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Ryu KB, Seo JA, Lee K, Choi J, Yoo G, Ha JH, Ahn MR. Drug-Resistance Biomarkers in Patient-Derived Colorectal Cancer Organoid and Fibroblast Co-Culture System. Curr Issues Mol Biol 2024; 46:5794-5811. [PMID: 38921017 PMCID: PMC11202770 DOI: 10.3390/cimb46060346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/27/2024] Open
Abstract
Colorectal cancer, the third most commonly occurring tumor worldwide, poses challenges owing to its high mortality rate and persistent drug resistance in metastatic cases. We investigated the tumor microenvironment, emphasizing the role of cancer-associated fibroblasts in the progression and chemoresistance of colorectal cancer. We used an indirect co-culture system comprising colorectal cancer organoids and cancer-associated fibroblasts to simulate the tumor microenvironment. Immunofluorescence staining validated the characteristics of both organoids and fibroblasts, showing high expression of epithelial cell markers (EPCAM), colon cancer markers (CK20), proliferation markers (KI67), and fibroblast markers (VIM, SMA). Transcriptome profiling was conducted after treatment with anticancer drugs, such as 5-fluorouracil and oxaliplatin, to identify chemoresistance-related genes. Changes in gene expression in the co-cultured colorectal cancer organoids following anticancer drug treatment, compared to monocultured organoids, particularly in pathways related to interferon-alpha/beta signaling and major histocompatibility complex class II protein complex assembly, were identified. These two gene groups potentially mediate drug resistance associated with JAK/STAT signaling. The interaction between colorectal cancer organoids and fibroblasts crucially modulates the expression of genes related to drug resistance. These findings suggest that the interaction between colorectal cancer organoids and fibroblasts significantly influences gene expression related to drug resistance, highlighting potential biomarkers and therapeutic targets for overcoming chemoresistance. Enhanced understanding of the interactions between cancer cells and their microenvironment can lead to advancements in personalized medical research..
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Affiliation(s)
| | | | | | | | | | - Ji-hye Ha
- Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju 28159, Chungcheongbuk-do, Republic of Korea; (K.-B.R.)
| | - Mee Ryung Ahn
- Clinical Research Division, National Institute of Food and Drug Safety Evaluation, Ministry of Food and Drug Safety, Cheongju 28159, Chungcheongbuk-do, Republic of Korea; (K.-B.R.)
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2
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Nenciarini S, Amoriello R, Bacci G, Cerasuolo B, Di Paola M, Nardini P, Papini A, Ballerini C, Cavalieri D. Yeast strains isolated from fermented beverage produce extracellular vesicles with anti-inflammatory effects. Sci Rep 2024; 14:730. [PMID: 38184708 PMCID: PMC10771474 DOI: 10.1038/s41598-024-51370-7] [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: 10/25/2023] [Accepted: 01/04/2024] [Indexed: 01/08/2024] Open
Abstract
Extracellular vesicles (EVs) are lipid-bilayered particles, containing various biomolecules, including nucleic acids, lipids, and proteins, released by cells from all the domains of life and performing multiple communication functions. Evidence suggests that the interaction between host immune cells and fungal EVs induces modulation of the immune system. Most of the studies on fungal EVs have been conducted in the context of fungal infections; therefore, there is a knowledge gap in what concerns the production of EVs by yeasts in other contexts rather than infection and that may affect human health. In this work, we characterized EVs obtained by Saccharomyces cerevisiae and Pichia fermentans strains isolated from a fermented milk product with probiotic properties. The immunomodulation abilities of EVs produced by these strains have been studied in vitro through immune assays after internalization from human monocyte-derived dendritic cells. Results showed a significant reduction in antigen presentation activity of dendritic cells treated with the fermented milk EVs. The small RNA fraction of EVs contained mainly yeast mRNA sequences, with a few molecular functions enriched in strains of two different species isolated from the fermented milk. Our results suggest that one of the mechanisms behind the anti-inflammatory properties of probiotic foods could be mediated by the interactions of human immune cells with yeast EVs.
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Affiliation(s)
| | - Roberta Amoriello
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giovanni Bacci
- Department of Biology, University of Florence, Florence, Italy
| | | | - Monica Di Paola
- Department of Biology, University of Florence, Florence, Italy
| | - Patrizia Nardini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessio Papini
- Department of Biology, University of Florence, Florence, Italy
| | - Clara Ballerini
- Department of Experimental and Clinical Medicine, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy.
| | - Duccio Cavalieri
- Department of Biology, University of Florence, Via Madonna del Piano 6, 50019, Sesto Fiorentino, Florence, Italy.
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3
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Lei PJ, Pereira ER, Andersson P, Amoozgar Z, Van Wijnbergen JW, O’Melia MJ, Zhou H, Chatterjee S, Ho WW, Posada JM, Kumar AS, Morita S, Menzel L, Chung C, Ergin I, Jones D, Huang P, Beyaz S, Padera TP. Cancer cell plasticity and MHC-II-mediated immune tolerance promote breast cancer metastasis to lymph nodes. J Exp Med 2023; 220:e20221847. [PMID: 37341991 PMCID: PMC10286805 DOI: 10.1084/jem.20221847] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 04/10/2023] [Accepted: 05/25/2023] [Indexed: 06/22/2023] Open
Abstract
Tumor-draining lymph nodes (TDLNs) are important for tumor antigen-specific T cell generation and effective anticancer immune responses. However, TDLNs are often the primary site of metastasis, causing immune suppression and worse outcomes. Through cross-species single-cell RNA-Seq analysis, we identified features defining cancer cell heterogeneity, plasticity, and immune evasion during breast cancer progression and lymph node metastasis (LNM). A subset of cancer cells in the lymph nodes exhibited elevated MHC class II (MHC-II) gene expression in both mice and humans. MHC-II+ cancer cells lacked costimulatory molecule expression, leading to regulatory T cell (Treg) expansion and fewer CD4+ effector T cells in TDLNs. Genetic knockout of MHC-II reduced LNM and Treg expansion, while overexpression of the MHC-II transactivator, Ciita, worsened LNM and caused excessive Treg expansion. These findings demonstrate that cancer cell MHC-II expression promotes metastasis and immune evasion in TDLNs.
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Affiliation(s)
- Pin-Ji Lei
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ethel R. Pereira
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Patrik Andersson
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zohreh Amoozgar
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jan Willem Van Wijnbergen
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Meghan J. O’Melia
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Hengbo Zhou
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Sampurna Chatterjee
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - William W. Ho
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jessica M. Posada
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - Ashwin S. Kumar
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Harvard–MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Satoru Morita
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lutz Menzel
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Charlie Chung
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Ilgin Ergin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Dennis Jones
- Department of Pathology and Laboratory Medicine, School of Medicine, Boston University, Boston, MA, USA
| | - Peigen Huang
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Semir Beyaz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
| | - Timothy P. Padera
- Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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4
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Koido S, Horiuchi S, Kan S, Bito T, Ito Z, Uchiyama K, Saruta M, Sato N, Ohkusa T. The stimulatory effect of fusobacteria on dendritic cells under aerobic or anaerobic conditions. Sci Rep 2022; 12:10698. [PMID: 35739324 PMCID: PMC9225986 DOI: 10.1038/s41598-022-14934-z] [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: 08/02/2021] [Accepted: 06/15/2022] [Indexed: 11/16/2022] Open
Abstract
Fusobacteria have been suspected to be pathobionts of colon cancer and inflammatory bowel disease. However, the immunomodulatory properties that affect these inflammatory reactions in dendritic cells (DCs) under anaerobic and aerobic conditions have not yet been characterized. We directly assessed the stimulatory effects of anaerobic commensal bacteria, including fusobacteria, on a human DC line through coculture under aerobic or anaerobic conditions. Under aerobic or anaerobic conditions, stimulation of the DC line with all live commensal bacteria examined, except the probiotic Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus), significantly increased the geometric mean fluorescent intensity (MFI) of marker proteins (HLA-ABC, HLA-DR, CD80, CD86, CD83, or CCR7) on the DC surface. In particular, both Fusobacterium nucleatum (F. nucleatum) and Escherichia coli (E. coli) significantly increased the expression of DC-associated molecules, except for CD83 under both aerobic and anaerobic conditions. The DC line stimulated with Fusobacterium varium (F. varium) significantly increased only CD80, HLA-ABC, and HLA-DR expression under anaerobic conditions. Moreover, differences in the levels of proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, were detected in the DC line stimulated by all live commensal bacteria under either aerobic or anaerobic conditions. Under aerobic conditions, the DC line stimulated with E. coli produced significantly more IL-6, IL-8, and TNF-α than did the cells stimulated with any of the bacteria examined. When E. coli were used to stimulate the DC line under anaerobic conditions, TNF-α was predominantly produced compared to stimulation with any other bacteria. Compared to the DC line stimulated with any other bacteria, the cells stimulated with F. nucleatum showed significantly increased production of IL-6, IL-8 and TNF-α only under anaerobic conditions. In particular, E. coli, F. nucleatum, and F. varium strongly stimulated the DC line, resulting in significantly increased expression of surface molecules associated with DCs and production of inflammatory cytokines.
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Affiliation(s)
- Shigeo Koido
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan.
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan.
| | - Sankichi Horiuchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Shin Kan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Tsuuse Bito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa City, Chiba, Japan
| | - Zensho Ito
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
| | - Kan Uchiyama
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
| | - Masayuki Saruta
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Nobuhiro Sato
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Toshifumi Ohkusa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa City, Chiba, 277-8567, Japan
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, Tokyo, Japan
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5
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Nutritional Regimes Enriched with Antioxidants as an Efficient Adjuvant for IBD Patients under Infliximab Administration, a Pilot Study. Antioxidants (Basel) 2022; 11:antiox11010138. [PMID: 35052642 PMCID: PMC8773281 DOI: 10.3390/antiox11010138] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/27/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Antioxidants are privileged candidates for the development of adjuvants able to improve the efficiency of pharmacological therapies, particularly for chronic inflammatory syndromes. During the last 20 years, anti-TNFα (tumor necrosis factor alpha) monoclonal antibodies infusion has been the biological therapy most frequently administered but there is still large space for improvement in disease remission rates and maintenance. In this context, nutritional bioactive compounds contained in dietary patterns or included as supplements, may act as adjuvants for the induction and maintenance of IBD (inflammatory bowel diseases) remission. To verify this possibility, a single-center preliminary study (SI-CURA, Soluzioni Innovative per la gestione del paziente e il follow up terapeutico della Colite UlceRosA) was designed and carried out to evaluate whether a daily administration of purple corn supplement could improve the response to Infliximab (IFX) infusion of IBD patients with both Crohn’s disease (CD) and ulcerative colitis (UC). A cohort of 47 patients was enrolled in the study. Biological samples were collected before the first and the third IFX infusion. All patients received nutritional guidelines, 27 of them received commercial red fruit tea with low anthocyanins content, while 20 received a purple corn supplement with a high anthocyanin content. Results show that the administration of an antioxidant-enriched purple corn supplement could improve IFX-mediated disease remission in terms of circulating inflammatory markers. Comparison between CD and UC patients revealed that, at this anthocyanin dosage, the purple corn extract administration improved the IFX response in CD but not in UC patients. Our results may pave the way for a new metacentric study of CD patients, recruiting a wider cohort and followed-up over a longer observational time.
