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Mahdavi M, Kim TY, Prévost K, Balthazar P, Gagné-Ouellet V, Hus IFP, Duchesne É, Harvey S, Gagnon C, Laforest-Lapointe I, Dumont NA, Massé E. Influence of CTG repeats from the human DM1 locus on murine gut microbiota. Comput Struct Biotechnol J 2025; 27:733-743. [PMID: 40092662 PMCID: PMC11908463 DOI: 10.1016/j.csbj.2025.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 02/17/2025] [Accepted: 02/17/2025] [Indexed: 03/19/2025] Open
Abstract
Myotonic Dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the 3' untranslated region of the DMPK gene. This expansion leads to the production of toxic RNA transcripts, which accumulate in the nucleus and interfere with normal RNA processing. DM1 affects a broad range of tissues and systems such as the skeletal muscle, the central nervous system, cardiac, visual, reproductive, and gastrointestinal (GI) system. GI dysfunction is a significant but poorly understood aspect of DM1. Particularly, it is unknown if there are alterations in the intestinal microbiome in DM1. Here, we used a transgenic humanized mouse model (DMSXL) to explore how the gut microbiome may be linked to GI issues in DM1. For this purpose, 68 stool samples from Homozygous, Heterozygous, and Wild-Type (WT) mice were collected. These samples were sequenced by MiSeq and analyzed with DADA2 to generate taxonomic profiles. Our analysis indicated that the overexpression of CTG repeats significantly influences the bacterial structure of the gut microbiome in Homozygous mice samples, especially in terms of the relative abundance of the Patescibacteria and Defferibacterota Phyla. These results provide valuable information about the gut microbiota structure thus improving the understanding of the role of these changes in the pathogenicity as well as GI problems of DM1 patients.
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Affiliation(s)
- Manijeh Mahdavi
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, QC J1E 4K8, Canada
| | - Tae-Yeon Kim
- Department of microbiology, infectiology and immunology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- CHU Sainte-Justine Research Center, Montréal, QC, Canada
| | - Karine Prévost
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, QC J1E 4K8, Canada
| | - Philippe Balthazar
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, QC J1E 4K8, Canada
| | - Valérie Gagné-Ouellet
- Department of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Isabelle Fissette-Paul Hus
- Department of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Élise Duchesne
- School of Rehabilitation Sciences, Faculty of Medicine, Université Laval, Quebec, Quebec, Canada
- Neuromuscular Diseases Interdisciplinary Research Group (GRIMN), Saguenay-Lac-St-Jean Integrated University Health and Social Services Center, Saguenay, Quebec, Canada
- Center for Interdisciplinary Research in Rehabilitation and Social Integration (Cirris), Capitale-Nationale Integrated University Health and Social Services Center, Quebec, Quebec, Canada
- CHU de Québec - Université Laval Research Center, Québec, Québec, Canada
| | - Séréna Harvey
- Department of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Cynthia Gagnon
- Department of Rehabilitation, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1E 4K8, Canada
| | - Isabelle Laforest-Lapointe
- Départment de Biologie, Faculté des Sciences, Université de Sherbrooke, QC J1E 4K8, Canada
- Centre de Recherche du Centre Hospitalier universitaire de Sherbrooke (CR-CHUS), Sherbrooke, QC J1H 5N4, Canada
| | - Nicolas A. Dumont
- CHU Sainte-Justine Research Center, Montréal, QC, Canada
- School of Rehabilitation, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
| | - Eric Massé
- Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, QC J1E 4K8, Canada
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2
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Heredia M, Charrout M, Klomberg RCW, Aardoom MA, Jongsma MME, Kemos P, Hulleman-van Haaften DH, Tuk B, van Berkel LA, Bley Folly B, Calado B, Nugteren S, Simons-Oosterhuis Y, Doukas M, Sanders MA, van Beek G, Ruemmele FM, Croft NM, Mahfouz A, Reinders MJT, Escher JC, de Ridder L, Samsom JN. Combined plasma protein and memory T cell profiling discern IBD-patient-immunotypes related to intestinal disease and treatment outcomes. Mucosal Immunol 2025; 18:76-89. [PMID: 39332767 DOI: 10.1016/j.mucimm.2024.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/29/2024] [Accepted: 09/21/2024] [Indexed: 09/29/2024]
Abstract
Inflammatory bowel disease (IBD) chronicity results from memory T helper cell (Tmem) reactivation. Identifying patient-specific immunotypes is crucial for tailored treatment. We conducted a comprehensive study integrating circulating immune proteins and circulating Tmem, with intestinal tissue histology and mRNA analysis, in therapy-naïve pediatric IBD (Crohn's disease, CD: n = 62; ulcerative colitis, UC: n = 20; age-matched controls n = 43), and after 10-12 weeks' induction therapy. At diagnosis, plasma protein profiles unveiled two UC and three CD clusters with distinct disease courses. UC patients displayed unchanged circulating Tmem, while CD exhibited increased frequencies of gut-homing ex-Th17, known for high IFN-γ production. UC#2 had elevated Th17/neutrophil-pathway-related proteins and severe disease, with higher endoscopic and histological damage and Th17/neutrophil infiltration. Although both UC#1 and UC#2 responded to therapy, UC#2 required earlier immunomodulation. CD#3 had lower plasma protein concentrations, especially IFN-γ pathway proteins, fewer gut-homing ex-Th17 and clinically milder disease, confirmed by intestinal gene expression. CD#1 and CD#2 had comparably high Th1-related immune profiles, but CD#1 exhibited higher concentrations of proteins previously associated with poorer prognosis. Both CD clusters responded to induction therapy, with similar one-year outcomes. This study highlights feasibility of discriminating patient-specific immunotypes in IBD, advancing our understanding of immune pathogenesis, needed for tailored treatment strategies.
