University, Port St. Lucie, FL 33199, USA
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, Earnest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA;
- Department of Veterans Affairs New Jersey Health Care System, East Orange, NJ 07018, USA
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18
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Toll-Like Receptors as Drug Targets in the Intestinal Epithelium. Handb Exp Pharmacol 2021; 276:291-314. [PMID: 34783909 DOI: 10.1007/164_2021_563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Toll-like receptors (TLRs) receptors are responsible for initiation of inflammatory responses by their recognition of molecular patterns present in invading microorganisms (such as bacteria, viruses or fungi) or in molecules released following tissue damage in disease states. Expressed in the intestinal epithelium, they initiate an intracellular signalling cascade in response to molecular patterns resulting in the activation of transcription factors and the release of cytokines, chemokines and vasoactive molecules. Intestinal epithelial cells are exposed to microorganisms on a daily basis and form part of the primary defence against pathogens by using TLRs. TLRs and their accessory molecules are subject to tight regulation in these cells so as to not overreact or react in unnecessary circumstances. TLRs have more recently been associated with chronic inflammatory diseases as a result of inappropriate regulation, this can be damaging and lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Targeting Toll-like receptors offers a potential therapeutic approach for IBD. In this review, the current knowledge on the TLRs is reviewed along with their association with intestinal diseases. Finally, compounds that target TLRs in animal models of IBD, clinic trials and their future merit as targets are discussed.
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19
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Enterocytes in Food Hypersensitivity Reactions. Animals (Basel) 2021; 11:ani11092713. [PMID: 34573679 PMCID: PMC8466009 DOI: 10.3390/ani11092713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/05/2021] [Accepted: 09/10/2021] [Indexed: 11/18/2022] Open
Abstract
Simple Summary Hypersensitivity to food, affecting both animals and humans, is increasing. Until a decade ago, it was thought that enterocytes, the most abundant constituent of the intestinal surface mucosa layer, served only to absorb digested food and prevent foreign and non-digested substances from passing below the intestinal layer. Growing evidence supports the involvement of enterocytes in immunological responses. Here, we present a comprehensive review of the new roles of enterocytes in food hypersensitivity conducted in animal models in order to better understand complicated immune pathological conditions. In addition, resources for further work in this area are suggested, along with a literature overview of the specific roles of enterocytes in maintaining oral tolerance. Lastly, it will be beneficial to investigate the various animal models involved in food hypersensitivity to reach the needed momentum necessary for the complete and profound understanding of the mechanisms of the ever-growing number of food allergies in animal and human populations. Abstract Food hypersensitivity reactions are adverse reactions to harmless dietary substances, whose causes are hidden within derangements of the complex immune machinery of humans and mammals. Until recently, enterocytes were considered as solely absorptive cells providing a physical barrier for unwanted lumen constituents. This review focuses on the enterocytes, which are the hub for innate and adaptive immune reactions. Furthermore, the ambiguous nature of enterocytes is also reflected in the fact that enterocytes can be considered as antigen-presenting cells since they constitutively express major histocompatibility complex (MHC) class II molecules. Taken together, it becomes clear that enterocytes have an immense role in maintaining oral tolerance to foreign antigens. In general, the immune system and its mechanisms underlying food hypersensitivity are still unknown and the involvement of components belonging to other anatomical systems, such as enterocytes, in these mechanisms make their elucidation even more difficult. The findings from studies with animal models provide us with valuable information about allergic mechanisms in the animal world, while on the other hand, these models are used to extrapolate results to the pathological conditions occurring in humans. There is a constant need for studies that deal with this topic and can overcome the glitches related to ethics in working with animals.
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20
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Nazeer N, Rodriguez-Lecompte JC, Ahmed M. Bacterial-Specific Aggregation and Killing of Immunomodulatory Host Defense Peptides. Pharmaceuticals (Basel) 2021; 14:839. [PMID: 34577539 PMCID: PMC8467575 DOI: 10.3390/ph14090839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 08/06/2021] [Accepted: 08/18/2021] [Indexed: 12/31/2022] Open
Abstract
This study involves the design and development of disulfide bridge-linked antimicrobial peptides using the host defense protein Angiogenin 4 (chAng4) as a template. The mini peptides derived from chAng4 (mCA4s) were evaluated for their antibacterial efficacies in various pathogenic bacterial strains, and the role of the oxidation state of thiols in the peptide sequence and its implication on antibacterial properties were explored. A remarkable property of these synthetic mCA4 peptides is their capability to flocculate bacteria and mediate bacterial-specific killing, in the absence of any other external stimulus. mCA4s were further evaluated for their cellular uptake, hemolytic activities, toxicities, and immunomodulatory activities in different eukaryotic cell lines. The results indicate that disulfide bridge-containing cationic amphipathic peptides show superior antibacterial efficacies, are nontoxic and nonhemolytic, and mediate bacterial flocculation and killing, in the absence of external stimuli.
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Affiliation(s)
- Nauman Nazeer
- Department of Chemistry, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada;
| | - Juan Carlos Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada;
| | - Marya Ahmed
- Department of Chemistry, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada;
- Faculty of Sustainable Design & Engineering, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada
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21
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Nazeer N, Uribe-Diaz S, Rodriguez-Lecompte JC, Ahmed M. Antimicrobial peptides as an alternative to relieve antimicrobial growth promoters in poultry. Br Poult Sci 2021; 62:672-685. [PMID: 33908289 DOI: 10.1080/00071668.2021.1919993] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
1. This review describes different classes of antimicrobial peptides (AMP) found in the gastrointestinal (GI) tract of avian species, and their antimicrobial and immunomodulatory activities. The potential benefits of synthetic AMP in poultry production are examined, in the context of the use of AMP as alternatives to antimicrobial growth promoters (AGP).2. Since the mid-1950s, antibiotic growth promoters (AGP) have been used in feed at low prophylactic doses to modulate the homoeostasis of intestinal microbiota, decreasing the risk of intestinal dysbacteriosis and the growth of pathogens within the avian gut. Over the last three decades, AGP have faced major regulatory restrictions due to concerns of generating antimicrobial resistance (AMR). It is now well documented that the rate of infectious disease outbreaks is higher in flocks that are not fed prophylactic antibiotics, resulting in a compensatory increase in antimicrobial use for therapeutic purposes.3. Endogenous natural AMP production is associated with the presence of microbiota and their interaction with the intestinal epithelial and lamina propria lymphoid cells. Their antimicrobial activity shapes the beneficial microbiota population and controls intestinal pathogens such Clostridium and Salmonella spp., and stimulates the development and maturation of the local immune system.4. Similar to AGP, AMP can establish a well-balanced gut beneficial microbiota for adequate immune-competence, animal health and high growth performance parameters such as feed intake, daily weight, feed conversion and accumulated mortality.5. Antimicrobial proteins and peptides constitute an essential part of the innate immune system of all organisms and protect the host from invading pathogenic bacteria, viruses, fungi, and parasites by interacting with the negatively charged pathogen membranes.