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6
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OHKUSA T, KOIDO S, HORIUCHI S, KAN S, ITO Z, NISHIKAWA Y, SATO N. Growth of various obligate and facultative anaerobic intestinal bacteria in cell culture medium under aerobic and anaerobic culture conditions. BIOSCIENCE OF MICROBIOTA, FOOD AND HEALTH 2022; 41:145-148. [PMID: 35854697 PMCID: PMC9246421 DOI: 10.12938/bmfh.2021-065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/03/2022] [Indexed: 01/12/2023]
Abstract
Eight bacterial strains were used in this study to examine the survival of intestinal
bacteria in immune cell cultures under aerobic and anaerobic culture conditions. With the
addition of penicillin G and streptomycin, viable Clostridium
clostridioforme and Fusobacterium varium cells did not
decrease after 6 or 24 hr, even under aerobic conditions. Without antibiotics, eight
bacterial strains did not decrease until 4 or 6 hr later, under both aerobic and anaerobic
conditions. Escherichia coli numbers increased by more than 10 times
under both conditions. In order to examine the effects of live gut bacteria on various
immune cells, the viability of bacteria should be checked in cell culture media and under
different conditions.
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Affiliation(s)
- Toshifumi OHKUSA
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Shigeo KOIDO
- Department of Gastroenterology and Hepatology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Sankichi HORIUCHI
- Department of Gastroenterology and Hepatology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Shin KAN
- Department of Gastroenterology and Hepatology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Zensho ITO
- Department of Gastroenterology and Hepatology, The Jikei University Kashiwa Hospital, 163-1 Kashiwashita, Kashiwa-shi, Chiba 277-0004, Japan
| | - Yuriko NISHIKAWA
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Nobuhiro SATO
- Department of Microbiota Research, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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7
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Miranda-Ribera A, Serena G, Liu J, Fasano A, Kingsbury MA, Fiorentino MR. The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota. Tissue Barriers 2021; 10:2000299. [PMID: 34775911 DOI: 10.1080/21688370.2021.2000299] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.
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Affiliation(s)
- Alba Miranda-Ribera
- Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Gloria Serena
- Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Jundi Liu
- Department of Poultry Science, University of Georgia, Athens, GA, USA
| | - Alessio Fasano
- Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, USA
| | - Marcy A Kingsbury
- Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, USA.,Lurie Center for Autism, Boston, MA, USA
| | - Maria R Fiorentino
- Department of Pediatric Gastroenterology and Nutrition, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.,Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA, USA
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8
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Bögels M, Braster R, Nijland PG, Gül N, van de Luijtgaarden W, Fijneman RJA, Meijer GA, Jimenez CR, Beelen RHJ, van Egmond M. Carcinoma origin dictates differential skewing of monocyte function. Oncoimmunology 2021; 1:798-809. [PMID: 23162747 PMCID: PMC3489735 DOI: 10.4161/onci.20427] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Macrophages are versatile cells, which phenotype is profoundly influenced by their environment. Pro-inflammatory classically activated or M1 macrophages, and anti-inflammatory alternatively-activated or M2 macrophages represent two extremes of a continuum of functional states. Consequently, macrophages that are present in tumors can exert tumor-promoting and tumor-suppressing activity, depending on the tumor milieu. In this study we investigated how human monocytes-the precursors of macrophages-are influenced by carcinoma cells of different origin. We demonstrate that monocytes, stimulated with breast cancer supernatant, showed increased expression of interleukin (IL)-10, IL-8 and chemokines CCL17 and CCL22, which are associated with an alternatively-activated phenotype. By contrast, monocytes that were cultured in supernatants of colon cancer cells produced more pro-inflammatory cytokines (e.g., IL-12 and TNFα) and reactive oxygen species. Secretome analysis revealed differential secretion of proteins by colon and breast cancer cell lines, of which the proteoglycan versican was exclusively secreted by colon carcinoma cell lines. Reducing active versican by blocking with monoclonal antibodies or shRNA diminished pro-inflammatory cytokine production by monocytes. Thus, colon carcinoma cells polarize monocytes toward a more classically-activated anti-tumorigenic phenotype, whereas breast carcinomas predispose monocytes toward an alternatively activated phenotype. Interestingly, presence of macrophages in breast or colon carcinomas correlates with poor or good prognosis in patients, respectively. The observed discrepancy in macrophage activation by either colon or breast carcinoma cells may therefore explain the dichotomy between patient prognosis and macrophage presence in these different tumors. Designing new therapies, directing development of monocytes toward M1 activated tumor macrophages in cancer patients, may have great clinical benefits.
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Affiliation(s)
- Marijn Bögels
- Department of Surgery; VU University Medical Center; Amsterdam, The Netherlands ; Department of Molecular Cell Biology and Immunology; VU University Medical Center; Amsterdam, The Netherlands
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9
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Pietrzak B, Tomela K, Olejnik-Schmidt A, Mackiewicz A, Schmidt M. Secretory IgA in Intestinal Mucosal Secretions as an Adaptive Barrier against Microbial Cells. Int J Mol Sci 2020; 21:ijms21239254. [PMID: 33291586 PMCID: PMC7731431 DOI: 10.3390/ijms21239254] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/28/2020] [Accepted: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Secretory IgA (SIgA) is the dominant antibody class in mucosal secretions. The majority of plasma cells producing IgA are located within mucosal membranes lining the intestines. SIgA protects against the adhesion of pathogens and their penetration into the intestinal barrier. Moreover, SIgA regulates gut microbiota composition and provides intestinal homeostasis. In this review, we present mechanisms of SIgA generation: T cell-dependent and -independent; in different non-organized and organized lymphoid structures in intestinal lamina propria (i.e., Peyer’s patches and isolated lymphoid follicles). We also summarize recent advances in understanding of SIgA functions in intestinal mucosal secretions with focus on its role in regulating gut microbiota composition and generation of tolerogenic responses toward its members.
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Affiliation(s)
- Bernadeta Pietrzak
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, 48 Wojska Polskiego, 60-627 Poznań, Poland;
- Correspondence: (B.P.); (M.S.)
| | - Katarzyna Tomela
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznań, Poland; (K.T.); (A.M.)
| | - Agnieszka Olejnik-Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, 48 Wojska Polskiego, 60-627 Poznań, Poland;
| | - Andrzej Mackiewicz
- Department of Cancer Immunology, Chair of Medical Biotechnology, Poznan University of Medical Sciences, 8 Rokietnicka Street, 60-806 Poznań, Poland; (K.T.); (A.M.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary Street, 61-866 Poznań, Poland
| | - Marcin Schmidt
- Department of Food Biotechnology and Microbiology, Poznan University of Life Sciences, 48 Wojska Polskiego, 60-627 Poznań, Poland;
- Correspondence: (B.P.); (M.S.)
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10
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Transcriptomic microRNA Profiling of Dendritic Cells in Response to Gut Microbiota-Secreted Vesicles. Cells 2020; 9:cells9061534. [PMID: 32585977 PMCID: PMC7349327 DOI: 10.3390/cells9061534] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/19/2022] Open
Abstract
The interconnection between nutrients, metabolites and microbes is a key factor governing the healthy/pathological status of an individual. Thus, microbiota-based research is essential in order to better understand human health and nutrition. Gut bacteria release membrane vesicles (MVs) as an intercellular communication mechanism that allows the direct delivery of factors that prime the host’s innate immune system. We have previously shown that MVs from intestinal E. coli activate dendritic cells (DCs) in a strain-specific manner. To gain insights into the regulatory mechanisms involved, here, we have used an RNA deep sequencing approach to identify differentially expressed miRNAs (microRNAs) in DCs which are challenged by the MVs of the probiotic Nissle 1917 (EcN) or the commensal ECOR12. MicroRNAs are post-transcriptional regulatory mediators that permit the fine tuning of signaling pathways. This approach allowed the identification of a common set of miRNAs which are modulated by MVs from both strains and miRNAs which are differentially expressed in response to EcN or ECOR12 MVs. Based on the differential expression of the target genes and subsequent validation experiments, we correlated some of the selected miRNAs with the reported cytokine profile and specific T cell responses. As far as we know, this is the first study to analyze the regulation of miRNAs in DCs by MVs released by gut microbiota.
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11
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Verna G, Liso M, De Santis S, Dicarlo M, Cavalcanti E, Crovace A, Sila A, Campiglia P, Santino A, Lippolis A, Serino G, Fasano A, Chieppa M. Iron Overload Mimicking Conditions Skews Bone Marrow Dendritic Cells Differentiation into MHCII lowCD11c +CD11b +F4/80 + Cells. Int J Mol Sci 2020; 21:ijms21041353. [PMID: 32079304 PMCID: PMC7072937 DOI: 10.3390/ijms21041353] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/14/2020] [Accepted: 02/15/2020] [Indexed: 12/21/2022] Open
Abstract
Iron overload is an undesired effect of frequent blood transfusions or genetic diseases. Myelodysplastic syndrome (MDS) patients become transfusion dependent, but due to the combination of ineffective haematopoiesis and repeated blood transfusions they are often subject to iron overload. In this study, we demonstrate that iron-overload mimicking condition alters bone marrow progenitor differentiation towards dendritic cells (DCs). Cells cultured in iron-enriched culture medium for seven days fail to differentiate into conventional CD11c+MHCIIhi DCs and fail to efficiently respond to LPS (Lipopolysaccharides). Cells appear smaller than control DCs but vital and able to perform FITC-dextran (Fluorescein isothiocyanate-dextran) endocytosis. At molecular level, cells cultured in iron-enriched conditions show increased ARG1 and PU.1, and decreased IRF8 expression.
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Affiliation(s)
- Giulio Verna
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
- Department of Immunology and Cell Biology, European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy; (P.C.); (A.F.)
| | - Marina Liso
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Stefania De Santis
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy;
- Department of Pharmacy-Drug Science, University of Bari Aldo Moro, 70126 Bari, Italy
| | - Manuela Dicarlo
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Elisabetta Cavalcanti
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Alberto Crovace
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Annamaria Sila
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Pietro Campiglia
- Department of Immunology and Cell Biology, European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy; (P.C.); (A.F.)