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Affiliation(s)
- Maud Heredia
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mohammed Charrout
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
| | - Renz C W Klomberg
- Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Martine A Aardoom
- Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Maria M E Jongsma
- Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Polychronis Kemos
- Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, UK
| | - Danielle H Hulleman-van Haaften
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Bastiaan Tuk
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Lisette A van Berkel
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Brenda Bley Folly
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Beatriz Calado
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Sandrine Nugteren
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ytje Simons-Oosterhuis
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Mathijs A Sanders
- Department of Hematology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Gregory van Beek
- Department of Hematology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Frank M Ruemmele
- Department of Pediatric Gastroenterology, Necker-Enfants Malades University Hospital, Institut Imagine, AP-HP, Université Paris Cité, Paris, France
| | - Nicholas M Croft
- Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London, UK
| | - Ahmed Mahfouz
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Marcel J T Reinders
- Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands
| | - Johanna C Escher
- Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Lissy de Ridder
- Department of Pediatric Gastroenterology, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Janneke N Samsom
- Laboratory of Pediatrics, Division Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Weischendorff S, de Pietri S, Rathe M, Schmiegelow K, Frandsen TL, Petersen MJ, Weimann A, Nielsen CH, Enevold C, Kocadag HB, Moser C, Müller K. Intestinal mucositis, systemic inflammation and bloodstream infections following high-dose methotrexate treatment in childhood acute lymphoblastic leukaemia: Comparison between the NOPHO ALL 2008 protocol and the ALLTogether1 protocol. Int J Cancer 2025; 156:164-173. [PMID: 39150399 DOI: 10.1002/ijc.35136] [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: 03/04/2024] [Revised: 06/14/2024] [Accepted: 07/18/2024] [Indexed: 08/17/2024]
Abstract
Severe intestinal mucositis (IM) increases the risk of bloodstream infections (BSI) and inflammatory toxicity during acute lymphoblastic leukaemia (ALL) induction treatment. However, the implications of IM in subsequent ALL therapy phases after achieving remission remain unknown. This study investigated the relationship between IM (measured by plasma citrulline and the chemokine CCL20) and the development of BSI and systemic inflammation (reflected by C-reactive protein, CRP) in children with ALL during high-dose methotrexate (HDMTX) treatment, an important part of ALL consolidation therapy. The study compared patients treated according to the NOPHO ALL 2008 protocol (n = 52) and the ALLTogether1 protocol (n = 42), both with identical HDMTX procedures but different scheduling. One week post-HDMTX, citrulline dropped to median levels of 14.5 and 16.9 μM for patients treated according to the NOPHO ALL 2008 and ALLTogether1 protocols, respectively (p = 0.11). In a protocol and neutrophil count-adjusted analysis, hypocitrullinaemia (<10 μmol/L) was associated with increased odds of BSI within 3 weeks from HDMTX (OR = 26.2, p = 0.0074). Patients treated according to the NOPHO ALL 2008 protocol exhibited increased mucosal- and systemic inflammation post-HDMTX compared to patients treated according to ALLTogether1, with increased CCL20 (14.6 vs. 3.7 pg/mL, p < 0.0001) and CRP levels (10.0 vs. 1.0 mg/L, p < 0.0001). Both citrulline and CCL20 correlated with CRP for these patients (rs = -0.44, p = 0.0016 and rs = 0.35, p = 0.016, respectively). These results suggest that hypocitrullinaemia following HDMTX increases the risk of BSI, confirming previous observations from more intensive treatments. Moreover, these data indicate that the patients' vulnerability to mucositis and inflammatory toxicity after chemotherapy varies with treatment protocol.
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Affiliation(s)
- Sarah Weischendorff
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute for Inflammation Research, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Silvia de Pietri
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mathias Rathe
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Kjeld Schmiegelow
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen
| | - Thomas Leth Frandsen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Malene Johanne Petersen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Allan Weimann
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Enevold
- Institute for Inflammation Research, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Helin Berna Kocadag
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus Moser
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Immunology and Microbiology, Copenhagen University Hospital, Copenhagen, Denmark
| | - Klaus Müller
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute for Inflammation Research, Centre for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen
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Ames SR, Lotoski LC, Rodriguez L, Brodin P, Mandhane PJ, Moraes TJ, Simons E, Turvey SE, Subbarao P, Azad MB. Human milk feeding practices and serum immune profiles of one-year-old infants in the CHILD birth cohort study. Am J Clin Nutr 2025; 121:60-73. [PMID: 39486685 PMCID: PMC11747196 DOI: 10.1016/j.ajcnut.2024.10.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 10/08/2024] [Accepted: 10/16/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Breastfeeding and human milk consumption are associated with immune system development; however, the underlying mechanisms and the impact of different infant feeding practices are unclear. OBJECTIVES This study aimed to investigate how current human milk feeding (HMF) status is related to infant immune biomarker profiles, as well as explore relationships with HMF history (i.e., duration, exclusivity, and method: directly from the breast or pumped and bottled). METHODS This observational birth cohort study involved 605 infants from the Canadian CHILD Cohort Study. Infant feeding was captured from hospital birth records and parent questionnaires. Ninety-two biomarkers reflecting immune system activity and development were measured in serum collected at 1 y (12.6 ± 1.4 mo) using the Olink Target 96 Inflammation panel. Associations were determined using multivariable regression (adjusted for sex, time until blood sample centrifugation, and study site). RESULTS Nearly half (42.6%) of infants were still receiving HMF at the time of blood sampling. Compared with non-HMF infants, HMF infants had higher levels of serum fibroblast growth factor 21 (FGF-21, adjusted standardized β coefficient: 0.56; 95% CI: 0.41, 0.72), cluster of differentiation 244 (CD244, β: 0.35; 95% CI: 0.19, 0.50), chemokine ligand 6 (CXCL6, β: 0.34; 95% CI: 0.18, 0.50), and chemokine ligand 20 (CCL20, β: 0.26; 95% CI: 0.09, 0.42) and lower extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE, β: -0.16; 95% CI: -0.29, -0.03). Among non-HMF infants, serum interleukin 7 (IL-7) had a marginally positive association with past HMF duration (β: 0.05; 95% CI: 0.02, 0.08) that persisted for ≤5 mo post-HMF cessation. Exclusive HMF duration and HMF method (at 3 mo of age) were not associated with any biomarkers. CONCLUSIONS Current HMF status and (to a lesser extent) HMF history are associated with several inflammation-associated biomarkers in 1-y-old infants. These results provide new evidence that HMF impacts immune activity and development and suggest hypotheses about the underlying mechanisms. They also highlight the importance of including current HMF status in immune system-focused infant serum proteomic studies.
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Affiliation(s)
- Spencer R Ames
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Interdisciplinary Lactation Centre (MILC), Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada
| | - Larisa C Lotoski
- Manitoba Interdisciplinary Lactation Centre (MILC), Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Lucie Rodriguez
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Petter Brodin
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | | | - Theo J Moraes
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
| | - Elinor Simons
- Manitoba Interdisciplinary Lactation Centre (MILC), Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Stuart E Turvey
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Padmaja Subbarao
- Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Meghan B Azad
- Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada; Manitoba Interdisciplinary Lactation Centre (MILC), Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.
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Xia X, Huang Z, Xu C, Fu H, Wang S, Tian J, Rui K. Regulation of intestinal tissue‑resident memory T cells: a potential target for inflammatory bowel disease. Cell Commun Signal 2024; 22:610. [PMID: 39695803 DOI: 10.1186/s12964-024-01984-1] [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: 06/25/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
Tissue-resident memory T (TRM) cells are populations which settle down in non-lymphoid tissues instead of returning to secondary lymph organs after the antigen presentation. These cells can provide rapid on-site immune protection as well as long-term tissue damage. It is reported that TRM cells from small intestine and colon exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional and functional heterogeneity. In this review, we focus on the reason why they lodge in intestinal tract, their developmental plasticity of going back to to circulation, as well as their regulators associated with retention, maintenance, exhaustion and metabolism. We also elaborate their role in the inflammatory bowel disease (IBD) and discuss the potential therapeutic strategies targeting TRM cells.