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Affiliation(s)
- N Nazeer
- Department of Chemistry, University of Prince Edward Island, Charlottetown, Canada
| | - S Uribe-Diaz
- Department of Chemistry, University of Prince Edward Island, Charlottetown, Canada.,Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Canada
| | | | - M Ahmed
- Department of Chemistry, University of Prince Edward Island, Charlottetown, Canada
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22
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Cox JR, Cruickshank SM, Saunders AE. Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes. Front Immunol 2021; 12:670471. [PMID: 33936115 PMCID: PMC8079635 DOI: 10.3389/fimmu.2021.670471] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Mucosal surfaces, as a first barrier with the environment are especially susceptible to damage from both pathogens and physical trauma. Thus, these sites require tightly regulated repair programs to maintain barrier function in the face of such insults. Barrier sites are also enriched for unconventional lymphocytes, which lack rearranged antigen receptors or express only a limited range of such receptors, such as ILCs (Innate Lymphoid Cells), γδ T Cells and MAIT (Mucosal-Associated Invariant T Cells). Recent studies have uncovered critical roles for unconventional lymphocytes in regulating mucosal barrier function, and, in particular, have highlighted their important involvement in barrier repair. The production of growth factors such as amphiregulin by ILC2, and fibroblast growth factors by γδ T cells have been shown to promote tissue repair at multiple barrier sites. Additionally, MAIT cells have been shown to exhibit pro-repair phenotypes and demonstrate microbiota-dependent promotion of murine skin healing. In this review we will discuss how immune responses at mucosal sites are controlled by unconventional lymphocytes and the ways in which these cells promote tissue repair to maintain barrier integrity in the skin, gut and lungs.
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Affiliation(s)
- Joshua R Cox
- Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, School of Biological Science, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.,Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Science, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Sheena M Cruickshank
- Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Science, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Amy E Saunders
- Manchester Collaborative Centre for Inflammation Research, Division of Infection, Immunity and Respiratory Medicine, School of Biological Science, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom.,Lydia Becker Institute of Immunology and Inflammation, Division of Infection, Immunity and Respiratory Medicine, School of Biological Science, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
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23
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Sun D, Bai R, Zhou W, Yao Z, Liu Y, Tang S, Ge X, Luo L, Luo C, Hu GF, Sheng J, Xu Z. Angiogenin maintains gut microbe homeostasis by balancing α-Proteobacteria and Lachnospiraceae. Gut 2021; 70:666-676. [PMID: 32843357 PMCID: PMC7904960 DOI: 10.1136/gutjnl-2019-320135] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Revised: 06/18/2020] [Accepted: 07/12/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Antimicrobial peptides (AMPs) play essential roles in maintaining gut health and are associated with IBD. This study is to elucidate the effect of angiogenin (ANG), an intestine-secreted AMP, on gut microbiota and its relevance with IBD. DESIGN The effect of ANG on microbiota and its contribution to colitis were evaluated in different colitis models with co-housing and faecal microbiota transplantation. ANG-regulated bacteria were determined by 16S rDNA sequencing and their functions in colitis were analysed by bacterial colonisation. The species-specific antimicrobial activity of ANG and its underlying mechanism were further investigated with microbiological and biochemical methods. ANG level and the key bacteria were characterised in IBD faecal samples. RESULTS ANG regulated microbiota composition and inhibited intestinal inflammation. Specifically, Ang1 deficiency in mice led to a decrease in the protective gut commensal strains of Lachnospiraceae but an increase in the colitogenic strains of α-Proteobacteria. Direct binding of ANG to α-Proteobacteria resulted in lethal disruption of bacterial membrane integrity, and consequently promoted the growth of Lachnospiraceae, which otherwise was antagonised by α-Proteobacteria. Oral administration of ANG1 reversed the dysbiosis and attenuated the severity of colitis in Ang1-deficient mice. The correlation among ANG, the identified bacteria and IBD status was established in patients. CONCLUSION These findings demonstrate a novel role of ANG in shaping gut microbe composition and thus maintaining gut health, suggesting that the ANG-microbiota axis could be developed as a potential preventive and/or therapeutic approach for dysbiosis-related gut diseases.
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Affiliation(s)
- Desen Sun
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Rongpan Bai
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Zhou
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhengrong Yao
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yaxin Liu
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shasha Tang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiaolong Ge
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Liang Luo
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chi Luo
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Bioelectromagnetics Laboratory, Zhejiang University School of Public Health, Hangzhou, Zhejiang, China
| | - Guo-Fu Hu
- Division of Hematology and Oncology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - Jinghao Sheng
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Bioelectromagnetics Laboratory, Zhejiang University School of Public Health, Hangzhou, Zhejiang, China
| | - Zhengping Xu
- Institute of Environmental Medicine, and Cancer Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems and Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
- Bioelectromagnetics Laboratory, Zhejiang University School of Public Health, Hangzhou, Zhejiang, China
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Ali A, Tan H, Kaiko GE. Role of the Intestinal Epithelium and Its Interaction With the Microbiota in Food Allergy. Front Immunol 2020; 11:604054. [PMID: 33365031 PMCID: PMC7750388 DOI: 10.3389/fimmu.2020.604054] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022] Open
Abstract
The intestinal epithelial tract forms a dynamic lining of the digestive system consisting of a range of epithelial cell sub-types with diverse functions fulfilling specific niches. The intestinal epithelium is more than just a physical barrier regulating nutrient uptake, rather it plays a critical role in homeostasis through its intrinsic innate immune function, pivotal regulation of antigen sensitization, and a bi-directional interplay with the microbiota that evolves with age. In this review we will discuss these functions of the epithelium in the context of food allergy.