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy;
| | - Angelo Santino
- Unit of Lecce, Institute of Sciences of Food Production C.N.R., via Monteroni, 73100 Lecce, Italy;
| | - Antonio Lippolis
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Grazia Serino
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
| | - Alessio Fasano
- Department of Immunology and Cell Biology, European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy; (P.C.); (A.F.)
- Harvard Medical School Division of Pediatric Gastroenterology and Nutrition and Mucosal Immunology and Biology Research Center, Massachusetts General Hospital for Children, Boston, MA 02114, USA
| | - Marcello Chieppa
- National Institute of Gastroenterology “S. de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (G.V.); (M.L.); (M.D.); (E.C.); (A.C.); (A.S.); (A.L.); (G.S.)
- Department of Immunology and Cell Biology, European Biomedical Research Institute of Salerno (EBRIS), 84125 Salerno, Italy; (P.C.); (A.F.)
- Correspondence:
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12
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Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res 2020; 9. [PMID: 32051759 PMCID: PMC6996528 DOI: 10.12688/f1000research.20510.1] [Citation(s) in RCA: 230] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2020] [Indexed: 12/19/2022] Open
Abstract
Improved hygiene leading to reduced exposure to microorganisms has been implicated as one possible cause for the recent "epidemic" of chronic inflammatory diseases (CIDs) in industrialized countries. That is the essence of the hygiene hypothesis that argues that rising incidence of CIDs may be, at least in part, the result of lifestyle and environmental changes that have made us too "clean" for our own good, so causing changes in our microbiota. Apart from genetic makeup and exposure to environmental triggers, inappropriate increase in intestinal permeability (which may be influenced by the composition of the gut microbiota), a "hyper-belligerent" immune system responsible for the tolerance-immune response balance, and the composition of gut microbiome and its epigenetic influence on the host genomic expression have been identified as three additional elements in causing CIDs. During the past decade, a growing number of publications have focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately influencing the close bidirectional interaction between gut microbiome and our immune system. This cross-talk is highly influential in shaping the host gut immune system function and ultimately shifting genetic predisposition to clinical outcome. This observation led to a re-visitation of the possible causes of CIDs epidemics, suggesting a key pathogenic role of gut permeability. Pre-clinical and clinical studies have shown that the zonulin family, a group of proteins modulating gut permeability, is implicated in a variety of CIDs, including autoimmune, infective, metabolic, and tumoral diseases. These data offer novel therapeutic targets for a variety of CIDs in which the zonulin pathway is implicated in their pathogenesis.
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Affiliation(s)
- Alessio Fasano
- Mucosal Immunology and Biology Research Center, Center for Celiac Research and Treatment and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, Massachusetts, USA.,European Biomedical Research Institute of Salerno, Salerno, Italy
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13
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Pan F, Tang W, Zhou Z, Gilkeson G, Lang R, Jiang W. Intestinal macrophages in mucosal immunity and their role in systemic lupus erythematosus disease. Lupus 2018; 27:1898-1902. [PMID: 30223707 DOI: 10.1177/0961203318797417] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Monocytes play an important role in inducing host systemic immunity against invading pathogens and inflammatory responses. After activation, monocytes migrate to tissue sites, where they initiate both innate and adaptive immune responses, and become macrophages. Although mucosal macrophages produce inflammatory cytokines in response to pathogens, the perturbations in innate immune signaling pathway have been implicated in autoimmune diseases such as systemic lupus erythematosus (SLE). In this review, we focus on the role of human macrophages in intestinal innate immune responses, homeostasis, and SLE disease. We further discuss sex differences in the intestinal macrophages and their role in the physiology and pathogenesis of SLE.
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Affiliation(s)
- F Pan
- 1 Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - W Tang
- 2 The First Affiliated Hospital, Harbin Medical University, Nangang, Harbin, China
| | - Z Zhou
- 3 State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Human Normal University, Changsha, China
| | - G Gilkeson
- 4 Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - R Lang
- 1 Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - W Jiang
- 5 Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.,6 Divison of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
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14
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Chang LL, Hsu WH, Kao MC, Chou CC, Lin CC, Liu CJ, Weng BC, Kuo FC, Kuo CH, Lin MH, Wang CJ, Lin CH, Wu DC, Huang SK. Stromal C-type lectin receptor COLEC12 integrates H. pylori, PGE2-EP2/4 axis and innate immunity in gastric diseases. Sci Rep 2018; 8:3821. [PMID: 29491476 PMCID: PMC5830506 DOI: 10.1038/s41598-018-20957-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 01/17/2018] [Indexed: 12/12/2022] Open
Abstract
Tissue stroma is known to be important in regulating Hp-mediated inflammation, but its interaction with Hp and dendritic cells (DCs) remains to be determined. To this end, the potential crosstalk between H. pylori (Hp) infected gastric stromal cells (Hp-GSCs) and DCs was investigated. Primary GSCs from cancerous and adjacent normal tissues were generated from gastric cancer patients, and monocyte-derived DCs were obtained from healthy individuals. Levels of cytokines and prostaglandin E2 (PGE2) were measured by ELISA, and C-type lectin expression in GSCs was assessed by flow cytometry and immunohistochemistry. In a trans-well co-culture system, significantly upregulated DC-derived IL-23 expression was found when DCs were co-cultured with Hp-infected GSCs (Hp-GSCs). Further, PGE2 from Hp-GSCs was discovered to possess the priming effect, which could be inhibited by anti-COLEC12 (Collectin subfamily member 12) Abs, COLEC12 knockdown or when alpha3-fucosyltransferase-null (futB; HP0651) strain of Hp was used. Also, the expression of COLEC12 was co-localized with CD90+ stromal cells in cancerous tissues. Hp-GSCs-conditioned DCs were able to induce the expression of IL-17 from CD4+ T cells, which could be inhibited by IL-23-neutralizing Abs. These results suggested the importance of COLEC12 as a receptor involved in Hp-stromal cell interaction and its subsequent conditioning effect on DCs.
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Affiliation(s)
- Lin-Li Chang
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.,Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Wen-Hung Hsu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Mou-Chieh Kao
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan.,Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chih-Chung Chou
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Cheng Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Jung Liu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Bi-Chuang Weng
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Fu-Chen Kuo
- School of Medicine, College of Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Chao-Hung Kuo
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Hong Lin
- Department of Microbiology and Immunology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chun-Jen Wang
- Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Chun-Hung Lin
- Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program and the Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Department of Chemistry, National Taiwan University, Taipei, Taiwan
| | - Deng-Chyang Wu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. .,Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan. .,Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
| | - Shau-Ku Huang
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, 35053, Taiwan. .,Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. .,Shen-Zhen University Lo-Hu Hospital, Shen-Zhen, China. .,Johns Hopkins Asthma and Allergy Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21224, USA.
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15
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Mowat AM, Scott CL, Bain CC. Barrier-tissue macrophages: functional adaptation to environmental challenges. Nat Med 2017; 23:1258-1270. [PMID: 29117177 DOI: 10.1038/nm.4430] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 09/29/2017] [Indexed: 12/12/2022]
Abstract
Macrophages are found throughout the body, where they have crucial roles in tissue development, homeostasis and remodeling, as well as being sentinels of the innate immune system that can contribute to protective immunity and inflammation. Barrier tissues, such as the intestine, lung, skin and liver, are exposed constantly to the outside world, which places special demands on resident cell populations such as macrophages. Here we review the mounting evidence that although macrophages in different barrier tissues may be derived from distinct progenitors, their highly specific properties are shaped by the local environment, which allows them to adapt precisely to the needs of their anatomical niche. We discuss the properties of macrophages in steady-state barrier tissues, outline the factors that shape their differentiation and behavior and describe how macrophages change during protective immunity and inflammation.
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Affiliation(s)
- Allan McI Mowat
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Charlotte L Scott
- Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Calum C Bain
- The University of Edinburgh/MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
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16
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De Santis S, Galleggiante V, Scandiffio L, Liso M, Sommella E, Sobolewski A, Spilotro V, Pinto A, Campiglia P, Serino G, Santino A, Notarnicola M, Chieppa M. Secretory Leukoprotease Inhibitor (Slpi) Expression Is Required for Educating Murine Dendritic Cells Inflammatory Response Following Quercetin Exposure. Nutrients 2017; 9:nu9070706. [PMID: 28684695 PMCID: PMC5537821 DOI: 10.3390/nu9070706] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/29/2017] [Accepted: 07/04/2017] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells' (DCs) ability to present antigens and initiate the adaptive immune response confers them a pivotal role in immunological defense against hostile infection and, at the same time, immunological tolerance towards harmless components of the microbiota. Food products can modulate the inflammatory status of intestinal DCs. Among nutritionally-derived products, we investigated the ability of quercetin to suppress inflammatory cytokines secretion, antigen presentation, and DCs migration towards the draining lymph nodes. We recently identified the Slpi expression as a crucial checkpoint required for the quercetin-induced inflammatory suppression. Here we demonstrate that Slpi-KO DCs secrete a unique panel of cytokines and chemokines following quercetin exposure. In vivo, quercetin-enriched food is able to induce Slpi expression in the ileum, while little effects are detectable in the duodenum. Furthermore, Slpi expressing cells are more frequent at the tip compared to the base of the intestinal villi, suggesting that quercetin exposure could be more efficient for DCs projecting periscopes in the intestinal lumen. These data suggest that quercetin-enriched nutritional regimes may be efficient for suppressing inflammatory syndromes affecting the ileo-colonic tract.
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Affiliation(s)
- Stefania De Santis
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
- Institute of Sciences of Food Production C.N.R., Unit of Lecce, via Monteroni, 73100 Lecce, Italy.
| | - Vanessa Galleggiante
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Letizia Scandiffio
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Marina Liso
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Eduardo Sommella
- Department of Pharmacy, School of Pharmacy, University of Salerno, 84084 Fisciano, Italy.
| | | | - Vito Spilotro
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Aldo Pinto
- Department of Pharmacy, School of Pharmacy, University of Salerno, 84084 Fisciano, Italy.
| | - Pietro Campiglia
- Department of Pharmacy, School of Pharmacy, University of Salerno, 84084 Fisciano, Italy.
- European Biomedical Research Institute of Salerno (EBRIS), Via S. de Renzi, 3, 84125 Salerno, Italy.
| | - Grazia Serino
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Angelo Santino
- Institute of Sciences of Food Production C.N.R., Unit of Lecce, via Monteroni, 73100 Lecce, Italy.
| | - Maria Notarnicola
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
| | - Marcello Chieppa
- National Institute of Gastroenterology "S. de Bellis", Institute of Research, Via Turi, 27, 70013 Castellana Grotte, Italy.