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Affiliation(s)
- Xin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhanjun Huang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Chengcheng Xu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hailong Fu
- Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengjun Wang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jie Tian
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Fong A, Rochus CM, Shandilya UK, Muniz MMM, Sharma A, Schenkel FS, Karrow NA, Baes CF. The role of interleukin-10 receptor alpha (IL10Rα) in Mycobacterium avium subsp. paratuberculosis infection of a mammary epithelial cell line. BMC Genom Data 2024; 25:58. [PMID: 38867147 PMCID: PMC11167801 DOI: 10.1186/s12863-024-01234-w] [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: 01/29/2024] [Accepted: 05/22/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Johne's disease is a chronic wasting disease caused by the bacterium Mycobacterium avium subspecies paratuberculosis (MAP). Johne's disease is highly contagious and MAP infection in dairy cattle can eventually lead to death. With no available treatment for Johne's disease, genetic selection and improvements in management practices could help reduce its prevalence. In a previous study, the gene coding interleukin-10 receptor subunit alpha (IL10Rα) was associated with Johne's disease in dairy cattle. Our objective was to determine how IL10Rα affects the pathogenesis of MAP by examining the effect of a live MAP challenge on a mammary epithelial cell line (MAC-T) that had IL10Rα knocked out using CRISPR/cas9. The wild type and the IL10Rα knockout MAC-T cell lines were exposed to live MAP bacteria for 72 h. Thereafter, mRNA was extracted from infected and uninfected cells. Differentially expressed genes were compared between the wild type and the IL10Rα knockout cell lines. Gene ontology was performed based on the differentially expressed genes to determine which biological pathways were involved. RESULTS Immune system processes pathways were targeted to determine the effect of IL10Rα on the response to MAP infection. There was a difference in immune response between the wild type and IL10Rα knockout MAC-T cell lines, and less difference in immune response between infected and not infected IL10Rα knockout MAC-T cells, indicating IL10Rα plays an important role in the progression of MAP infection. Additionally, these comparisons allowed us to identify other genes involved in inflammation-mediated chemokine and cytokine signalling, interleukin signalling and toll-like receptor pathways. CONCLUSIONS Identifying differentially expressed genes in wild type and ILR10α knockout MAC-T cells infected with live MAP bacteria provided further evidence that IL10Rα contributes to mounting an immune response to MAP infection and allowed us to identify additional potential candidate genes involved in this process. We found there was a complex immune response during MAP infection that is controlled by many genes.
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Affiliation(s)
- Aisha Fong
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Christina M Rochus
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada.
- The Roslin Institute, The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.
| | - Umesh K Shandilya
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Maria M M Muniz
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Ankita Sharma
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Flavio S Schenkel
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Niel A Karrow
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Christine F Baes
- Department of Animal Biosciences, Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, N1G 2W1, Canada.
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 3002, Switzerland.
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7
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Weischendorff S, Rathe M, Petersen MJ, Weimann A, Enevold C, Nielsen CH, Als-Nielsen B, Nygaard U, Moser C, Müller K. Markers of intestinal mucositis to predict blood stream infections at the onset of fever during treatment for childhood acute leukemia. Leukemia 2024; 38:14-20. [PMID: 37919603 PMCID: PMC10776407 DOI: 10.1038/s41375-023-02077-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/16/2023] [Accepted: 10/18/2023] [Indexed: 11/04/2023]
Abstract
Despite chemotherapy-induced intestinal mucositis being a main risk factor for blood stream infections (BSIs), no studies have investigated mucositis severity to predict BSI at fever onset during acute leukemia treatment. This study prospectively evaluated intestinal mucositis severity in 85 children with acute leukemia, representing 242 febrile episodes (122 with concurrent neutropenia) by measuring plasma levels of citrulline (reflecting enterocyte loss), regenerating islet-derived-protein 3α (REG3α, an intestinal antimicrobial peptide) and CCL20 (a mucosal immune regulatory chemokine) along with the general neutrophil chemo-attractants CXCL1 and CXCL8 at fever onset. BSI was documented in 14% of all febrile episodes and in 20% of the neutropenic febrile episodes. In age-, sex-, diagnosis- and neutrophil count-adjusted analyses, decreasing citrulline levels and increasing REG3α and CCL20 levels were independently associated with increased odds of BSI (OR = 1.6, 1.5 and 1.7 per halving/doubling, all p < 0.05). Additionally, higher CXCL1 and CXCL8 levels increased the odds of BSI (OR = 1.8 and 1.7 per doubling, all p < 0.0001). All three chemokines showed improved diagnostic accuracy compared to C-reactive protein and procalcitonin. These findings underline the importance of disrupted intestinal integrity as a main risk factor for BSI and suggest that objective markers for monitoring mucositis severity may help predicting BSI at fever onset.
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Affiliation(s)
- Sarah Weischendorff
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen, Denmark.
| | - Mathias Rathe
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | | | - Allan Weimann
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Christian Enevold
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen, Denmark
| | - Claus H Nielsen
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen, Denmark
| | - Bodil Als-Nielsen
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Ulrikka Nygaard
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Claus Moser
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen, Denmark
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Mehandru S, Colombel JF, Juarez J, Bugni J, Lindsay JO. Understanding the molecular mechanisms of anti-trafficking therapies and their clinical relevance in inflammatory bowel disease. Mucosal Immunol 2023; 16:859-870. [PMID: 37574127 PMCID: PMC11141405 DOI: 10.1016/j.mucimm.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 08/06/2023] [Indexed: 08/15/2023]
Abstract
In patients with inflammatory bowel disease (IBD), a combination of dysbiosis, increased intestinal permeability, and insufficient regulatory responses facilitate the development of chronic inflammation, which is driven by a complex interplay between the mucosal immune system and the environment and sustained by immune priming and ongoing cellular recruitment to the gut. The localization of immune cells is mediated by their expression of chemokine receptors and integrins, which bind to chemokines and adhesion molecules, respectively. In this article, we review the mechanisms of action of anti-trafficking therapies for IBD and consider clinical observations in the context of the different mechanisms of action. Furthermore, we discuss the evolution of molecular resistance to anti-cytokines, in which the composition of immune cells in the gut changes in response to treatment, and the potential implications of this for treatment sequencing. Lastly, we discuss the relevance of mechanism of action to combination therapy for IBD.