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Affiliation(s)
- Ayesha Ali
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - HuiYing Tan
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Gerard E Kaiko
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.,Hunter Medical Research Institute, Newcastle, NSW, Australia
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25
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Fischer MA, Golovchenko NB, Edelblum KL. γδ T cell migration: Separating trafficking from surveillance behaviors at barrier surfaces. Immunol Rev 2020; 298:165-180. [PMID: 32845516 PMCID: PMC7968450 DOI: 10.1111/imr.12915] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/23/2022]
Abstract
γδ T cells are found in highest numbers at barrier surfaces throughout the body, including the skin, intestine, lung, gingiva, and uterus. Under homeostatic conditions, γδ T cells provide immune surveillance of the epidermis, intestinal, and oral mucosa, whereas the presence of pathogenic microorganisms in the dermis or lungs elicits a robust γδ17 response to clear the infection. Although T cell migration is most frequently defined in the context of trafficking, analysis of specific migratory behaviors of lymphocytes within the tissue microenvironment can provide valuable insight into their function. Intravital imaging and computational analyses have been used to define "search" behavior associated with conventional αβ T cells; however, based on the known role of γδ T cells as immune sentinels at barrier surfaces and their TCR-independent functions, we put forth the need to classify distinct migratory patterns that reflect the surveillance capacity of these unconventional lymphocytes. This review will focus on how γδ T cells traffic to various barrier surfaces and how recent investigation into their migratory behavior has provided unique insight into the contribution of γδ T cells to barrier immunity.
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Affiliation(s)
- Matthew A. Fischer
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Natasha B. Golovchenko
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Karen L. Edelblum
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
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26
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Puértolas-Balint F, Schroeder BO. Does an Apple a Day Also Keep the Microbes Away? The Interplay Between Diet, Microbiota, and Host Defense Peptides at the Intestinal Mucosal Barrier. Front Immunol 2020; 11:1164. [PMID: 32655555 PMCID: PMC7325984 DOI: 10.3389/fimmu.2020.01164] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/12/2020] [Indexed: 12/13/2022] Open
Abstract
A crucial mechanism of intestinal defense includes the production and secretion of host defense peptides (HDPs). HDPs control pathogens and commensals at the intestinal interface by direct killing, by sequestering vital ions, or by causing bacterial cells to aggregate in the mucus layer. Accordingly, the combined activity of various HDPs neutralizes gut bacteria before reaching the mucosa and thus helps to maintain the homeostatic balance between the host and its microbes at the mucosal barrier. Defects in the mucosal barrier have been associated with various diseases that are on the rise in the Western world. These include metabolic diseases, such as obesity and type 2 diabetes, and inflammatory intestinal disorders, including ulcerative colitis and Crohn's disease, the two major entities of inflammatory bowel disease. While the etiology of these diseases is multifactorial, highly processed Western-style diet (WSD) that is rich in carbohydrates and fat and low in dietary fiber content, is considered to be a contributing lifestyle factor. As such, WSD does not only profoundly affect the resident microbes in the intestine, but can also directly alter HDP function, thereby potentially contributing to intestinal mucosal barrier dysfunction. In this review we aim to decipher the complex interaction between diet, microbiota, and HDPs. We discuss how HDP expression can be modulated by specific microbes and their metabolites as well as by dietary factors, including fibers, lipids, polyphenols and vitamins. We identify several dietary compounds that lead to reduced HDP function, but also factors that stimulate HDP production in the intestine. Furthermore, we argue that the effect of HDPs against commensal bacteria has been understudied when compared to pathogens, and that local environmental conditions also need to be considered. In addition, we discuss the known molecular mechanisms behind HDP modulation. We believe that a better understanding of the diet-microbiota-HDP interdependence will provide insights into factors underlying modern diseases and will help to identify potential dietary interventions or probiotic supplementation that can promote HDP-mediated intestinal barrier function in the Western gut.
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Affiliation(s)
- Fabiola Puértolas-Balint
- Laboratory for Molecular Infection Medicine Sweden (MIMS) -The Nordic EMBL Partnership for Molecular Medicine, Umeå University, Umeå, Sweden.,Department of Molecular Biology, Umeå University, Umeå, Sweden
| | - Bjoern O Schroeder
- Laboratory for Molecular Infection Medicine Sweden (MIMS) -The Nordic EMBL Partnership for Molecular Medicine, Umeå University, Umeå, Sweden.,Department of Molecular Biology, Umeå University, Umeå, Sweden
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27
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Losada-Medina D, Yitbarek A, Nazeer N, Uribe-Diaz S, Ahmed M, Rodriguez-Lecompte JC. Identification, tissue characterization, and innate immune role of Angiogenin-4 expression in young broiler chickens. Poult Sci 2020; 99:2992-3000. [PMID: 32475434 PMCID: PMC7597696 DOI: 10.1016/j.psj.2020.03.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/21/2020] [Accepted: 03/09/2020] [Indexed: 12/29/2022] Open
Abstract
Intestinal epithelial cells are major producers of antimicrobial proteins, which play an important role in innate immunity. In addition to defensins, the Ribonuclease A superfamily includes important antimicrobial proteins involved in host-defense mechanisms in vertebrates. Angiogenin-4 (Ang4), a member of this RNase superfamily, has been demonstrated to be secreted by Paneth cells in mice. We have successfully cloned and characterized a new chicken gene (chAng4), found for the first time in a nonmammalian species, from intestinal epithelial and lymphoid cells. Characterization of chAng4 revealed 99% nucleotide and 97% amino acid sequence homology to mouse Ang4. Similar functional regions were identified, suggesting a role in innate immunity and regulation of gut microbiota. Furthermore, the mRNA expression pattern of chAng4 was studied in broilers in the presence or absence of beneficial bacteria (probiotics) and organic acids. The results showed that one-day-old chickens expressed low levels of Ang4 in almost all the evaluated tissues (crop, proventriculus, duodenum, jejunum, ileum, and cecal tonsils), except in the bursa of Fabricius that presented the highest expression level. The addition of probiotics and organic acids for either 7 or 14 consecutive days demonstrated a direct effect of probiotics and organic acids on chAng4 expression; moreover, broilers receiving probiotics and organic acids for only 7 D showed higher levels of chAng4 expression compared with those treated for 14 D. Broilers without treatment had a constant high level of expression in cecal tonsils and bursa. In conclusion, we were able to identify and characterize a new antimicrobial gene in chickens (chAng4) throughout the gastrointestinal tract. chAng4 mRNA gene expression was associated with the presence of naturally occurring and supplemented (probiotic) bacteria. The encoded protein might have a potential bactericidal effect against intestinal nonpathogenic and pathogenic microbes, modulating the intestinal microbiota and the innate immunity, and thereby may help minimize the use of antibiotics in poultry feed.
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Affiliation(s)
- Daniela Losada-Medina
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada; Department of Chemistry, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Alexander Yitbarek
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Canada
| | - Nauman Nazeer
- Department of Chemistry, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Santiago Uribe-Diaz
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada; Department of Chemistry, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Marya Ahmed
- Department of Chemistry, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Juan C Rodriguez-Lecompte
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada.