- Department of Pharmacy, School of Pharmacy, University of Salerno, 84084 Fisciano, Italy.
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17
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Crookenden MA, Walker CG, Peiris H, Koh Y, Almughlliq F, Vaswani K, Reed S, Heiser A, Loor JJ, Kay JK, Meier S, Donkin SS, Murray A, Dukkipati VSR, Roche JR, Mitchell MD. Effect of circulating exosomes from transition cows on Madin-Darby bovine kidney cell function. J Dairy Sci 2017; 100:5687-5700. [PMID: 28456398 DOI: 10.3168/jds.2016-12152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 03/05/2017] [Indexed: 12/19/2022]
Abstract
The greatest risk of metabolic and infectious disease in dairy cows is during the transition from pregnancy to lactating (i.e., the transition period). The objective of this experiment was to determine the effects of extracellular vesicles (microvesicles involved in cell-to-cell signaling) isolated from transition cows on target cell function. We previously identified differences in the protein profiles of exosomes isolated from cows divergent in metabolic health status. Therefore, we hypothesized that these exosomes would affect target tissues differently. To investigate this, 2 groups of cows (n = 5/group) were selected based on the concentration of β-hydroxybutyrate and fatty acids in plasma and triacylglycerol concentration in liver at wk 1 and 2 postcalving. Cows with high concentrations of β-hydroxybutyrate, fatty acids, and triacylglycerol were considered at increased risk of clinical disease during the transition period (high-risk group; n = 5) and were compared with cows that had low concentrations of the selected health indicators (low-risk group; n = 5). At 2 time points during the transition period (postcalving at wk 1 and 4), blood was sampled and plasma exosomes were isolated from the high-risk and low-risk cows. The exosomes were applied at concentrations of 10 and 1 µg/mL to 5 × 103 Madin-Darby bovine kidney cells grown to 50% confluence in 96-well plates. Results indicate a numerical increase in cell proliferation when exosomes from high-risk cows were applied compared with those from low-risk cows. Consistent with an effect on cell proliferation, quantitative reverse transcriptase PCR indicated a trend for upregulation of 3 proinflammatory genes (granulocyte colony-stimulating factor, ciliary neurotrophic factor, and CD27 ligand) with the application of high-risk exosomes, which are involved in cellular growth and survival. Proteomic analysis indicated 2 proteins in the low-risk group that were not identified in the high-risk group (endoplasmin and catalase), which may also be indicative of the metabolic state of origin. It is likely that the metabolic state of the transition cow affects cellular function through exosomal messaging; however, more in-depth research into cross-talk between exosomes and target cells is required to determine whether exosomes influence Madin-Darby bovine kidney cells in this manner.
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Affiliation(s)
- M A Crookenden
- DairyNZ, Auckland 1010, New Zealand; Institute of Vet, Animal, and Biomedical Sciences, Massey University, Palmerston North 4442, New Zealand
| | | | - H Peiris
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
| | - Y Koh
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
| | - F Almughlliq
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
| | - K Vaswani
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
| | - S Reed
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
| | - A Heiser
- Institute of Vet, Animal, and Biomedical Sciences, Massey University, Palmerston North 4442, New Zealand; AgResearch, Hopkirk Research Institute, Palmerston North 4442, New Zealand
| | - J J Loor
- Department of Animal Sciences, University of Illinois, Urbana 61801
| | - J K Kay
- DairyNZ, Hamilton 3284, New Zealand
| | - S Meier
- DairyNZ, Hamilton 3284, New Zealand
| | - S S Donkin
- Department of Animal Science, Purdue University, West Lafayette, IN 47907
| | - A Murray
- Institute of Vet, Animal, and Biomedical Sciences, Massey University, Palmerston North 4442, New Zealand
| | - V S R Dukkipati
- Institute of Vet, Animal, and Biomedical Sciences, Massey University, Palmerston North 4442, New Zealand
| | - J R Roche
- DairyNZ, Hamilton 3284, New Zealand.
| | - M D Mitchell
- University of Queensland, Centre for Clinical Research, Herston, Queensland 4029, Australia
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18
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Sturgeon C, Lan J, Fasano A. Zonulin transgenic mice show altered gut permeability and increased morbidity/mortality in the DSS colitis model. Ann N Y Acad Sci 2017; 1397:130-142. [PMID: 28423466 DOI: 10.1111/nyas.13343] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 02/24/2017] [Accepted: 03/01/2017] [Indexed: 12/22/2022]
Abstract
Increased small intestinal permeability (IP) has been proposed to be an integral element, along with genetic makeup and environmental triggers, in the pathogenies of chronic inflammatory diseases (CIDs). We identified zonulin as a master regular of intercellular tight junctions linked to the development of several CIDs. We aim to study the role of zonulin-mediated IP in the pathogenesis of CIDs. Zonulin transgenic Hp2 mice (Ztm) were subjected to dextran sodium sulfate (DSS) treatment for 7 days, followed by 4-7 days' recovery and compared to C57Bl/6 (wild-type (WT)) mice. IP was measured in vivo and ex vivo, and weight, histology, and survival were monitored. To mechanistically link zonulin-dependent impairment of small intestinal barrier function with clinical outcome, Ztm were treated with the zonulin inhibitor AT1001 added to drinking water in addition to DSS. We observed increased morbidity (more pronounced weight loss and colitis) and mortality (40-70% compared with 0% in WT) at 11 days post-DSS treatment in Ztm compared with WT mice. Both in vivo and ex vivo measurements showed an increased IP at baseline in Ztm compared to WT mice, which was exacerbated by DSS treatment and was associated with upregulation of zonulin gene expression (fourfold in the duodenum, sixfold in the jejunum). Treatment with AT1001 prevented the DSS-induced increased IP both in vivo and ex vivo without changing zonulin gene expression and completely reverted morbidity and mortality in Ztm. Our data show that zonulin-dependent small intestinal barrier impairment is an early step leading to the break of tolerance with subsequent development of CIDs.
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Affiliation(s)
- Craig Sturgeon
- Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, Massachusetts.,Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, Maryland
| | - Jinggang Lan
- Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, Massachusetts
| | - Alessio Fasano
- Mucosal Immunology and Biology Research Center, Center for Celiac Research, and Division of Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital for Children, Boston, Massachusetts.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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19
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Harbige LS, Pinto E, Allgrove J, Thomas LV. Immune Response of Healthy Adults to the Ingested Probiotic Lactobacillus casei Shirota. Scand J Immunol 2017; 84:353-364. [PMID: 27718254 DOI: 10.1111/sji.12495] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/04/2016] [Indexed: 12/18/2022]
Abstract
Daily ingestion of a probiotic drink containing Lactobacillus casei Shirota (LcS; 1.3 × 1010 live cells) by healthy adults for (1) 4-week LcS, (2) 6-week discontinuation of LcS and (3) a final 4 weeks of LcS was investigated. There was a significant increase in expression of the T cell activation marker CD3+ CD69+ in ex vivo unstimulated blood cells at weeks 10 and 14, and there was a significant increase in the NK cell marker CD3+ CD16/56+ in ex vivo unstimulated blood cells at weeks 4, 10 and 14. Expression of the NK cell activation marker CD16/56+ CD69+ in ex vivo unstimulated blood cells was 62% higher at week 10 and 74% higher at week 14. Intracellular staining of IL-4 in ex vivo unstimulated and PMA-/ionomycin-stimulated CD3+ β7+ integrin blood cells was significantly lower at weeks 10 and 14. Intracellular staining of IL-12 in ex vivo unstimulated and LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Intracellular staining of TNF-α in LPS-stimulated CD14+ blood cells was significantly lower at weeks 4, 10 and 14. Mucosal salivary IFN-γ, IgA1 and IgA2 concentrations were significantly higher at week 14, but LcS did not affect systemic circulating influenza A-specific IgA or IgG and tetanus-specific IgG antibody levels. In addition to the decrease in CD3+ β7+ integrin cell IL-4 and a reduced CD14+ cell pro-inflammatory cytokine profile, at week 14 increased expression of activation markers on circulating T cells and NK cells and higher mucosal salivary IgA1 and IgA2 concentration indicated a secondary boosting effect of LcS.
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Affiliation(s)
- L S Harbige
- Department of Life Sciences, Faculty of Engineering and Science, University of Greenwich at Medway, Chatham Maritime, Kent, UK
| | - E Pinto
- Department of Life Sciences, Faculty of Engineering and Science, University of Greenwich at Medway, Chatham Maritime, Kent, UK
| | - J Allgrove
- Faculty of Science, Engineering and Computing, Kingston University, Surrey, UK
| | - L V Thomas
- Yakult UK Ltd, Anteros, Odyssey Business Park, South Ruislip, Middlesex, UK
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Frizzell H, Park J, Comandante Lou N, Woodrow KA. Role of heterogeneous cell population on modulation of dendritic cell phenotype and activation of CD8 T cells for use in cell-based immunotherapies. Cell Immunol 2017; 311:54-62. [PMID: 27793335 PMCID: PMC5283719 DOI: 10.1016/j.cellimm.2016.10.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/11/2016] [Accepted: 10/11/2016] [Indexed: 02/05/2023]
Abstract
Dendritic cell (DC)-based immunotherapies have much utility in their ability to prime antigen-specific adaptive immune responses. However, there does not yet exist a consensus standard to how DCs should be primed. In this study, we aimed to determine the role of heterogeneous co-cultures, composed of both CD11c+ (DCs) and CD11c- cells, in combination with monophosphoryl lipid A (MPLA) stimulation on DC phenotype and function. Upon DC priming in different co-culture ratios, we observed reduced expression of MHCII and CD86 and increased antigen uptake among CD11c+ cells in a CD11c- dependent manner. DCs from all culture conditions were induced to mature by MPLA treatment, as determined by secretion of pro-inflammatory cytokines IL-12 and TNF-α. Antigen-specific stimulation of CD4+ T cells was not modulated by co-culture composition, in terms of proliferation nor levels of IFN-γ. However, the presence of CD11c- cells enhanced cross-presentation to CD8+ T cells compared to purified CD11c+ cells, resulting in increased cell proliferation along with higher IFN-γ production. These findings demonstrate the impact of cell populations present during DC priming, and point to the use of heterogeneous cultures of DCs and innate immune cells to enhance cell-mediated immunity.
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Affiliation(s)
- Hannah Frizzell
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA
| | - Jaehyung Park
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA
| | - Natacha Comandante Lou
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA
| | - Kim A Woodrow
- Department of Bioengineering, University of Washington, 3720 15th Ave NE, Seattle, WA 98105, USA.