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Affiliation(s)
- Saurabh Mehandru
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Jean-Frederic Colombel
- The Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Julius Juarez
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James Bugni
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, UK
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9
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De Pietri S, Weischendorff S, Rathe M, Frandsen TL, Hasle H, Nersting J, Nielsen CH, Moser C, Müller K. Gastrointestinal barrier integrity and mucosal inflammation as risk factors of blood stream infections in children treated for acute lymphoblastic leukaemia. Int J Cancer 2023; 153:1635-1642. [PMID: 37387257 DOI: 10.1002/ijc.34639] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 06/08/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Chemotherapy-induced mucositis increases the risk of blood stream infections (BSI) due to translocation of bacteria across the intestinal epithelium. Our study investigated if quantitative measures of intestinal mucositis severity, including plasma citrulline (a marker of functional enterocytes) and CCL20 (an intestinal immune homeostatic chemokine), could identify patients at risk of BSI. A total of 106 children with ALL undergoing induction treatment (NOPHO ALL 2008) were included and information regarding BSI episodes was collected from the patients' medical records. Twenty-seven patients (25%) developed BSI during induction. Patients with BSI had a larger decrease in citrulline after chemotherapy than patients without BSI, and nearly all BSI episodes (25/27) occurred in the group of patients exhibiting a drop in citrulline (OR = 6.4 [95% CI: 1.4-29.3], P = .008). Patients who developed BSI had higher plasma CCL20 levels on days 8, 15 and 22 than patients without BSI (all P < .05), and elevated CCL20 levels on day 8 increased the risk of subsequent BSI (OR = 1.57 [1.11-2.22] per doubling of CCL20 level, P = .01) in a multivariable logistic regression analysis. These findings suggest that children with ALL who develop BSI during chemotherapy are characterised by more severe intestinal mucositis, as measured by plasma citrulline and CCL20. These markers may be useful in early risk stratification to guide treatment decisions.
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Affiliation(s)
- Silvia De Pietri
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Sarah Weischendorff
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Mathias Rathe
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Thomas Leth Frandsen
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Henrik Hasle
- Department of Paediatrics, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jacob Nersting
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus H Nielsen
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Claus Moser
- Department of Clinical Microbiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Klaus Müller
- Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
- Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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10
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He R, Zhao S, Cui M, Chen Y, Ma J, Li J, Wang X. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations. Front Immunol 2023; 14:1234535. [PMID: 37954590 PMCID: PMC10637386 DOI: 10.3389/fimmu.2023.1234535] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease typically involving the gastrointestinal tract but not limited to it. IBD can be subdivided into Crohn's disease (CD) and ulcerative colitis (UC). Extraintestinal manifestations (EIMs) are observed in up to 47% of patients with IBD, with the most frequent reports of cutaneous manifestations. Among these, pyoderma gangrenosum (PG) and erythema nodosum (EN) are the two most common skin manifestations in IBD, and both are immune-related inflammatory skin diseases. The presence of cutaneous EIMs may either be concordant with intestinal disease activity or have an independent course. Despite some progress in research on EIMs, for instance, ectopic expression of gut-specific mucosal address cell adhesion molecule-1 (MAdCAM-1) and chemokine CCL25 on the vascular endothelium of the portal tract have been demonstrated in IBD-related primary sclerosing cholangitis (PSC), little is understood about the potential pathophysiological associations between IBD and cutaneous EIMs. Whether cutaneous EIMs are inflammatory events with a commonly shared genetic background or environmental risk factors with IBD but independent of IBD or are the result of an extraintestinal extension of intestinal inflammation, remains unclear. The review aims to provide an overview of the two most representative cutaneous manifestations of IBD, describe IBD's epidemiology, clinical characteristics, and histology, and discuss the immunopathophysiology and existing treatment strategies with biologic agents, with a focus on the potential pathophysiological associations between IBD and cutaneous EIMs.
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Affiliation(s)
- Ronghua He
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Subei Zhao
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mingyu Cui
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yanhao Chen
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinrong Ma
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jintao Li
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaodong Wang
- Department of Gastroenterology, The Second Hospital of Jilin University, Changchun, Jilin, China
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11
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Li J, Ji Y, Chen N, Dai L, Deng H. Colitis-associated carcinogenesis: crosstalk between tumors, immune cells and gut microbiota. Cell Biosci 2023; 13:194. [PMID: 37875976 PMCID: PMC10594787 DOI: 10.1186/s13578-023-01139-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. One of the main causes of colorectal cancer is inflammatory bowel disease (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD). Intestinal epithelial cells (IECs), intestinal mesenchymal cells (IMCs), immune cells, and gut microbiota construct the main body of the colon and maintain colon homeostasis. In the development of colitis and colitis-associated carcinogenesis, the damage, disorder or excessive recruitment of different cells such as IECs, IMCs, immune cells and intestinal microbiota play different roles during these processes. This review aims to discuss the various roles of different cells and the crosstalk of these cells in transforming intestinal inflammation to cancer, which provides new therapeutic methods for chemotherapy, targeted therapy, immunotherapy and microbial therapy.
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Affiliation(s)
- Junshu Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Yanhong Ji
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Na Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China
| | - Lei Dai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China.
| | - Hongxin Deng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Ke Yuan Road 4, No. 1 Gao Peng Street, Chengdu, 610041, China.
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12
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Kamal S, Parkash N, Beattie W, Christensen B, Segal JP. Are We Ready to Reclassify Crohn's Disease Using Molecular Classification? J Clin Med 2023; 12:5786. [PMID: 37762727 PMCID: PMC10532006 DOI: 10.3390/jcm12185786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/21/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Crohn's disease (CD) is a type of inflammatory bowel disease. The number of IBD cases worldwide was estimated to be 4.9 million in 2019. CD exhibits heterogeneity in clinical presentation, anatomical involvement, disease behaviour, clinical course and response to treatment. The classical description of CD involves transmural inflammation with skip lesions anywhere along the entire gastrointestinal tract. The complexity and heterogeneity of Crohn's disease is not currently reflected in the conventional classification system. Though the knowledge of Crohn's pathophysiology remains far from understood, the established complex interplay of the omics-genomics, transcriptomics, proteomics, epigenomics, metagenomics, metabolomics, lipidomics and immunophenomics-provides numerous targets for potential molecular markers of disease. Advancing technology has enabled identification of small molecules within these omics, which can be extrapolated to differentiate types of Crohn's disease. The multi-omic future of Crohn's disease is promising, with potential for advancements in understanding of its pathogenesis and implementation of personalised medicine.