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28
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Wehkamp J, Stange EF. An Update Review on the Paneth Cell as Key to Ileal Crohn's Disease. Front Immunol 2020; 11:646. [PMID: 32351509 PMCID: PMC7174711 DOI: 10.3389/fimmu.2020.00646] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 03/23/2020] [Indexed: 12/12/2022] Open
Abstract
The Paneth cells reside in the small intestine at the bottom of the crypts of Lieberkühn, intermingled with stem cells, and provide a niche for their neighbors by secreting growth and Wnt-factors as well as different antimicrobial peptides including defensins, lysozyme and others. The most abundant are the human Paneth cell α-defensin 5 and 6 that keep the crypt sterile and control the local microbiome. In ileal Crohn's disease various mechanisms including established genetic risk factors contribute to defects in the production and ordered secretion of these peptides. In addition, life-style risk factors for Crohn's disease like tobacco smoking also impact on Paneth cell function. Taken together, current evidence suggest that defective Paneth cells may play the key role in initiating inflammation in ileal, and maybe ileocecal, Crohn's disease by allowing bacterial attachment and invasion.
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Affiliation(s)
- Jan Wehkamp
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
| | - Eduard F Stange
- University of Tübingen, Medizinische Klinik I, Tübingen, Germany
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29
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Gao YL, Shao LH, Dong LH, Chang PY. Gut commensal bacteria, Paneth cells and their relations to radiation enteropathy. World J Stem Cells 2020; 12:188-202. [PMID: 32266051 PMCID: PMC7118286 DOI: 10.4252/wjsc.v12.i3.188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/12/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.
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Affiliation(s)
- Yan-Li Gao
- Department of Pediatric Ultrasound, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hong Shao
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Hua Dong
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Peng-Yu Chang
- Department of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Jilin Provincial Key Laboratory of Radiation Oncology and Therapy, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China.
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30
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Pomegranate peel extract reduced colonic damage and bacterial translocation in a mouse model of infectious colitis induced by Citrobacter rodentium. Nutr Res 2019; 73:27-37. [PMID: 31841745 DOI: 10.1016/j.nutres.2019.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/09/2019] [Accepted: 11/01/2019] [Indexed: 12/15/2022]
Abstract
The pomegranate fruit peel is a rich source of polyphenols including punicalins, punicalagins, and ellagic acids, but is considered an agricultural waste product. Pomegranate derived products have been reported to have a wide variety of health promoting benefits including antibacterial properties in vitro but there is limited evidence of their antibacterial properties in vivo. The purpose of this study was to test the in vivo antibacterial properties of a pomegranate peel extract (PPX) containing punicalin, punicalagin, and ellagic acid. C3H/He mice were orally pre-treated with water or PPX prior to infection with the mouse bacterial pathogen, Citrobacter rodentium (Cr) that mimics many aspects of human enteropathogenic Escherichia coli infections. Fecal excretion of Cr was monitored and mice were euthanized on day 12 post-infection to assess Cr colonization of the colon and spleen, histological changes, and gene expression. PPX-treatment reduced Cr infection induced weight loss and mortality that was observed in water-treated infected mice. However, Cr colonization of the colon and clearance was unaffected by PPX-treatment. Consistent with this, PPX treatment did not alter the potent Th1/Th17 pro-inflammatory response elicited by Cr infection. Significant colonization of the spleen was only seen in water-treated infected mice and was inversely correlated with the dose of PPX administered. PPX treatment decreased the extent of Cr-induced colon damage that correlated with decreased mortality and reduced colonization of the spleen. Thus, a pomegranate peel extract contains bioactive compounds that mitigate the deleterious effects of an in vivo infection with the model enteropathogenic bacteria, Cr.
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31
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Hennessy C, O'Connell S, Egan LJ, McKernan DP. Inhibition of anti-viral responses in intestinal epithelial cells by epigenetic modifying drugs is mediated by a reduction in viral pattern recognition receptor expression and activity. Immunopharmacol Immunotoxicol 2019; 41:527-537. [PMID: 31505962 DOI: 10.1080/08923973.2019.1661430] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 08/18/2019] [Indexed: 12/21/2022]
Abstract
Background: Pattern recognition receptors form an essential part of the host defenses against pathogens, in particular in the intestinal epithelium. However, despite their importance relatively little is understood about the regulation of their expression. Increasing evidence suggesting that epigenetic mechanisms such as DNA methylation and histone acetylation have substantial effects on gene expression and regulation. Epigenetic modifying drugs are now used to treat certain cancers but not a lot is known about their effects on the innate immune system. Thus, we set out to examine the role of such drugs in the expression and function of Toll-like receptors. Methods: Using the HCT116 epithelial cell line, we determined the effects of genetic knockout of the DNA methyltransferases enzymes (DNMTs), as well as pharmacological inhibition of the DNMTs and histone deacetylase complexes (HDACs) on TLR responses to their ligands. Results: Our initial results showed that anti-viral responses were affected by changes in the epigenome, with TLR3 responses showing the most dramatic differences. We determined that inhibition of methylation and acetylation inhibited poly I:C induced increases in signaling protein phosphorylation, as well as increases in cytokine mRNA expression and release. We also observed that treatment with epigenetic modifying drugs were leading to large increases in IRF8 expression, a protein that is a known negative regulator of TLR3. When we overexpressed IRF8 in our WT cells we noticed inhibition of poly I:C responses. Conclusion: This research highlighted the potential immunoregulatory role of epigenetic modifying drugs specifically in response to viral stimulation.
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Affiliation(s)
- Conor Hennessy
- Pharmacology & Therapeutics, School of Medicine, National University of Ireland , Galway , Ireland
| | - Sarah O'Connell
- Pharmacology & Therapeutics, School of Medicine, National University of Ireland , Galway , Ireland
| | - Laurence J Egan
- Pharmacology & Therapeutics, School of Medicine, National University of Ireland , Galway , Ireland
| | - Declan P McKernan
- Pharmacology & Therapeutics, School of Medicine, National University of Ireland , Galway , Ireland
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32
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Chung LK, Raffatellu M. G.I. pros: Antimicrobial defense in the gastrointestinal tract. Semin Cell Dev Biol 2019; 88:129-137. [PMID: 29432952 PMCID: PMC6087682 DOI: 10.1016/j.semcdb.2018.02.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 02/06/2018] [Accepted: 02/06/2018] [Indexed: 01/11/2023]
Abstract
The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota.
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Affiliation(s)
- Lawton K Chung
- Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego, La Jolla, CA, 92093-0704, United States
| | - Manuela Raffatellu
- Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego, La Jolla, CA, 92093-0704, United States; Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla CA, United States.