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Zhou Z, Ding M, Huang L, Gilkeson G, Lang R, Jiang W. Toll-like receptor-mediated immune responses in intestinal macrophages; implications for mucosal immunity and autoimmune diseases. Clin Immunol 2016; 173:81-86. [PMID: 27620642 PMCID: PMC5148676 DOI: 10.1016/j.clim.2016.09.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 09/04/2016] [Accepted: 09/07/2016] [Indexed: 12/21/2022]
Abstract
Monocytes are precursors of macrophages and key players during inflammation and pathogen challenge in the periphery, whereas intestinal resident macrophages act as innate effector cells to engulf and clear bacteria, secrete cytokines, and maintain intestinal immunity and homeostasis. However, perturbation of toll-like receptor signaling pathway in intestinal macrophages has been associated with tolerance breakdown in autoimmune diseases. In the present review, we have summarized and discussed the role of toll-like receptor signals in human intestinal macrophages, and the role of human intestinal macrophages in keeping human intestinal immunity, homeostasis, and autoimmune diseases.
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Affiliation(s)
- Zejun Zhou
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA
| | - Miao Ding
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA
| | - Lei Huang
- The 302 Hospital of PLA, Treatment and Research Center for Infectious Diseases, Beijing 100039, China
| | - Gary Gilkeson
- Division of Rheumatology, Department of Medicine, Medical University of South Carolina, Charleston 29425, SC, USA
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chaoyang Hospital, Capital Medical University, Beijing 10020, China.
| | - Wei Jiang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston 29425, USA; Division of Infectious Diseases, Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.
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22
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Suda Y, Villena J, Takahashi Y, Hosoya S, Tomosada Y, Tsukida K, Shimazu T, Aso H, Tohno M, Ishida M, Makino S, Ikegami S, Kitazawa H. Immunobiotic Lactobacillus jensenii as immune-health promoting factor to improve growth performance and productivity in post-weaning pigs. BMC Immunol 2014; 15:24. [PMID: 24943108 PMCID: PMC4068960 DOI: 10.1186/1471-2172-15-24] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 06/09/2014] [Indexed: 11/10/2022] Open
Abstract
Background Immunoregulatory probiotics (immunobiotics) have been proposed to improve piglets’ immune system to avoid intestinal infections and reduce unproductive inflammation after weaning. Previously, it was demonstrated that Lactobacillus jensenii TL2937 (LjTL2937) attenuated the inflammatory response triggered by activation of Toll-like receptor 4 (TLR-4) in porcine intestinal epithelial (PIE) cells and antigen presenting cells (APCs) from porcine Peyer’s patches (PP). Objective In view of the critical importance of PIE-APCs interactions in the regulation of intestinal immune responses, we aimed to examine the effect of LjTL2937 on activation patterns of APCs from swine PPs in co-cultures with PIE cells. In addition, we investigated whether LjTL2937 was able to beneficially modulate intestinal immunity of piglets after weaning to improve immune-health status. Results Stimulation of PIE-APCs co-cultures with LjTL2937 increased the expression of MHC-II, CD80/86, IL-10, and Bcl-3 in CD172a+CD11R1- and CD172a+CD11R1high APCs. In addition, the TL2937 strain caused the upregulation of three negative regulators of TLR4 in PIE cells: MKP-1, Bcl-3 and A20. These changes significantly reduced the inflammatory response triggered by TLR4 activation in PIE-APCs co-cultures. The in vivo experiments using castrated male piglets (crossbreeding (LWD) with Landrace (L), Large Yorkshire (W) and Duroc (D))of 3 weeks of age demonstrated that feeding with LjTL2937 significantly reduced blood complement activity and C reactive protein concentrations while no changes were observed in blood leukocytes, ratio of granulocytes to lymphocyte numbers, macrophages’ activity and antibody levels. In addition, treatment with LjTL2937 significantly improved growth performance and productivity, and increased carcass quality. Conclusions We demonstrated that the use of immunobiotics strains like LjTL2937, as supplemental additives for piglets feedings, could be used as a strategy to maintain and improve intestinal homeostasis; that is important for the development of the pig and for health and performance throughout the productive life of the animal.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Haruki Kitazawa
- Food and Feed Immunology Group, Laboratory of Animal Products Chemistry, Graduate School of Agricultural Science Tohoku University, 981-8555 Sendai, Japan.
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Moyat M, Velin D. Immune responses to Helicobacter pylori infection. World J Gastroenterol 2014; 20:5583-5593. [PMID: 24914318 PMCID: PMC4024767 DOI: 10.3748/wjg.v20.i19.5583] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/13/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is one of the most common infections in human beings worldwide. H. pylori express lipopolysaccharides and flagellin that do not activate efficiently Toll-like receptors and express dedicated effectors, such as γ-glutamyl transpeptidase, vacuolating cytotoxin (vacA), arginase, that actively induce tolerogenic signals. In this perspective, H. pylori can be considered as a commensal bacteria belonging to the stomach microbiota. However, when present in the stomach, H. pylori reduce the overall diversity of the gastric microbiota and promote gastric inflammation by inducing Nod1-dependent pro-inflammatory program and by activating neutrophils through the production of a neutrophil activating protein. The maintenance of a chronic inflammation in the gastric mucosa and the direct action of virulence factors (vacA and cytotoxin-associated gene A) confer pro-carcinogenic activities to H. pylori. Hence, H. pylori cannot be considered as symbiotic bacteria but rather as part of the pathobiont. The development of a H. pylori vaccine will bring health benefits for individuals infected with antibiotic resistant H. pylori strains and population of underdeveloped countries.
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Abstract
Healthy individuals possess an immune system comprising physical barriers, innate and acquired immunity as well as the indigenous microflora that populate the body surfaces. The immune system maintains constant vigilance over the body at the cellular level as well as at the interface between the host integument and the resident microflora. However, neoplastic diseases and their treatment often lead to impaired immunity resulting in an increased risk of infections due to viruses, bacteria, fungi, and protozoa. This chapter explores the various aspects of host impairment focusing on the components of immunity and the interplay between them to explain why it is that these patients succumb to infections per se. In so doing, we hope that the reader will be better equipped to understand the risks patients face so as to anticipate potential infectious complications and implement appropriate measures to help attain successful remission of the neoplastic diseases and maintain the best quality of life for the patient.
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Affiliation(s)
- Valentina Stosor
- Div. Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois USA
| | - Teresa R. Zembower
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois USA
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25
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Swiatczak B. Immune balance: the development of the idea and its applications. JOURNAL OF THE HISTORY OF BIOLOGY 2014; 47:411-442. [PMID: 24129740 DOI: 10.1007/s10739-013-9370-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
It has long been taken for granted that the immune system's capacity to protect an individual from infection and disease depends on the power of the system to distinguish between self and nonself. However, accumulating data have undermined this fundamental concept. Evidence against the self/nonself discrimination model left researchers in need of a new overarching framework able to capture the immune system's reactivity. Here, I highlight that along with the self/nonself model, another powerful representation of the immune system's reactivity has been developed in the twentieth century immunology. According to this alternative view, the immune system is not a killer of nonself strangers but a peace-maker helping to establish harmony with the environment. The balance view of the system has never become part of the dominant paradigm. However, it is gaining more and more currency as new research develops. Advances in mucosal immunology confirm that instead of distinguishing between self and foreign the immune system reacts to microbial, chemical and self-induced alterations to produce responses that counterbalance effects of these changes.
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Affiliation(s)
- Bartlomiej Swiatczak
- Department of History of Science, University of Science and Technology of China, 96 Jinzhai Road, Hefei, 230026, People's Republic of China,
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26
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Eri R, Chieppa M. Messages from the Inside. The Dynamic Environment that Favors Intestinal Homeostasis. Front Immunol 2013; 4:323. [PMID: 24130559 PMCID: PMC3793270 DOI: 10.3389/fimmu.2013.00323] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 09/23/2013] [Indexed: 12/15/2022] Open
Abstract
An organism is defined as "an individual living thing capable of responding to stimuli, growing, reproducing, and maintaining homeostasis." Early during evolution multicellular organisms explored the advantages of a symbiotic life. Mammals harbor a complex aggregate of microorganisms (called microbiota) that includes bacteria, fungi, and archaea. Some of these bacteria have already defined beneficial roles for the human host that include the ability to break down nutrients that could not otherwise be digested, preventing the growth of harmful species, as well as the ability to produce vitamins or hormones. It is intuitive that along the evolutionary path several mechanisms favored bacteria that provided advantages to the host which, in return, avoided launching an aggressive immunological response against them. The intestinal immunological response does not ignore the lumenal content, on the contrary, immune surveillance is favored by continuous antigen sampling. Some intestinal epithelial cells (ECs) are crucial during the sampling process, others actively participate in the defense mechanism. In essence the epithelium acts as a traffic light, communicating to the inside world whether conditions are safe or dangerous, and thus influencing immunological response. In this review we will discuss the dynamic factors that act on the intestinal ECs and how they directly or indirectly influence immune cells during states of health and disease.
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Affiliation(s)
- Rajaraman Eri
- Mucosal Biology, School of Human Life Sciences, University of Tasmania, Launceston, TAS, Australia
| | - Marcello Chieppa
- Laboratory of Experimental Immunopathology, IRCCS “De Bellis,” Castellana Grotte, Bari, Italy
- *Correspondence: Marcello Chieppa, Laboratory of Experimental Immunopathology, IRCCS “De Bellis,” Via Turi 27, Castellana Grotte, Bari 70013, Italy e-mail:
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Pickler L, Beirão BC, Hayashi RM, Durau JF, Lourenço MC, Caron LF, Santin E. Effect of sanguinarine in drinking water on Salmonella control and the expression of immune cells in peripheral blood and intestinal mucosa of broilers. J APPL POULTRY RES 2013. [DOI: 10.3382/japr.2012-00649] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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Hocès de la Guardia A, Staedel C, Kaafarany I, Clément A, Roubaud Baudron C, Mégraud F, Lehours P. Inflammatory cytokine and microRNA responses of primary human dendritic cells cultured with Helicobacter pylori strains. Front Microbiol 2013; 4:236. [PMID: 23970881 PMCID: PMC3747313 DOI: 10.3389/fmicb.2013.00236] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 07/30/2013] [Indexed: 12/31/2022] Open
Abstract
Primary human dendritic cells (DC) were used to explore the inflammatory effectors, including cytokines and microRNAs, regulated by Helicobacter pylori. In a 48 h ex-vivo co-culture system, both H. pylori B38 and B45 strains activated human DCs and promoted a strong inflammatory response characterized by the early production of pro-inflammatory TNFα and IL-6 cytokines, followed by IL-10, IL-1β, and IL-23 secretion. IL-23 was the only cytokine dependent on the cag pathogenicity island status of the bacterial strains. DC activation and cytokine production were accompanied by an early miR-146a upregulation followed by a strong miR-155 induction, which mainly controlled TNFα production. These results pave the way for further investigations into the nature of H. pylori antigens and the subsequently activated signaling pathways involved in the inflammatory response to H. pylori infection, the deregulation of which may likely contribute to gastric lymphomagenesis.