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Affiliation(s)
- Shahed Kamal
- Department of Gastroenterology, Northern Hospital, Epping, Melbourne VIC 3076, Australia
| | - Nikita Parkash
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - William Beattie
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
| | - Britt Christensen
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
| | - Jonathan P. Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Parkville, Melbourne VIC 3052, Australia
- Department of Gastroenterology, The University of Melbourne, Parkville, Melbourne VIC 3010, Australia
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13
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Tanaka T, Tawara M, Suzuki H, Kaneko MK, Kato Y. Identification of the Binding Epitope of an Anti-Mouse CCR6 Monoclonal Antibody (C 6Mab-13) Using 1× Alanine Scanning. Antibodies (Basel) 2023; 12:antib12020032. [PMID: 37218898 DOI: 10.3390/antib12020032] [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: 03/16/2023] [Revised: 03/28/2023] [Accepted: 04/17/2023] [Indexed: 05/24/2023] Open
Abstract
CC chemokine receptor 6 (CCR6) is one of the members of the G-protein-coupled receptor (GPCR) family that is upregulated in many immune-related cells, such as B lymphocytes, effector and memory T cells, regulatory T cells, and immature dendritic cells. The coordination between CCR6 and its ligand CC motif chemokine ligand 20 (CCL20) is deeply involved in the pathogenesis of various diseases, such as cancer, psoriasis, and autoimmune diseases. Thus, CCR6 is an attractive target for therapy and is being investigated as a diagnostic marker for various diseases. In a previous study, we developed an anti-mouse CCR6 (mCCR6) monoclonal antibody (mAb), C6Mab-13 (rat IgG1, kappa), that was applicable for flow cytometry by immunizing a rat with the N-terminal peptide of mCCR6. In this study, we investigated the binding epitope of C6Mab-13 using an enzyme-linked immunosorbent assay (ELISA) and the surface plasmon resonance (SPR) method, which were conducted with respect to the synthesized point-mutated-peptides within the 1-20 amino acid region of mCCR6. In the ELISA results, C6Mab-13 lost its ability to react to the alanine-substituted peptide of mCCR6 at Asp11, thereby identifying Asp11 as the epitope of C6Mab-13. In our SPR analysis, the dissociation constants (KD) could not be calculated for the G9A and D11A mutants due to the lack of binding. The SPR analysis demonstrated that the C6Mab-13 epitope comprises Gly9 and Asp11. Taken together, the key binding epitope of C6Mab-13 was determined to be located around Asp11 on mCCR6. Based on the epitope information, C6Mab-13 could be useful for further functional analysis of mCCR6 in future studies.
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Affiliation(s)
- Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mayuki Tawara
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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14
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Allodi M, Giorgio C, Incerti M, Corradi D, Flammini L, Ballabeni V, Barocelli E, Radi M, Bertoni S. Probing the effects of MR120 in preclinical chronic colitis: A first-in-class anti-IBD agent targeting the CCL20/CCR6 axis. Eur J Pharmacol 2023; 945:175613. [PMID: 36841282 DOI: 10.1016/j.ejphar.2023.175613] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/17/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
Concerning the growing interest in the role played by the CCL20/CCR6 axis in IBD pathogenesis and in the search for novel anti-IBD small molecules, we have recently discovered the first small-molecule (MR120) endowed with protective action against TNBS-induced colitis and zymosan-induced peritonitis. This protective action occurs through interference with the CCL20/CCR6 signaling. The aim of the present work is to expand the preclinical investigation of MR120, evaluating its beneficial anti-inflammatory effect on a model of chronic colitis obtained by cyclically exposing C57BL/6 mice to 3% DSS. Subcutaneous administration of MR120 at 1 mg/kg, the same dose effective against acute inflammation, helped attenuate several systemic and local inflammatory responses induced by DSS. Besides significantly improving murine health conditions, MR120 counteracted mucosal macroscopic injury, the increase of colonic edema and neutrophils oxidative activity, and mitigated spleen enlargement, while not significantly lowering intestinal IL-6 concentration. Overall, repeated daily treatment with MR120 for approximately 30 days was well tolerated and showed moderate protection in a relevant model of chronic colitis, in line with the beneficial effect previously observed in acute models of intestinal inflammation. Although more potent analogues of MR120 will be needed to more fully evaluate their clinical translatability, the present work provides a valuable example of in vivo efficacy of CCL20/CCR6 modulators in a chronic model of IBD.
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Affiliation(s)
- Marika Allodi
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Carmine Giorgio
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Matteo Incerti
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Domenico Corradi
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Via Gramsci 14, 43126, Parma, Italy
| | - Lisa Flammini
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Vigilio Ballabeni
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Elisabetta Barocelli
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy
| | - Marco Radi
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy.
| | - Simona Bertoni
- Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Viale Delle Scienze, 27/A, 43124, Parma, Italy.
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15
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Zhang Y, Qin W, Zhang W, Qin Y, Zhou YL. Guidelines on lung adenocarcinoma prognosis based on immuno-glycolysis-related genes. Clin Transl Oncol 2023; 25:959-975. [PMID: 36447119 PMCID: PMC10025218 DOI: 10.1007/s12094-022-03000-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/29/2022] [Indexed: 12/05/2022]
Abstract
OBJECTIVES This study developed a new model for risk assessment of immuno-glycolysis-related genes for lung adenocarcinoma (LUAD) patients to predict prognosis and immunotherapy efficacy. METHODS LUAD samples and data obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases are used as training and test columns, respectively. Twenty-two (22) immuno-glycolysis-related genes were screened, the patients diagnosed with LUAD were divided into two molecular subtypes by consensus clustering of these genes. The initial prognosis model was developed using the multiple regression analysis method and Receiver Operating characteristic (ROC) analysis was used to verify its predictive potential. Gene set enrichment analysis (GSEA) showed the immune activities and pathways in different risk populations, we calculated immune checkpoints, immune escape, immune phenomena (IPS), and tumor mutation burden (TMB) based on TCGA datasets. Finally, the relationship between the model and drug sensitivity was analyzed. RESULTS Fifteen (15) key differentially expressed genes (DEGs) with prognostic value were screened and a new prognostic model was constructed. Four hundred and forty-three (443) samples were grouped into two different risk cohorts based on median model risk values. It was observed that survival rates in high-risk groups were significantly low. ROC curves were used to evaluate the model's accuracy in determining the survival time and clinical outcome of LUAD patients. Cox analysis of various clinical factors proved that the risk score has great potential as an independent prognostic factor. The results of immunological analysis can reveal the immune infiltration and the activity of related functions in different pathways in the two risk groups, and immunotherapy was more effective in low-risk patients. Most chemotherapeutic agents are more sensitive to low-risk patients, making them more likely to benefit. CONCLUSION A novel prognostic model for LUAD patients was established based on IGRG, which could more accurately predict the prognosis and an effective immunotherapy approach for patients.
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Affiliation(s)
- Yuting Zhang
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Wen Qin
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Wenhui Zhang
- Department of Thoracic Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, Jiangsu, China
- Nantong Key Laboratory of Translational Medicine in Cardiothoracic Diseases, Research Institution of Translational Medicine in Cardiothoracic Diseases, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China
| | - Yi Qin
- Nursing Department, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
| | - You Lang Zhou
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China.