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33
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Yokoi Y, Nakamura K, Yoneda T, Kikuchi M, Sugimoto R, Shimizu Y, Ayabe T. Paneth cell granule dynamics on secretory responses to bacterial stimuli in enteroids. Sci Rep 2019; 9:2710. [PMID: 30804449 PMCID: PMC6389922 DOI: 10.1038/s41598-019-39610-7] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 01/29/2019] [Indexed: 12/19/2022] Open
Abstract
Paneth cells at the base of small intestinal crypts secrete granules containing α-defensins in response to bacteria and maintain the intestinal environment by clearing enteric pathogens and regulating the composition of the intestinal microbiota. However, Paneth cell secretory responses remain debatable and the mechanisms that regulate the secretion are not well understood. Although enteroids, three-dimensional cultures of small intestinal epithelial cells, have proven useful for analyzing intestinal epithelial cell functions including ion transport, their closed structures have imposed limitations to investigating interactions between Paneth cells and the intestinal microbiota. Here, we report that microinjection of bacteria or lipopolysaccharide (LPS) into the enteroid lumen provides an ex vivo system for studying Paneth cell secretion in real-time. The results show that Paneth cells released granules immediately when the apical surfaces of enteroid epithelial cells were exposed to LPS or live bacteria by microinjection. However, Paneth cells did not respond to LPS delivered in culture media to enteroid exterior basolateral surface, although they responded to basolateral carbamyl choline. In addition, Paneth cells replenished their granules after secretion, enabling responses to second stimulation. These findings provide new insight for apically-induced Paneth cell secretory responses in regulating the intestinal environment.
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Affiliation(s)
- Yuki Yokoi
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Kiminori Nakamura
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan.,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Tsukasa Yoneda
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Mani Kikuchi
- Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Rina Sugimoto
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Yu Shimizu
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan
| | - Tokiyoshi Ayabe
- Innate Immunity Laboratory, Graduate School of Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan. .,Department of Cell Biological Science, Faculty of Advanced Life Science, Hokkaido University, Kita-21, Nishi-11, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan.
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34
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P. McKernan D. Toll-like receptors and immune cell crosstalk in the intestinal epithelium. AIMS ALLERGY AND IMMUNOLOGY 2019. [DOI: 10.3934/allergy.2019.1.13] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Hu MD, Ethridge AD, Lipstein R, Kumar S, Wang Y, Jabri B, Turner JR, Edelblum KL. Epithelial IL-15 Is a Critical Regulator of γδ Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. THE JOURNAL OF IMMUNOLOGY 2018; 201:747-756. [PMID: 29884699 DOI: 10.4049/jimmunol.1701603] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 05/17/2018] [Indexed: 12/17/2022]
Abstract
Intraepithelial lymphocytes (IELs) expressing the γδ TCR (γδ IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to γδ IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of γδ T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for γδ IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates γδ IEL migration into cultured epithelial monolayers, and inhibition of IL-2Rβ significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2Rβ signaling induced γδ IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of γδ T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating γδ T cell localization within the intestinal mucosa and regulating γδ IEL motility and patrolling behavior as a critical component of host defense.
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Affiliation(s)
- Madeleine D Hu
- Department of Pathology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Alexander D Ethridge
- Department of Pathology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Rebecca Lipstein
- Department of Pathology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Sushil Kumar
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Yitang Wang
- Department of Pathology, University of Chicago, Chicago, IL 60637
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, IL 60637
| | - Jerrold R Turner
- Department of Pathology, University of Chicago, Chicago, IL 60637.,Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; and.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Karen L Edelblum
- Department of Pathology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, NJ 07103; .,Department of Pathology, University of Chicago, Chicago, IL 60637
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Al-Barazie RM, Bashir GH, Qureshi MM, Mohamed YA, Al-Sbiei A, Tariq S, Lammers WJ, Al-Ramadi BK, Fernandez-Cabezudo MJ. Cholinergic Activation Enhances Resistance to Oral Salmonella Infection by Modulating Innate Immune Defense Mechanisms at the Intestinal Barrier. Front Immunol 2018; 9:551. [PMID: 29616040 PMCID: PMC5867304 DOI: 10.3389/fimmu.2018.00551] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 03/05/2018] [Indexed: 12/29/2022] Open
Abstract
Inflammation is a crucial defense mechanism that protects the body from the devastating effects of invading pathogens. However, an unrestrained inflammatory reaction may result in systemic manifestations with dire consequences to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. Previously, we demonstrated that cholinergic stimulation confers enhanced protection in experimental animals orally infected with virulent Salmonella enterica serovar Typhimurium. In this study, we investigated the mechanism by which this enhanced protection takes place. Cholinergic stimulation was induced by a 3-week pretreatment with paraoxon, a highly specific acetylcholinesterase (AChE) inhibitor. This treatment enhanced host survival following oral-route infection and this correlated with significantly reduced bacterial load in systemic target organs. Enhanced protection was not due to increased gut motility or rapid bacterial clearance from the gastrointestinal tract. Moreover, protection against bacterial infection was not evident when the animals were infected systemically, suggesting that acetylcholine-mediated protective effect was mostly confined to the gut mucosal tissue. In vivo imaging demonstrated a more localized infection and delay in bacterial dissemination into systemic organs in mice pretreated with paraoxon. Morphological analysis of the small intestine (ileum) showed that AChE inhibition induced the degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrate a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against oral pathogens.
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Affiliation(s)
- Ray M Al-Barazie
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Ghada Hassan Bashir
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Mohammed M Qureshi
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Yassir A Mohamed
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Ashraf Al-Sbiei
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Saeed Tariq
- Department of Anatomy, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Wim J Lammers
- Department of Physiology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Basel K Al-Ramadi
- Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
| | - Maria J Fernandez-Cabezudo
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab University, Al-Ain, United Arab Emirates
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Hu MD, Jia L, Edelblum KL. Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes. CURRENT PATHOBIOLOGY REPORTS 2018; 6:35-46. [PMID: 29755893 PMCID: PMC5943048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
PURPOSE OF REVIEW This review will explore the contribution of IELs to mucosal innate immunity and highlight the similarities in IEL functional responses to bacteria, viruses and protozoan parasite invasion. RECENT FINDINGS IELs rapidly respond to microbial invasion by activating host defense responses, including the production of mucus and antimicrobial peptides to prevent microbes from reaching the epithelial surface. During active infection, IELs promote epithelial cytolysis, cytokine and chemokine production to limit pathogen invasion, replication and dissemination. Commensal-induced priming of IEL effector function or continuous surveillance of the epithelium may be important contributing factors to the rapidity of response. SUMMARY Impaired microbial recognition, dysregulated innate immune signaling or microbial dysbiosis may limit the protective function of IELs and increase susceptibility to disease. Further understanding of the mechanisms regulating IEL surveillance and sentinel function may provide insight into the development of more effective targeted therapies designed to reinforce the mucosal barrier.