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Affiliation(s)
- Anaïs Hocès de la Guardia
- Bacteriology Laboratory, Université Bordeaux Bordeaux, France ; Institut National de la Santé et de la Recherche Médicale, U853 Bordeaux, France
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Rabinowitz K, Mayer L. Working out mechanisms of controlled/physiologic inflammation in the GI tract. Immunol Res 2013; 54:14-24. [PMID: 22466933 DOI: 10.1007/s12026-012-8315-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The mucosal immune system is distinct from its systemic counterpart by virtue of its enormous antigenic exposure (commensal flora, food antigen, pathogens). Despite this, the mucosal immune system maintains a response defined as controlled or physiologic inflammation. This is regulated by many different mechanisms, among which there are physical, cellular and soluble factors. Our laboratory has focused on unique Tregs in the gut controlled by, in one instance, intestinal epithelial cells that serve as non-professional antigen-presenting cells. We believe that intestinal epithelial cells, expressing classical and non-classical MHC molecules, serve to activate Tregs and thus maintain controlled or physiologic inflammation. In this review, we describe regulatory cytokines and T cells that are one part of the emphasis of our laboratory.
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Affiliation(s)
- Keren Rabinowitz
- Mount Sinai School of Medicine, Immunology Institute, 1425 Madison Avenue, Box 1089, New York, NY 10029, USA
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Abstract
There is currently a major focus on the role of the gut barrier function in balancing mucosal immune responses. Increased epithelial permeability for exogenous antigens is a crucial primary or secondary event in the pathogenesis of several disorders affecting body surfaces and beyond. The epithelial gate-keeper function is determined by the individual's age (e.g. preterm vs. term infant), diet, genetics, mucus composition, interactions between mast cells, nerves and neuropeptides, concurrent infection, the commensal microbiota and the epithelium-shielding effect of secretory IgA (SIgA) antibodies provided by breast milk or produced in the individual's gut. The integrity of the epithelial barrier furthermore depends on homeostatic regulatory mechanisms, including mucosal induction of regulatory T cells, where commensal microbiota-host interactions apparently play decisive roles. Thus, both extrinsic and intrinsic factors have been identified that may have an impact on the dynamics of the epithelial cell-cell junctions in the gut and thereby increase or reduce paracellular permeability. Experiments have shown that SIgA normally cooperates with innate defence factors to protect the epithelium and reinforce its barrier function. In the absence of SIgA commensal gut bacteria overstimulate innate epithelial immunity at the expense of expression of genes that regulate fat and carbohydrate metabolism, resulting in an epithelial gene signature that correlates with the development of lipid malabsorption. This shows that the intestinal epithelial barrier is a cross-road between defence and nutrition, and that SIgA is essential to keep the balance between these two functions.
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Affiliation(s)
- P. Brandtzaeg
- Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Centre for Immune Regulation (CIR), University of Oslo
- Department of Pathology, Oslo University Hospital, Rikshospitalet, P.O. Box 4950, 0424 Oslo, Norway
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Kusu T, Kayama H, Kinoshita M, Jeon SG, Ueda Y, Goto Y, Okumura R, Saiga H, Kurakawa T, Ikeda K, Maeda Y, Nishimura JI, Arima Y, Atarashi K, Honda K, Murakami M, Kunisawa J, Kiyono H, Okumura M, Yamamoto M, Takeda K. Ecto-nucleoside triphosphate diphosphohydrolase 7 controls Th17 cell responses through regulation of luminal ATP in the small intestine. THE JOURNAL OF IMMUNOLOGY 2012; 190:774-83. [PMID: 23241884 DOI: 10.4049/jimmunol.1103067] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Extracellular ATP is released from live cells in controlled conditions, as well as dying cells in inflammatory conditions, and, thereby, regulates T cell responses, including Th17 cell induction. The level of extracellular ATP is closely regulated by ATP hydrolyzing enzymes, such as ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases). ENTPDase1/CD39, which is expressed in immune cells, was shown to regulate immune responses by downregulating the ATP level. In this study, we analyzed the immunomodulatory function of ENTPDase7, which is preferentially expressed in epithelial cells in the small intestine. The targeted deletion of Entpd7 encoding ENTPDase7 in mice resulted in increased ATP levels in the small intestinal lumen. The number of Th17 cells was selectively increased in the small intestinal lamina propria in Entpd7(-/-) mice. Th17 cells were decreased by oral administration of antibiotics or the ATP antagonist in Entpd7(-/-) mice, indicating that commensal microbiota-dependent ATP release mediates the enhanced Th17 cell development in the small intestinal lamina propria of Entpd7(-/-) mice. In accordance with the increased number of small intestinal Th17 cells, Entpd7(-/-) mice were resistant to oral infection with Citrobacter rodentium. Entpd7(-/-) mice suffered from severe experimental autoimmune encephalomyelitis, which was associated with increased numbers of CD4(+) T cells producing both IL-17 and IFN-γ. Taken together, these findings demonstrate that ENTPDase7 controls the luminal ATP level and, thereby, regulates Th17 cell development in the small intestine.
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Affiliation(s)
- Takashi Kusu
- Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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Colton CA. Immune heterogeneity in neuroinflammation: dendritic cells in the brain. J Neuroimmune Pharmacol 2012; 8:145-62. [PMID: 23114889 PMCID: PMC4279719 DOI: 10.1007/s11481-012-9414-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 10/22/2012] [Indexed: 12/20/2022]
Abstract
Dendritic cells (DC) are critical to an integrated immune response and serve as the key link between the innate and adaptive arms of the immune system. Under steady state conditions, brain DC’s act as sentinels, continually sampling their local environment. They share this function with macrophages derived from the same basic hemopoietic (bone marrow-derived) precursor and with parenchymal microglia that arise from a unique non-hemopoietic origin. While multiple cells may serve as antigen presenting cells (APCs), dendritic cells present both foreign and self-proteins to naïve T cells that, in turn, carry out effector functions that serve to protect or destroy. The resulting activation of the adaptive response is a critical step to resolution of injury or infection and is key to survival. In this review we will explore the critical roles that DCs play in the brain’s response to neuroinflammatory disease with emphasis on how the brain’s microenvironment impacts these actions.
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Affiliation(s)
- Carol A Colton
- Neurology, Duke University Medical Center, Box 2900, Durham, NC 27710, USA.
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Kim SH, Lee KY, Jang YS. Mucosal Immune System and M Cell-targeting Strategies for Oral Mucosal Vaccination. Immune Netw 2012; 12:165-75. [PMID: 23213309 PMCID: PMC3509160 DOI: 10.4110/in.2012.12.5.165] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Revised: 10/05/2012] [Accepted: 10/09/2012] [Indexed: 02/08/2023] Open
Abstract
Vaccination is one of the most effective methods available to prevent infectious diseases. Mucosa, which are exposed to heavy loads of commensal and pathogenic microorganisms, are one of the first areas where infections are established, and therefore have frontline status in immunity, making mucosa ideal sites for vaccine application. Moreover, vaccination through the mucosal immune system could induce effective systemic immune responses together with mucosal immunity in contrast to parenteral vaccination, which is a poor inducer of effective immunity at mucosal surfaces. Among mucosal vaccines, oral mucosal vaccines have the advantages of ease and low cost of vaccine administration. The oral mucosal immune system, however, is generally recognized as poorly immunogenic due to the frequent induction of tolerance against orally-introduced antigens. Consequently, a prerequisite for successful mucosal vaccination is that the orally introduced antigen should be transported across the mucosal surface into the mucosa-associated lymphoid tissue (MALT). In particular, M cells are responsible for antigen uptake into MALT, and the rapid and effective transcytotic activity of M cells makes them an attractive target for mucosal vaccine delivery, although simple transport of the antigen into M cells does not guarantee the induction of specific immune responses. Consequently, development of mucosal vaccine adjuvants based on an understanding of the biology of M cells has attracted much research interest. Here, we review the characteristics of the oral mucosal immune system and delineate strategies to design effective oral mucosal vaccines with an emphasis on mucosal vaccine adjuvants.
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Affiliation(s)
- Sae-Hae Kim
- Department of Molecular Biology and the Institute for Molecular Biology and Genetics, Chonbuk National University, Jeonju 561-756, Korea
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Tiscornia I, Sánchez-Martins V, Hernández A, Bollati-Fogolín M. Human monocyte-derived dendritic cells from leukoreduction system chambers after plateletpheresis are functional in an in vitro co-culture assay with intestinal epithelial cells. J Immunol Methods 2012; 384:164-70. [DOI: 10.1016/j.jim.2012.07.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 07/14/2012] [Accepted: 07/16/2012] [Indexed: 01/08/2023]
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35
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Functional RNA delivery targeted to dendritic cells by synthetic nanoparticles. Ther Deliv 2012; 3:1077-99. [DOI: 10.4155/tde.12.90] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Dendritic cells (DCs) are essential to many aspects of immune defense development and regulation. They provide important targets for prophylactic and therapeutic delivery. While protein delivery has had considerable success, RNA delivery is still expanding. Delivering RNA molecules for RNAi has shown particular success and there are reports on successful delivery of mRNA. Central, therein, is the application of cationic entities. Following endocytosis of the delivery vehicle for the RNA, cationic entities should promote vesicular membrane perturbation, facilitating cytosolic release. The present review explains the diversity of DC function in immune response development and control. Promotion of delivered RNA cytosolic release is discussed, relating to immunoprophylactic and therapeutic potential, and DC endocytic machinery is reviewed, showing how DC endocytic pathways influence the handling of internalized material. The potential advantages for application of replicating RNA are presented and discussed, in consideration of their value and development in the near future.