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16
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Maddipatla SC, Kolachala VL, Venkateswaran S, Dodd AF, Pelia RS, Geem D, Yin H, Sun Y, Xu C, Mo A, Kosters A, Yang J, Matthews JD, Ghosn E, Kugathasan S, Qiu P. Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn's Disease. Inflamm Bowel Dis 2023; 29:274-285. [PMID: 36206201 PMCID: PMC9890215 DOI: 10.1093/ibd/izac201] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Crohn's disease is a lifelong disease characterized by chronic inflammation of the gastrointestinal tract. Defining the cellular and transcriptional composition of the mucosa at different stages of disease progression is needed for personalized therapy in Crohn's. METHODS Ileal biopsies were obtained from (1) control subjects (n = 6), (2) treatment-naïve patients (n = 7), and (3) established (n = 14) Crohn's patients along with remission (n = 3) and refractory (n = 11) treatment groups. The biopsies processed using 10x Genomics single cell 5' yielded 139 906 cells. Gene expression count matrices of all samples were analyzed by reciprocal principal component integration, followed by clustering analysis. Manual annotations of the clusters were performed using canonical gene markers. Cell type proportions, differential expression analysis, and gene ontology enrichment were carried out for each cell type. RESULTS We identified 3 cellular compartments with 9 epithelial, 1 stromal, and 5 immune cell subtypes. We observed differences in the cellular composition between control, treatment-naïve, and established groups, with the significant changes in the epithelial subtypes of the treatment-naïve patients, including microfold, tuft, goblet, enterocyte,s and BEST4+ cells. Surprisingly, fewer changes in the composition of the immune compartment were observed; however, gene expression in the epithelial and immune compartment was different between Crohn's phenotypes, indicating changes in cellular activity. CONCLUSIONS Our study identified cellular and transcriptional signatures associated with treatment-naïve Crohn's disease that collectively point to dysfunction of the intestinal barrier with an increase in inflammatory cellular activity. Our analysis also highlights the heterogeneity among patients within the same disease phenotype, shining a new light on personalized treatment responses and strategies.
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Affiliation(s)
- Sushma Chowdary Maddipatla
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Vasantha L Kolachala
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Suresh Venkateswaran
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Anne F Dodd
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Ranjit Singh Pelia
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Duke Geem
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Hong Yin
- Department of Pathology, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, USA
| | - Yutong Sun
- School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, USA
| | - Congmin Xu
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Angela Mo
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA
| | - Astrid Kosters
- Lowance Center for Human Immunology, Division of Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Junkai Yang
- Lowance Center for Human Immunology, Division of Immunology and Rheumatology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jason D Matthews
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
| | - Eliver Ghosn
- Emory Vaccine Center, Lowance Center for Human Immunology, Departments of Medicine and Pediatrics, Emory University School of Medicine, Atlanta, GA, USA
| | - Subra Kugathasan
- Division of Pediatric Gastroenterology, Department of Pediatrics and Pediatric Research Institute, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, USA
- Genetics and Molecular Biology Program, Emory University School of Medicine, Atlanta, GA, USAand
- Department of Human Genetics, Emory University, Atlanta, GA, USA
| | - Peng Qiu
- Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
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17
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Cardoso Dal Pont G, Lee A, Bortoluzzi C, Farnell YZ, Gougoulias C, Kogut MH. Novel model for chronic intestinal inflammation in chickens: (2) Immunologic mechanism behind the inflammatory response. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 138:104524. [PMID: 36067905 DOI: 10.1016/j.dci.2022.104524] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/25/2022] [Accepted: 08/25/2022] [Indexed: 06/15/2023]
Abstract
Intestinal inflammation in poultry is a complex response that involves immune and intestinal cells which is still not fully understood. Thus, to better understand the mechanisms that drive the chronic intestinal inflammation in fowl we conducted an experiment applying a previously established nutritional model of low-grade chronic intestinal inflammation to evaluate cytokine and chemokine profiles in the chicken intestine. For this, we placed 90 one-day chickens into two treatments: (1) a control group (CNT) fed a corn-soybean diet, and (2) a group fed a diet high in non-starch polysaccharides (NSP). At days 14, 22, 28 and 36 of age, 6 birds from each treatment were euthanized, jejunal and ileal samples were collected for histological examination and cytokine measurements. The cytokines interferon-alpha (IFN-α), IFN-γ, interleukin-16 (IL-16), IL-10, IL-21, IL-6, macrophage-colony stimulating factor (M-CSF), chemokine C-C motif ligand 20 (CCL20), CCL4, CCL5 and vascular endothelial growth factor (VEGF) were quantified in the intestinal tissue. Histologically, both jejunum and ileum of broilers fed NSP diet showed marked infiltration of mononuclear immune cells into the villi. Further, these birds exhibited a significant (P < 0.05) increase in CCL20 concentration in the jejunum at 14d, but a dramatic reduction of M-CSF at 14 and 21d. Later at 28d and 36d, birds fed the NSP diet exhibited increased IL-16 concentration in the jejunum. Since M-CSF is a monocyte stimulatory cytokine and CCL20 a chemokine of T-cells, the reduced M-CSF and increased production of CCL20 may indicate the involvement of the adaptive immune response, specifically driven by T-cells, occurring around the third week of age in the NSP model. Lastly, as a result of the mononuclear cell infiltration and activation of T-cells, IL-16, a pro-inflammatory T-cell cytokine, increased. Therefore, the current work indicates the importance of adaptive immune cells, especially T-cells, in the chronic intestinal inflammation in broiler chicken.
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Affiliation(s)
- Gabriela Cardoso Dal Pont
- Department of Poultry Science, Texas A&M AgriLife Research, Texas A&M University, College Station, TX, USA.
| | - A Lee
- Department of Poultry Science, Texas A&M AgriLife Research, Texas A&M University, College Station, TX, USA
| | - C Bortoluzzi
- Department of Poultry Science, Texas A&M AgriLife Research, Texas A&M University, College Station, TX, USA
| | - Y Z Farnell
- Department of Poultry Science, Texas A&M AgriLife Research, Texas A&M University, College Station, TX, USA
| | - C Gougoulias
- Innovad NV/SA, Postbaan 69, 2910, Essen, Belgium
| | - M H Kogut
- USDA-ARS, Southern Plains Agricultural Research Center, College Station, TX, USA.