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Affiliation(s)
- Madeleine D Hu
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Luo Jia
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Karen L Edelblum
- Center for Immunity and Inflammation, Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
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Pardo-Camacho C, González-Castro AM, Rodiño-Janeiro BK, Pigrau M, Vicario M. Epithelial immunity: priming defensive responses in the intestinal mucosa. Am J Physiol Gastrointest Liver Physiol 2018; 314:G247-G255. [PMID: 29146676 DOI: 10.1152/ajpgi.00215.2016] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
As the largest interface between the outside and internal milieu, the intestinal epithelium constitutes the first structural component facing potential luminal threats to homeostasis. This single-cell layer is the epicenter of a tightly regulated communication network between external and internal factors that converge to prime defensive responses aimed at limiting antigen penetration and the maintenance of intestinal barrier function. The defensive role developed by intestinal epithelial cells (IEC) relies largely on the variety of receptors they express at both extracellular (apical and basolateral) and intracellular compartments, and the capacity of IEC to communicate with immune and nervous systems. IEC recognize pathogen-associated molecules by innate receptors that promote the production of mucus, antimicrobial substances, and immune mediators. Epithelial cells are key to oral tolerance maintenance and also participate in adaptive immunity through the expression of immunoglobulin (Ig) receptors and by promoting local Ig class switch recombination. In IEC, different types of antigens can be sensed by multiple immune receptors that share signaling pathways to assure effective responses. Regulated defensive activity maintains intestinal homeostasis, whereas a breakdown in the control of epithelial immunity can increase the intestinal passage of luminal content and microbial invasion, leading to inflammation and tissue damage. In this review, we provide an updated overview of the type of immune receptors present in the human intestinal epithelium and the responses generated to promote effective barrier function and maintain mucosal homeostasis.
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Affiliation(s)
- Cristina Pardo-Camacho
- Laboratory of Translational Mucosal Immunology, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron , Barcelona , Spain.,Facultat de Medicina, Universitat Autònoma de Barcelona , Barcelona , Spain
| | - Ana M González-Castro
- Laboratory of Translational Mucosal Immunology, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron , Barcelona , Spain.,Facultat de Medicina, Universitat Autònoma de Barcelona , Barcelona , Spain
| | - Bruno K Rodiño-Janeiro
- Laboratory of Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron , Barcelona , Spain.,Facultat de Medicina, Universitat Autònoma de Barcelona , Barcelona , Spain
| | - Marc Pigrau
- Laboratory of Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron , Barcelona , Spain.,Facultat de Medicina, Universitat Autònoma de Barcelona , Barcelona , Spain
| | - María Vicario
- Laboratory of Translational Mucosal Immunology, Digestive Diseases Research Unit, Vall d'Hebron Institut de Recerca , Barcelona , Spain.,Department of Gastroenterology, Hospital Universitari Vall d'Hebron , Barcelona , Spain.,Facultat de Medicina, Universitat Autònoma de Barcelona , Barcelona , Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas , Madrid , Spain
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Policing the Intestinal Epithelial Barrier: Innate Immune Functions of Intraepithelial Lymphocytes. CURRENT PATHOBIOLOGY REPORTS 2018. [DOI: 10.1007/s40139-018-0157-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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40
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Hu MD, Edelblum KL. Sentinels at the frontline: the role of intraepithelial lymphocytes in inflammatory bowel disease. ACTA ACUST UNITED AC 2017; 3:321-334. [PMID: 29242771 DOI: 10.1007/s40495-017-0105-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Purpose of review Intestinal mucosal immunity is tightly regulated to ensure effective host defense against invasive microorganisms while limiting the potential for aberrant damage. In inflammatory bowel disease (IBD), an imbalance between effector and regulatory T cell populations results in an uncontrolled inflammatory response to commensal bacteria. Intraepithelial lymphocytes (IEL) are perfectly positioned within the intestinal epithelium to provide the first line of mucosal defense against luminal microbes or rapidly respond to epithelial injury. This review will highlight how IELs promote protective intestinal immunity and discuss the evidence indicating that altered IEL responses contribute to the pathogenesis of IBD. Recent findings Although the role of IELs in mucosal homeostasis has been largely underappreciated, many of the same factors that contribute to the dysregulation of host defense in IBD also adversely affect IELs. For example, IL-23 and the endoplasmic reticulum stress response can enhance IEL lytic activity toward enterocytes. Microbial dysbiosis or defective microbial recognition results in the loss of regulatory IELs, further amplifying these pro-inflammatory effects. Migration of T cells into or within the intraepithelial compartment has a profound effect on their differentiation or effector function demonstrating that IELs are exquisitely sensitive to changes in the local intestinal microenvironment. Summary Enhanced mechanistic insight into the regulation of IEL survival, differentiation and effector function may provide useful tools to modulate IEL surveillance or enhance IEL regulatory function. Elucidation of these processes may result in the development of novel therapeutics to reduce intestinal inflammation and reinforce the mucosal barrier in IBD.
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Affiliation(s)
- Madeleine D Hu
- Center for Immunity and Inflammation, Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103
| | - Karen L Edelblum
- Center for Immunity and Inflammation, Department of Pathology, Rutgers New Jersey Medical School, Newark, NJ 07103
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Interleukin-17 receptor A (IL-17RA) as a central regulator of the protective immune response against Giardia. Sci Rep 2017; 7:8520. [PMID: 28819174 PMCID: PMC5561107 DOI: 10.1038/s41598-017-08590-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Accepted: 07/12/2017] [Indexed: 12/16/2022] Open
Abstract
The protozoan parasite Giardia is a highly prevalent intestinal pathogen with a wide host range. Data obtained in mice, cattle and humans revealed the importance of IL-17A in the development of a protective immune response against Giardia. The aim of this study was to further unravel the protective effector mechanisms triggered by IL-17A following G. muris infection in mice, by an RNA-sequencing approach. C57BL/6 WT and C57BL/6 IL-17RA KO mice were orally infected with G. muris cysts. Three weeks post infection, intestinal tissue samples were collected for RNA-sequencing, with samples from uninfected C57BL/6 WT and C57BL/6 IL-17RA KO animals serving as negative controls. Differential expression analysis showed that G. muris infection evoked the transcriptional upregulation of a wide array of genes, mainly in animals with competent IL-17RA signaling. IL-17RA signaling induced the production of various antimicrobial peptides, such as angiogenin 4 and α- and β-defensins and regulated complement activation through mannose-binding lectin 2. The expression of the receptor that regulates the secretion of IgA into the intestinal lumen, the polymeric immunoglobulin receptor, was also dependent on IL-17RA signaling. Interestingly, the transcriptome data showed for the first time the involvement of the circadian clock in the host response following Giardia infection.