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36
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Weisser SB, van Rooijen N, Sly LM. Depletion and reconstitution of macrophages in mice. J Vis Exp 2012:4105. [PMID: 22871793 DOI: 10.3791/4105] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Macrophages are critical players in the innate immune response to infectious challenge or injury, initiating the innate immune response and directing the acquired immune response. Macrophage dysfunction can lead to an inability to mount an appropriate immune response and as such, has been implicated in many disease processes, including inflammatory bowel diseases. Macrophages display polarized phenotypes that are broadly divided into two categories. Classically activated macrophages, activated by stimulation with IFNγ or LPS, play an essential role in response to bacterial challenge whereas alternatively activated macrophages, activated by IL-4 or IL-13, participate in debris scavenging and tissue remodeling and have been implicated in the resolution phase of inflammation. During an inflammatory response in vivo, macrophages are found amid a complex mixture of infiltrating immune cells and may participate by exacerbating or resolving inflammation. To define the role of macrophages in situ in a whole animal model, it is necessary to examine the effect of depleting macrophages from the complex environment. To ask questions about the role of macrophage phenotype in situ, phenotypically defined polarized macrophages can be derived ex vivo, from bone marrow aspirates and added back to mice, with or without prior depletion of macrophages. In the protocol presented here clodronate-containing liposomes, versus PBS injected controls, were used to deplete colonic macrophages during dextran sodium sulfate (DSS)-induced colitis in mice. In addition, polarized macrophages were derived ex vivo and transferred to mice by intravenous injection. A caveat to this approach is that clodronate-containing liposomes deplete all professional phagocytes, including both dendritic cells and macrophages so to ensure the effect observed by depletion is macrophage-specific, reconstitution of phenotype by adoptive transfer of macrophages is necessary. Systemic macrophage depletion in mice can also be achieved by backcrossing mice onto a CD11b-DTR background, which is an excellent complementary approach. The advantage of clodronate-containing liposome-mediated depletion is that it does not require the time and expense involved in backcrossing mice and it can be used in mice regardless of the background of the mice (C57BL/6, BALB/c, or mixed background).
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Diesner SC, Förster-Waldl E, Olivera A, Pollak A, Jensen-Jarolim E, Untersmayr E. Perspectives on immunomodulation early in life. Pediatr Allergy Immunol 2012; 23:210-23. [PMID: 22299601 DOI: 10.1111/j.1399-3038.2011.01259.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The immune system early in life is characterized by immature activation and function of immune cells and a preponderance of Th2 cytokines. Together with other factors such as genetics and epigenetics, these immature immune responses might prone newborns susceptible to severe infections as well as allergic diseases. Immunomodulation therapy may have potential as therapeutic strategy against those disorders and might have implication in early-life interventions in the future. In this review, we will focus on two immunomodulatory substance classes, Toll-like receptor (TLR) ligands and sphingolipids, which are the focus of extensive research to date. Both TLRs and sphingolipid receptors have a very distinct distribution pattern and function on immune cells. Therefore, they can potentially modulate and balance immune responses, which might be in particular beneficial for the immaturity of the immune response early in life.
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Affiliation(s)
- Susanne C Diesner
- Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria
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Bonnefont CMD, Rainard P, Cunha P, Gilbert FB, Toufeer M, Aurel MR, Rupp R, Foucras G. Genetic susceptibility to S. aureus mastitis in sheep: differential expression of mammary epithelial cells in response to live bacteria or supernatant. Physiol Genomics 2012; 44:403-16. [PMID: 22337903 DOI: 10.1152/physiolgenomics.00155.2011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Staphylococcus aureus is a prevalent pathogen for mastitis in dairy ruminants and is responsible for both clinical and subclinical mastitis. Mammary epithelial cells (MEC) represent not only a physical barrier against bacterial invasion but are also active players of the innate immune response permitting infection clearance. To decipher their functions in general and in animals showing different levels of genetic predisposition to Staphylococcus in particular, MEC from ewes undergoing a divergent selection on milk somatic cell count were stimulated by S. aureus. MEC response was also studied according to the stimulation condition with live bacteria or culture supernatant. The early MEC response was studied during a 5 h time course by microarray to identify differentially expressed genes with regard to the host genetic background and as a function of the conditions of stimulation. In both conditions of stimulation, metabolic processes were altered, the apoptosis-associated pathways were considerably modified, and inflammatory and immune responses were enhanced with the upregulation of il1a, il1b, and tnfa and several chemokines known to enhance neutrophil (cxcl8) or mononuclear leukocyte (ccl20) recruitment. Genes associated with oxidative stress were increased after live bacteria stimulation, whereas immune response-related genes were higher after supernatant stimulation in the early phase. Only 20 genes were differentially expressed between Staphylococcus spp-mastitis resistant and susceptible animals without any clearly defined role on the control of infection. To conclude, this suggests that MEC may not represent the cell type at the origin of the difference of mastitis susceptibility, at least as demonstrated in our genetic model. Supernatant or heat-killed S. aureus produce biological effects that are essentially different from those induced by live bacteria.
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Affiliation(s)
- Cécile M D Bonnefont
- Université de Toulouse, Institut National Polytechnique (INP), École Nationale Vétérinaire de Toulouse (ENVT), Unité Mixte de Recherche (UMR)1225, Interactions Hôtes - Agents Pathogènes (IHAP), Toulouse, France
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Hörmannsperger G, Clavel T, Haller D. Gut matters: microbe-host interactions in allergic diseases. J Allergy Clin Immunol 2012; 129:1452-9. [PMID: 22322009 DOI: 10.1016/j.jaci.2011.12.993] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 12/09/2011] [Accepted: 12/21/2011] [Indexed: 02/07/2023]
Abstract
The human body can be considered a metaorganism made up of its own eukaryotic cells and trillions of microbes that colonize superficial body sites, such as the skin, airways, and gastrointestinal tract. The coevolution of host and microbes brought about a variety of molecular mechanisms, which ensure a peaceful relationship. The mammalian barrier and immune functions warrant simultaneous protection of the host against deleterious infections, as well as tolerance toward harmless commensals. Because these pivotal host functions evolved under high microbial pressure, they obviously depend on a complex network of microbe-host interactions. The rapid spread of immune-mediated disorders, such as autoimmune diseases, inflammatory bowel diseases, and allergies, in westernized countries is thus thought to be due to environmentally mediated disturbances of this microbe-host interaction network. The aim of the present review is to highlight the importance of the intestinal microbiota in shaping host immune mechanisms, with particular emphasis on allergic diseases and possible intervention strategies.
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Affiliation(s)
- Gabriele Hörmannsperger
- Biofunctionality, ZIEL-Research Center for Nutrition and Food Science, CDD Center for Diet and Disease, Technische Universität München, Freising-Weihenstephan, Germany
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Renz H, Autenrieth IB, Brandtzæg P, Cookson WO, Holgate S, von Mutius E, Valenta R, Haller D. Gene-environment interaction in chronic disease: a European Science Foundation Forward Look. J Allergy Clin Immunol 2012; 128:S27-49. [PMID: 22118218 DOI: 10.1016/j.jaci.2011.09.039] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2011] [Accepted: 09/20/2011] [Indexed: 12/13/2022]
Abstract
Over the last half century, a dramatic increase in the incidence of chronic inflammatory diseases, such as asthma, allergy, and irritable bowel syndrome, has rightfully led to concern about how the modern lifestyle might inappropriately trigger innate physiologic defense mechanisms. Health care research in the Western world is faced with a significant challenge if it is to meet the needs of its populations in the decades ahead. The tools with which we hope to advance our understanding of the intrinsic and extrinsic mechanisms of chronic inflammatory diseases must therefore be adequately exploited and further developed to identify treatment and prevention strategies. There is an urgent need to prioritize resources and identify the most efficient scientific and societal initiatives to be adopted within this area. In this context national collaboration within Europe and beyond to establish state-of-the-art practices with an interdisciplinary perspective and promote an efficient exchange of best practices is essential. Such an approach likely represents the most efficient manner in which strategies for amelioration of the increase of chronic inflammatory diseases in the Western world can be achieved. The present report is based on a Forward Look initiative conducted by the European Medical Research Councils under the European Science Foundation. Experts from industry and academia, as well as relevant interest organizations, have been consulted in the process of conducting this initiative and have, based on this work, developed a set of final recommendations that target academic research, science funders, and policy makers.
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Affiliation(s)
- Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University Marburg, Marburg, Germany.
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41
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Yang W, Bhandaru M, Pasham V, Bobbala D, Zelenak C, Jilani K, Rotte A, Lang F. Effect of Thymoquinone on Cytosolic pH and Na +/H + Exchanger Activity in Mouse Dendritic Cells. Cell Physiol Biochem 2012; 29:21-30. [DOI: 10.1159/000337583] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2012] [Indexed: 01/13/2023] Open
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Rodriguez Rodrigues C, Cabrini M, Remes Lenicov F, Sabatté J, Ceballos A, Jancic C, Raiden S, Ostrowski M, Silberstein C, Geffner J. Epithelial cells activate plasmacytoid dendritic cells improving their anti-HIV activity. PLoS One 2011; 6:e28709. [PMID: 22163327 PMCID: PMC3233592 DOI: 10.1371/journal.pone.0028709] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 11/14/2011] [Indexed: 12/03/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) play a major role in anti-viral immunity by virtue of their ability to produce high amounts of type I interferons (IFNs) and a variety of inflammatory cytokines and chemokines in response to viral infections. Since recent studies have established that pDCs accumulate at the site of virus entry in the mucosa, here we analyzed whether epithelial cells were able to modulate the function of pDCs. We found that the epithelial cell lines HT-29 and Caco-2, as well as a primary culture of human renal tubular epithelial cells (HRTEC), induced the phenotypic maturation of pDCs stimulating the production of inflammatory cytokines. By contrast, epithelial cells did not induce any change in the phenotype of conventional or myeloid DCs (cDCs) while significantly stimulated the production of the anti-inflammatory cytokine IL-10. Activation of pDCs by epithelial cells was prevented by Bafilomycin A1, an inhibitor of endosomal acidification as well as by the addition of RNase to the culture medium, suggesting the participation of endosomal TLRs. Interestingly, the cross-talk between both cell populations was shown to be associated to an increased expression of TLR7 and TLR9 by pDCs and the production of LL37 by epithelial cells, an antimicrobial peptide able to bind and transport extracellular nucleic acids into the endosomal compartments. Interestingly, epithelium-activated pDCs impaired the establishment of a productive HIV infection in two susceptible target cells through the stimulation of the production of type I IFNs, highlighting the anti-viral efficiency of this novel activation pathway.