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Wang X, Yip KC, He A, Tang J, Liu S, Yan R, Zhang Q, Li R. Plasma Olink Proteomics Identifies CCL20 as a Novel Predictive and Diagnostic Inflammatory Marker for Preeclampsia. J Proteome Res 2022; 21:2998-3006. [PMID: 36301636 PMCID: PMC9724708 DOI: 10.1021/acs.jproteome.2c00544] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Indexed: 01/19/2023]
Abstract
Inflammation is generally thought to be involved in the occurrence and development of preeclampsia (PE), but its specific effect on PE remains unclear. In the present study, the expression levels of 92 inflammation-related proteins were measured in the late pregnancy maternal plasma from patients with PE (n = 15) and normal pregnant controls (n = 15) using the Olink inflammation panel based on the highly sensitive and specific proximity extension assay technology. A total of 28 inflammation-related markers differed between the PE and control groups. Among them, fibroblast growth factor 21 (FGF-21) and cysteine-cysteine motif chemokine ligand 20 (CCL20) had the largest fold changes. We further validated the levels of CCL20 in the late (43 with PE and 44 controls) and early (37 with PE and 37 controls) pregnancy maternal plasma using enzyme-linked immunosorbent assay (ELISA). To the best of our knowledge, for the first time, CCL20 was found to be upregulated in the late and early pregnancy plasma of patients with PE and had an area under the curve (AUC) of 0.753 and 0.668, respectively. In conclusion, patients with PE had increased levels of most inflammatory markers, and CCL20 might be a novel potential predictive and diagnostic biomarker for PE.
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Affiliation(s)
- Xiufang Wang
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Ka Cheuk Yip
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Andong He
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Jinqing Tang
- Department
of Obstetrics and Gynecology, Qingyuan People’s
Hospital, Qingyuan 511518, Guangdong, China
| | - Shisan Liu
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
| | - Ruiling Yan
- Department
of Fetal Medicine, The First Affiliated
Hospital of Jinan University, Guangzhou 510630, Guangdong, China
| | - Qiao Zhang
- Institute
of Molecular and Medical Virology, School of Medicine, Jinan University, No. 601, Huangpu Road West, Tianhe
District, Guangzhou 510632, Guangdong, China
| | - Ruiman Li
- Department
of Obstetrics and Gynecology, The First
Affiliated Hospital of Jinan University, No. 613, Huangpu Road West, Tianhe
District, Guangzhou 510630, Guangdong, China
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19
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Li Y, Tang M, Zhang FJ, Huang Y, Zhang J, Li J, Wang Y, Yang J, Zhu S. Screening of ulcerative colitis biomarkers and potential pathways based on weighted gene co-expression network, machine learning and ceRNA hypothesis. Hereditas 2022; 159:42. [PMID: 36419192 PMCID: PMC9685902 DOI: 10.1186/s41065-022-00259-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 11/12/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Ulcerative colitis (UC) refers to an intractable intestinal inflammatory disease. Its increasing incidence rate imposes a huge burden on patients and society. The UC etiology has not been determined, so screening potential biomarkers is critical to preventing disease progression and selecting optimal therapeutic strategies more effectively. METHODS The microarray datasets of intestinal mucosal biopsy of UC patients were selected from the GEO database, and integrated with R language to screen differentially expressed genes and draw proteins interaction network diagrams. GO, KEGG, DO and GSEA enrichment analyses were performed to explore their biological functions. Through machine learning and WGCNA analysis, targets that can be used as UC potential biomarkers are screened out. ROC curves were drawn to verify the reliability of the results and predicted the mechanism of marker genes from the aspects of immune cell infiltration, co-expression analysis, and competitive endogenous network (ceRNA). RESULTS Two datasets GSE75214 and GSE87466 were integrated for screening, and a total of 107 differentially expressed genes were obtained. They were mainly related to biological functions such as humoral immune response and inflammatory response. Further screened out five marker genes, and found that they were associated with M0 macrophages, quiescent mast cells, M2 macrophages, and activated NK cells in terms of immune cell infiltration. The co-expression network found significant co-expression relationships between 54 miRNAs and 5 marker genes. According to the ceRNA hypothesis, NEAT1-miR-342-3p/miR-650-SLC6A14, NEAT1-miR-650-IRAK3, and XIST-miR-342-3p-IRAK3 axes were found as potential regulatory pathways in UC. CONCLUSION This study screened out five biomarkers that can be used for the diagnosis and treatment of UC, namely SLC6A14, TIMP1, IRAK3, HMGCS2, and APOBEC3B. Confirmed that they play a role in the occurrence and development of UC at the level of immune infiltration, and proposed a potential RNA regulatory pathway that controls the progression of UC.
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Affiliation(s)
- Ying Li
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan, China ,grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, The First College for Clinical Medicine, Jinan, China
| | - Mengyao Tang
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Innovation and Research of Traditional Chinese Medicine, Jinan, 250000 China
| | - Feng Jun Zhang
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan, China ,grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, The First College for Clinical Medicine, Jinan, China
| | - Yihan Huang
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan, China
| | - Jing Zhang
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan, China
| | - Junqi Li
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Jinan, China
| | - Yunpeng Wang
- grid.479672.9Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Department of Gastroenterology, Jinan, China
| | - Jinguang Yang
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, The First College for Clinical Medicine, Jinan, China
| | - Shu Zhu
- grid.464402.00000 0000 9459 9325Shandong University of Traditional Chinese Medicine, College of Innovation and Research of Traditional Chinese Medicine, Jinan, 250000 China
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20
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Fcα Receptor-1-Activated Monocytes Promote B Lymphocyte Migration and IgA Isotype Switching. Int J Mol Sci 2022; 23:ijms231911132. [PMID: 36232432 PMCID: PMC9569671 DOI: 10.3390/ijms231911132] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/18/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.
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21
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The Memory T Cell “Communication Web” in Context with Gastrointestinal Disorders—How Memory T Cells Affect Their Surroundings and How They Are Influenced by It. Cells 2022; 11:cells11182780. [PMID: 36139354 PMCID: PMC9497182 DOI: 10.3390/cells11182780] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/30/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022] Open
Abstract
Gut-related diseases like ulcerative colitis, Crohn’s disease, or colorectal cancer affect millions of people worldwide. It is an ongoing process finding causes leading to the development and manifestation of those disorders. This is highly relevant since understanding molecular processes and signalling pathways offers new opportunities in finding novel ways to interfere with and apply new pharmaceuticals. Memory T cells (mT cells) and their pro-inflammatory properties have been proven to play an important role in gastrointestinal diseases and are therefore increasingly spotlighted. This review focuses on mT cells and their subsets in the context of disease pathogenesis and maintenance. It illustrates the network of regulatory proteins and metabolites connecting mT cells with other cell types and tissue compartments. Furthermore, the crosstalk with various microbes will be a subject of discussion. Characterizing mT cell interactions will help to further elucidate the sophisticated molecular and cellular networking system in the intestine and may present new ideas for future research approaches to control gut-related diseases.