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Manko A, Motta JP, Cotton JA, Feener T, Oyeyemi A, Vallance BA, Wallace JL, Buret AG. Giardia co-infection promotes the secretion of antimicrobial peptides beta-defensin 2 and trefoil factor 3 and attenuates attaching and effacing bacteria-induced intestinal disease. PLoS One 2017. [PMID: 28622393 PMCID: PMC5473565 DOI: 10.1371/journal.pone.0178647] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Our understanding of polymicrobial gastrointestinal infections and their effects on host biology remains incompletely understood. Giardia duodenalis is an ubiquitous intestinal protozoan parasite infecting animals and humans. Concomitant infections with Giardia and other gastrointestinal pathogens commonly occur. In countries with poor sanitation, Giardia infection has been associated with decreased incidence of diarrheal disease and fever, and reduced serum inflammatory markers release, via mechanisms that remain obscure. This study analyzed Giardia spp. co-infections with attaching and effacing (A/E) pathogens, and assessed whether and how the presence of Giardia modulates host responses to A/E enteropathogens, and alters intestinal disease outcome. In mice infected with the A/E pathogen Citrobacter rodentium, co-infection with Giardia muris significantly attenuated weight loss, macro- and microscopic signs of colitis, bacterial colonization and translocation, while concurrently enhancing the production and secretion of antimicrobial peptides (AMPs) mouse β-defensin 3 and trefoil factor 3 (TFF3). Co-infection of human intestinal epithelial cells (Caco-2) monolayers with G. duodenalis trophozoites and enteropathogenic Escherichia coli (EPEC) enhanced the production of the AMPs human β-defensin 2 (HBD-2) and TFF3; this effect was inhibited with treatment of G. duodenalis with cysteine protease inhibitors. Collectively, these results suggest that Giardia infections are capable of reducing enteropathogen-induced colitis while increasing production of host AMPs. Additional studies also demonstrated that Giardia was able to directly inhibit the growth of pathogenic bacteria. These results reveal novel mechanisms whereby Giardia may protect against gastrointestinal disease induced by a co-infecting A/E enteropathogen. Our findings shed new light on how microbial-microbial interactions in the gut may protect a host during concomitant infections.
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Affiliation(s)
- Anna Manko
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, Alberta, Canada
| | - Jean-Paul Motta
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, Alberta, Canada
| | - James A. Cotton
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, Alberta, Canada
| | - Troy Feener
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
| | - Ayodele Oyeyemi
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, Alberta, Canada
| | - Bruce A. Vallance
- Department of Pediatrics, Division of Gastroenterology, Child and Family Research Institute, Vancouver, British Columbia, Canada
| | - John L. Wallace
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Department of Physiology & Pharmacology, University of Calgary, Alberta, Canada
| | - Andre G. Buret
- Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada
- Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions, University of Calgary, Calgary, Alberta, Canada
- * E-mail:
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Li S, Chen Y, Sun D, Bai R, Gao X, Yang Y, Sheng J, Xu Z. Angiogenin Prevents Progranulin A9D Mutation-Induced Neuronal-Like Cell Apoptosis Through Cleaving tRNAs into tiRNAs. Mol Neurobiol 2017; 55:1338-1351. [DOI: 10.1007/s12035-017-0396-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 01/10/2017] [Indexed: 12/20/2022]
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Koczera P, Martin L, Marx G, Schuerholz T. The Ribonuclease A Superfamily in Humans: Canonical RNases as the Buttress of Innate Immunity. Int J Mol Sci 2016; 17:ijms17081278. [PMID: 27527162 PMCID: PMC5000675 DOI: 10.3390/ijms17081278] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Revised: 07/29/2016] [Accepted: 08/01/2016] [Indexed: 12/18/2022] Open
Abstract
In humans, the ribonuclease A (RNase A) superfamily contains eight different members that have RNase activities, and all of these members are encoded on chromosome 14. The proteins are secreted by a large variety of different tissues and cells; however, a comprehensive understanding of these proteins’ physiological roles is lacking. Different biological effects can be attributed to each protein, including antiviral, antibacterial and antifungal activities as well as cytotoxic effects against host cells and parasites. Different immunomodulatory effects have also been demonstrated. This review summarizes the available data on the human RNase A superfamily and illustrates the significant role of the eight canonical RNases in inflammation and the host defence system against infections.
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Affiliation(s)
- Patrick Koczera
- Department of Intensive Care and Intermediate Care, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany.
- Department for Experimental Molecular Imaging, University Hospital RWTH Aachen and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen 52074, Germany.
| | - Lukas Martin
- Department of Intensive Care and Intermediate Care, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany.
| | - Gernot Marx
- Department of Intensive Care and Intermediate Care, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany.
| | - Tobias Schuerholz
- Department of Intensive Care and Intermediate Care, University Hospital Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen 52074, Germany.
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Interleukin-25 Mediated Induction of Angiogenin-4 Is Interleukin-13 Dependent. PLoS One 2016; 11:e0153572. [PMID: 27089535 PMCID: PMC4835063 DOI: 10.1371/journal.pone.0153572] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 03/31/2016] [Indexed: 01/21/2023] Open
Abstract
The intestinal surface is directly exposed to both commensal microorganisms as well as pathogens with a single layer of epithelium separating luminal microorganisms from internal tissues. Antimicrobial peptides play a crucial role in allowing epithelial cells to contain in the lumen beneficial and pathogenic microorganisms. The commensal dependent, epithelial produced, Th2 cytokine IL-25 can induce IL-13 and potentially the antimicrobial peptide angiogenin-4. Here we show that IL-13 downstream of IL-25 is required to induce angiogenin-4. IL-25 mediated induction of angiogenin-4 is furthermore not dependent on IL-22 or IL-17.