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Affiliation(s)
| | - Mercedes Cabrini
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Federico Remes Lenicov
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Juan Sabatté
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Ana Ceballos
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Carolina Jancic
- IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Silvina Raiden
- IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina
| | - Matías Ostrowski
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
| | - Claudia Silberstein
- Laboratorio de Fisiopatogenia, Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge Geffner
- Centro Nacional de Referencia para el SIDA, Facultad de Medicina, Universidad de Buenos Aires, Argentina
- IIHEMA, Academia Nacional de Medicina, Buenos Aires, Argentina
- * E-mail:
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Swiatczak B, Rescigno M, Cohen IR. Systemic features of immune recognition in the gut. Microbes Infect 2011; 13:983-91. [DOI: 10.1016/j.micinf.2011.06.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 06/23/2011] [Accepted: 06/24/2011] [Indexed: 12/15/2022]
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Fujie H, Villena J, Tohno M, Morie K, Shimazu T, Aso H, Suda Y, Shimosato T, Iwabuchi N, Xiao JZ, Yaeshima T, Iwatsuki K, Saito T, Numasaki M, Kitazawa H. Toll-like receptor-2-activating bifidobacteria strains differentially regulate inflammatory cytokines in the porcine intestinal epithelial cell culture system: finding new anti-inflammatory immunobiotics. ACTA ACUST UNITED AC 2011; 63:129-39. [PMID: 21711398 DOI: 10.1111/j.1574-695x.2011.00837.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A total of 23 strains of bifidobacteria taxonomically belonging to five species were tested for their potent immunomodulatory effect using a combination of two methods: the NF-κB-reporter assay using a toll-like receptor 2-expressing transfectant (HEK(pTLR2) system) and the mitogenic assay using porcine Peyer's patches immunocompetent cells. Among the four preselected strains from different immunomodulatory groups, Bifidobacterium breve MCC-117 was able to efficiently modulate the inflammatory response triggered by enterotoxigenic Escherichia coli (ETEC) in a porcine intestinal epithelial (PIE) cell line. Moreover, using PIE cells and swine Peyer's patches immunocompetent cell co-culture system, we demonstrated that the immunoregulatory effect of B. breve MCC-117 was related to the capacity of the strain to influence PIE and immune cell interactions, leading to the stimulation of regulatory T cells. The results suggested that bifidobacteria that express high activity in both the HEK(pTLR2) and the mitogenic assays may behave like potential anti-inflammatory strains. The combination of the HEK(pTLR2) system, the evaluation of mitogenic activity and PIE cells will be of value for the development of new immunologically functional foods and feeds that could prevent inflammatory intestinal disorders. Although our findings should be proven in appropriate experiments in vivo, the results of the present work provide a scientific rationale for the use of B. breve MCC-117 to prevent ETEC-induced intestinal inflammation.
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Affiliation(s)
- Hitomi Fujie
- Food Immunology Group, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
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Brandtzaeg P. The gut as communicator between environment and host: immunological consequences. Eur J Pharmacol 2011; 668 Suppl 1:S16-32. [PMID: 21816150 DOI: 10.1016/j.ejphar.2011.07.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 07/01/2011] [Accepted: 07/07/2011] [Indexed: 12/18/2022]
Abstract
During human evolution, the mucosal immune system developed two anti-inflammatory mechanisms: immune exclusion by secretory antibodies (SIgA and SIgM) to control epithelial colonization of microorganisms and inhibit penetration of harmful substances; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens such as food proteins. The latter function is referred to as oral tolerance when induced via the gut. Similar mechanisms also control immunity to commensal bacteria. The development of immune homeostasis depends on "windows of opportunity" where adaptive and innate immunities are coordinated by antigen-presenting cells; their function is not only influenced by microbial products but also by dietary constituents, including vitamin A and lipids like polyunsaturated omega-3 fatty acids. These factors can in several ways exert beneficial effects on the immunophenotype of the infant. Also breast milk provides immune-modulating factors and SIgA antibodies - reinforcing the gut barrier. Mucosal immunity is most abundantly expressed in the gut, and the intestinal mucosa of an adult contains at least 80% of the body's activated B cells - terminally differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric IgA which is exported by secretory epithelia expressing the polymeric Ig receptor (pIgR), also called membrane secretory component (SC). Immune exclusion is therefore performed mainly by SIgA. Notably, pIgR knockout mice which lack SIgs show increased uptake of food and microbial antigens and they have a hyper-reactive immune system with disposition for anaphylaxis; but this untoward development is counteracted by cognate oral tolerance induction as a homeostatic back-up mechanism.
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Affiliation(s)
- Per Brandtzaeg
- Laboratory for Immunohistochemistry and Immunopathology, Centre for Immune Regulation, University of Oslo, and Department of Pathology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
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Bile retinoids imprint intestinal CD103+ dendritic cells with the ability to generate gut-tropic T cells. Mucosal Immunol 2011; 4:438-47. [PMID: 21289617 PMCID: PMC3130189 DOI: 10.1038/mi.2010.91] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Small intestinal lamina propria (SI-LP) CD103(+) dendritic cells (DCs) are imprinted with an ability to metabolize vitamin A (retinol), a property underlying their enhanced capacity to induce the gut-homing receptors CC chemokine receptor-9 and α4β7 on responding T cells. In this study, we demonstrate that imprinting of CD103(+) DCs is itself critically dependent on vitamin A and occurs locally within the small intestine (SI). The major vitamin A metabolite retinoic acid (RA) induced retinol-metabolizing activity in DCs both in vitro and in vivo, suggesting a direct role for RA in this process. Consistent with this, SI-LP CD103(+) DCs constitutively received RA signals in vivo at significantly higher levels than did colonic CD103(+) DCs. Remarkably, SI CD103(+) DCs remained imprinted in mice depleted of dietary but not of systemic retinol. We found that bile contained high levels of retinol, induced RA receptor-dependent retinol-metabolizing activity in bone marrow-derived DCs, and imprinted these cells with the ability to generate gut-tropic T cells. Taken together, these results suggest a novel and unexpected role for bile in SI-LP CD103(+) DC imprinting.
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Abstract
Mucosal surfaces are colonized by large communities of commensal bacteria and represent the primary site of entry for pathogenic agents. To prevent microbial intrusion, mucosal B cells release large amounts of immunoglobulin (Ig) molecules through multiple follicular and extrafollicular pathways. IgA is the most abundant antibody isotype in mucosal secretions and owes its success in frontline immunity to its ability to undergo transcytosis across epithelial cells. In addition to translocating IgA onto the mucosal surface, epithelial cells educate the mucosal immune system as to the composition of the local microbiota and instruct B cells to initiate IgA responses that generate immune protection while preserving immune homeostasis. Here we review recent advances in our understanding of the cellular interactions and signaling pathways governing IgA production at mucosal surfaces and discuss new findings on the regulation and function of mucosal IgD, the most enigmatic isotype of our mucosal antibody repertoire.
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Affiliation(s)
- Andrea Cerutti
- ICREA, Catalan Institute for Research and Advanced Studies, Barcelona Biomedical Research Park, Spain.
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Xuan NT, Shumilina E, Schmid E, Bhavsar SK, Rexhepaj R, Götz F, Gulbins E, Lang F. Role of acidic sphingomyelinase in thymol-mediated dendritic cell death. Mol Nutr Food Res 2011; 54:1833-41. [PMID: 20603831 DOI: 10.1002/mnfr.200900577] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
SCOPE Thymol is a component of several plants with antimicrobial activity. Little is known about the effects of thymol on immune cells of the host. This study addressed the effects of thymol on dendritic cells (DCs), regulators of innate and adaptive immunity. METHODS AND RESULTS Immunohistochemistry, Western blotting and fluorescence-activated cell sorting analysis were performed in bone marrow-derived DCs either from wild-type mice or from mice lacking acid sphingomyelinase (ASM⁻/⁻) treated and untreated for 24 h with thymol (2-100 μg/mL). Thymol treatment resulted in activation of ASM, stimulation of ceramide formation, downregulation of anti-apoptotic Bcl-2 and Bcl-xL proteins, activation of caspase 3 and caspase 8, DNA fragmentation as well as cell membrane scrambling. The effects were dependent on the presence of ASM and were lacking in ASM⁻/⁻ mice or in wild-type DCs treated with sphingomyelinase inhibitor amitriptyline. CONCLUSION Thymol triggers suicidal DC death, an effect mediated by and requiring activation of ASM.
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Affiliation(s)
- Nguyen Thi Xuan
- Department of Physiology, University of Tübingen, Tübingen, Germany
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49
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Martins AJ, Spanton S, Sheikh HI, Kim SO. The anti-inflammatory role of granulocyte colony-stimulating factor in macrophage–dendritic cell crosstalk after Lactobacillus rhamnosusGR-1 exposure. J Leukoc Biol 2011; 89:907-915. [DOI: 10.1189/jlb.0810445] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
Abstract
ABSTRACTMΦs are important sensory cells of the innate immune system and regulate immune responses through releasing different combinations of cytokines. In this study, we examined whether cytokines released by MΦs in response to the probiotic bacterial strain GR-1 modulate the responses of DCs. The cytokine profile released by GR-1-treated MΦs was characterized by low levels of TNF-α, GM-CSF, IL-6, and IL-12 but very high levels of G-CSF. GR-1 CM did not induce expression of the shared p40 subunit of IL-12 and IL-23 and costimulatory molecules CD80 or CD86 or increase T cell stimulatory capacity in DCs. However, in G-CSFR-deficient DCs or after antibody-mediated neutralization of G-CSF, GR-1 CM induced IL-12/23 p40 production significantly, indicating that G-CSF within the GR-1 CM inhibits IL-12/23 p40 production induced by other CM components. GR-1 CM and rG-CSF also inhibited LPS-induced IL-12 production at the mRNA and protein levels. The inhibition of IL-12 production by G-CSF was at least in part mediated through inhibition of JNK activation. Finally, splenic DCs of GR-1-injected mice produced less IL-12/23 p40 than those of PBS-injected mice in response to LPS ex vivo, and this was at least partially dependent on exposure to GR-1-induced G-CSF in vivo. Altogether, these results suggest that G-CSF modulates the IL-12/23 p40 response of DCs in the context of the probiotic GR-1 through MΦ–DC crosstalk.
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Affiliation(s)
- Andrew J Martins
- Department of Microbiology and Immunology, University of Western Ontario , London, Ontario, Canada
- Centre for Human Immunology, University of Western Ontario , London, Ontario, Canada
| | - Sarah Spanton
- Department of Microbiology and Immunology, University of Western Ontario , London, Ontario, Canada
| | - Haroon I Sheikh
- Department of Microbiology and Immunology, University of Western Ontario , London, Ontario, Canada
| | - Sung Ouk Kim
- Department of Microbiology and Immunology, University of Western Ontario , London, Ontario, Canada
- Centre for Human Immunology, University of Western Ontario , London, Ontario, Canada
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Abstract
While largely studied because of their harmful effects on human health, there is growing appreciation that bacteria are important partners for invertebrates and vertebrates, including man. Epithelia in metazoans do not only select their microbiota; a coevolved consortium of microbes enables both invertebrates and vertebrates to expand the range of diet supply, to shape the complex immune system and to control pathogenic bacteria. Microbes in zebrafish and mice regulate gut epithelial homeostasis. In a squid, microbes control the development of the symbiotic light organ. These discoveries point to a key role for bacteria in any metazoan existence, and imply that beneficial bacteria-host interactions should be considered an integral part of development and evolution.
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Affiliation(s)
- Sebastian Fraune
- Zoological Institute, Christian-Albrechts-University Kiel, Olshausen Strasse 40, 24098 Kiel, Germany
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