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The effects of STAT1 dysfunction on the gut. LYMPHOSIGN JOURNAL-THE JOURNAL OF INHERITED IMMUNE DISORDERS 2016. [DOI: 10.14785/lpsn-2015-0012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Introduction: Mutations in the signal transducer and activator of transcription1 (STAT1) have been associated with a variety of clinical patterns. Interestingly patients with heterozygous mutations in the DNA binding domain (DBD) of STAT1 suffer acute and chronic colitis. Methods: To further analyze the role of STAT1 deficiency in intestinal inflammation, we employed protein expression analysis of total and activated STAT1 in intestinal biopsy samples from 2 patients with heterozygous mutations in the DBD of the STAT1 gene. Results: Both patients showed clinical and histological features of colitis. Total and activated STAT1 were decreased in duodenal and colonic enterocytes, and total STAT1 was found to be mislocalized in aggregates subapically. In addition, intestinal biopsy samples showed decreased numbers of lymphocytes. Patient-derived lymphoblasts demonstrated lack of viability and high susceptibility for cell death. Conclusion: STAT1 expression and distribution in the gut of patients with mutations in the DBD are abnormal, suggesting a primary role of STAT1 dysfunction in enterocytes in addition to the secondary effect of aberrant inflammation. Statement of novelty: Colitis associated with STAT1 mutations appears to have unique features distinct from typical inflammatory bowel disease.
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Edelblum KL, Singh G, Odenwald MA, Lingaraju A, El Bissati K, McLeod R, Sperling AI, Turner JR. γδ Intraepithelial Lymphocyte Migration Limits Transepithelial Pathogen Invasion and Systemic Disease in Mice. Gastroenterology 2015; 148:1417-26. [PMID: 25747597 PMCID: PMC4685713 DOI: 10.1053/j.gastro.2015.02.053] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 02/16/2015] [Accepted: 02/21/2015] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Intraepithelial lymphocytes that express the γδ T-cell receptor (γδ IELs) limit pathogen translocation across the intestinal epithelium by unknown mechanisms. We investigated whether γδ IEL migration and interaction with epithelial cells promote mucosal barrier maintenance during enteric infection. METHODS Salmonella typhimurium or Toxoplasma gondii were administered to knockout (KO) mice lacking either the T cell receptor δ chain (Tcrd) or CD103, or control TcrdEGFP C57BL/6 reporter mice. Intravital microscopy was used to visualize migration of green fluorescent protein (GFP)-tagged γδ T cells within the small intestinal mucosa of mice infected with DsRed-labeled S typhimurium. Mixed bone marrow chimeras were generated to assess the effects of γδ IEL migration on early pathogen invasion and chronic systemic infection. RESULTS Morphometric analyses of intravital video microscopy data showed that γδ IELs rapidly localized to and remained near epithelial cells in direct contact with bacteria. Within 1 hour, greater numbers of T gondii or S typhimurium were present within mucosae of mice with migration-defective occludin KO γδ T cells, compared with controls. Pathogen invasion in Tcrd KO mice was quantitatively similar to that in mice with occludin-deficient γδ T cells, whereas invasion in CD103 KO mice, which have increased migration of γδ T cells into the lateral intercellular space, was reduced by 63%. Consistent with a role of γδ T-cell migration in early host defense, systemic salmonellosis developed more rapidly and with greater severity in mice with occludin-deficient γδ IELs, relative to those with wild-type or CD103 KO γδ IELs. CONCLUSIONS In mice, intraepithelial migration to epithelial cells in contact with pathogens is essential to γδ IEL surveillance and immediate host defense. γδ IEL occludin is required for early surveillance that limits systemic disease.
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Affiliation(s)
| | | | | | | | - Kamal El Bissati
- Department of Ophthalmology and Visual Sciences and Department of Pediatrics, The University of Chicago
| | - Rima McLeod
- Department of Ophthalmology and Visual Sciences and Department of Pediatrics, The University of Chicago
| | - Anne I. Sperling
- Department of Medicine, The University of Chicago,Section of Pulmonary and Critical Care, The University of Chicago
| | - Jerrold R. Turner
- Department of Pathology, The University of Chicago,Department of Medicine, The University of Chicago
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Bowcutt R, Forman R, Glymenaki M, Carding SR, Else KJ, Cruickshank SM. Heterogeneity across the murine small and large intestine. World J Gastroenterol 2014; 20:15216-15232. [PMID: 25386070 PMCID: PMC4223255 DOI: 10.3748/wjg.v20.i41.15216] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 03/18/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
The small and large intestine of the gastrointestinal tract (GIT) have evolved to have discrete functions with distinct anatomies and immune cell composition. The importance of these differences is underlined when considering that different pathogens have uniquely adapted to live in each region of the gut. Furthermore, different regions of the GIT are also associated with differences in susceptibility to diseases such as cancer and chronic inflammation. The large and small intestine, given their anatomical and functional differences, should be seen as two separate immunological sites. However, this distinction is often ignored with findings from one area of the GIT being inappropriately extrapolated to the other. Focussing largely on the murine small and large intestine, this review addresses the literature relating to the immunology and biology of the two sites, drawing comparisons between them and clarifying similarities and differences. We also highlight the gaps in our understanding and where further research is needed.
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50
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Fuell C, Kober OI, Hautefort I, Juge N. Mice deficient in intestinal γδ intraepithelial lymphocytes display an altered intestinal O-glycan profile compared with wild-type littermates. Glycobiology 2014; 25:42-54. [PMID: 25187161 DOI: 10.1093/glycob/cwu088] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Intestinal γδ T-cell receptor-bearing intraepithelial lymphocytes (γδ IELs) play a multifaceted role in maintaining mucosal homeostasis. In order to investigate the relationship between O-glycosylation and inflammation, we carried out an in-depth mass spectrometric comparison of the intestinal O-glycosylation profile of mice lacking γδ IELs (TCRδ(-/-)) and of their wild-type (WT) littermates. A total of 69 nonsulfated and 59 sulfated compositional types of O-glycans were identified in the small intestine and colon of TCRδ(-/-) and WT mice. Our results demonstrated structural differences in intestinal glycosylation in TCRδ(-/-) mice compared with WT littermates. TCRδ(-/-) colons contained a lower proportion of core-2 structures and an increased proportion of core-1 structures whereas TCRδ(-/-) small intestines had a decreased percentage of core-3 structures. The glycan antennae in TCRδ(-/-) colon and small intestine showed altered structural diversity compared with WT mice. There were significant differences in the sialylated species between the TCRδ(-/-) and WT mice with the sialylated Tn antigen found exclusively in the TCRδ(-/-)small intestine, whereas the sulfation pattern remained mostly unchanged. These findings provide novel molecular insights underpinning the role of γδ IELs in maintaining gut homeostasis.
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Affiliation(s)
- Christine Fuell
- Gut Health and Food Safety Institute Strategic Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
| | - Olivia I Kober
- Gut Health and Food Safety Institute Strategic Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
| | - Isabelle Hautefort
- Gut Health and Food Safety Institute Strategic Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
| | - Nathalie Juge
- Gut Health and Food Safety Institute Strategic Programme, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
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