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22
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Martina MG, Giorgio C, Allodi M, Palese S, Barocelli E, Ballabeni V, Szpakowska M, Chevigne A, Piet van Hamburg J, Davelaar N, Lubberts E, Bertoni S, Radi M. Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases. Eur J Med Chem 2022; 243:114703. [DOI: 10.1016/j.ejmech.2022.114703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/18/2022] [Accepted: 08/19/2022] [Indexed: 11/03/2022]
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23
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Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2022; 19:351-366. [PMID: 35165437 DOI: 10.1038/s41575-021-00574-7] [Citation(s) in RCA: 80] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/22/2021] [Indexed: 12/12/2022]
Abstract
Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab). Promising preclinical and clinical data with several oral S1P modulators suggest that inhibition of lymphocyte egress from the lymph nodes to the bloodstream might be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including Crohn's disease and ulcerative colitis. Although various questions remain, including the potential positioning of S1P modulators in treatment algorithms and their long-term safety, this novel class of compounds holds great promise. This Review summarizes the critical mediators and mechanisms involved in immune cell trafficking in IBD and the available evidence for efficacy, safety and pharmacokinetics of S1P receptor modulators in IBD and other immune-mediated disorders. Further, it discusses potential future approaches to incorporate S1P modulators into the treatment of IBD.
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24
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Kwantwi LB, Wang S, Sheng Y, Wu Q. Multifaceted roles of CCL20 (C-C motif chemokine ligand 20): mechanisms and communication networks in breast cancer progression. Bioengineered 2021; 12:6923-6934. [PMID: 34569432 PMCID: PMC8806797 DOI: 10.1080/21655979.2021.1974765] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging studies have demonstrated notable roles of CCL20 in breast cancer progression. Based on these findings, CCL20 has become a potential therapeutic target for cancer immunotherapy. Accordingly, studies utilizing monoclonal antibodies to target CCL20 are currently being experimented. However, the existence of cytokine network in the tumor microenvironment collectively regulates tumor progression. Hence, a deeper understanding of the role of CCL20 and the underlying signaling pathways regulating the functions of CCL20 may provide a novel strategy for therapeutic interventions. This review provides the current knowledge on how CCL20 interacts with breast cancer cells to influence tumor progression via immunosuppression, angiogenesis, epithelial to mesenchymal transition, migration/invasion and chemoresistance. As a possible candidate biomarker, we also reviewed signal pathways and other factors in the tumor microenvironment regulating the tumor-promoting functions of CCL20.These new insights may be useful to design new potent and selective CCL20 inhibitors against breast cancer in the future.
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Affiliation(s)
- Louis Boafo Kwantwi
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Shujing Wang
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Immunology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Youjing Sheng
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
| | - Qiang Wu
- Department of Pathology, School of Basic Medical Science, Anhui Medical University, Hefei, PR China
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
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25
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Chia AYT, Ang GWX, Chan ASY, Chan W, Chong TKY, Leung YY. Managing Psoriatic Arthritis With Inflammatory Bowel Disease and/or Uveitis. Front Med (Lausanne) 2021; 8:737256. [PMID: 34604268 PMCID: PMC8481670 DOI: 10.3389/fmed.2021.737256] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 08/20/2021] [Indexed: 12/15/2022] Open
Abstract
Psoriatic arthritis (PsA) is a chronic inflammatory disease that presents with psoriasis (PsO), peripheral and axial arthropathy. The heterogeneity of disease presentation leads to the term "psoriatic disease (PsD)" which is thought to better encompass the range of clinical manifestations. PsA is associated with several comorbidities such as cardiovascular diseases, metabolic syndrome and other extra-articular manifestations including uveitis, and inflammatory bowel disease (IBD). While novel therapeutics are being developed following advances in our understanding of the pathogenesis of the disease, the diverse combinations of PsA with its various comorbidities still pose a clinical challenge in managing patients with PsA. This article reviews our current understanding of the pathogenesis of PsA and how various pathways in the pathogenesis lead to the two comorbid extra-articular manifestations - uveitis and IBD. We also review current evidence of treatment strategies in managing patients with PsA with comorbidities of uveitis and/or IBD.
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Affiliation(s)
- Alfred Yu Ting Chia
- Duke-NUS Medical School, Singapore, Singapore
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, Singapore, Singapore
| | - Gladys Wei Xin Ang
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, Singapore, Singapore
| | - Anita Sook Yee Chan
- Duke-NUS Medical School, Singapore, Singapore
- Singapore National Eye Center and Singapore Eye Research Center, Singapore, Singapore
| | - Webber Chan
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore, Singapore
| | | | - Ying Ying Leung
- Duke-NUS Medical School, Singapore, Singapore
- Department of Rheumatology and Immunology, Singapore General Hospital, Singapore, Singapore
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26
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Meitei HT, Jadhav N, Lal G. CCR6-CCL20 axis as a therapeutic target for autoimmune diseases. Autoimmun Rev 2021; 20:102846. [PMID: 33971346 DOI: 10.1016/j.autrev.2021.102846] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 03/15/2021] [Accepted: 03/23/2021] [Indexed: 12/11/2022]
Abstract
Chemokine receptor CCR6 is expressed on various cells such as B cells, immature dendritic cells, innate lymphoid cells (ILCs), regulatory CD4 T cells, and Th17 cells. CCL20 is the only known high-affinity ligand that binds to CCR6 and drives CCR6+ cells' migration in tissues. CCL20 is mainly produced by epithelial cells, and its expression is increased by several folds under inflammatory conditions. Genome-wide association studies (GWAS) in patients with inflammatory bowel disease (IBD), psoriasis (PS), rheumatoid arthritis (RA), and multiple sclerosis (MS) showed a very strong correlation between the expression of CCR6 and disease severity. It has been shown that disruption of CCR6-CCL20 interaction by using antibodies or antagonists prevents the migration of CCR6 expressing immune cells at the site of inflammation and reduces the severity of the disease. This review discussed the importance of the CCR6-CCL20 axis in IBD, PS, RA, and MS, and recent advances in targeting the CCR6-CCL20 in controlling these autoimmune diseases.
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Affiliation(s)
| | - Nandadeep Jadhav
- National Centre for Cell Science, Ganeshkhind, Pune MH-411007, India
| | - Girdhari Lal
- National Centre for Cell Science, Ganeshkhind, Pune MH-411007, India.
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27
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Pergolizzi S, Rizzo G, Favaloro A, Alesci A, Pallio S, Melita G, Cutroneo G, Lauriano ER. Expression of VAChT and 5-HT in Ulcerative colitis dendritic cells. Acta Histochem 2021; 123:151715. [PMID: 33940317 DOI: 10.1016/j.acthis.2021.151715] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 02/07/2023]
Abstract
Ulcerative colitis is a chronic inflammatory condition of the gastrointestinal tract that can affect people of worldwide. In contrast with Crohn's disease, that can relate the entire thickness of the bowel wall, the inflammation of ulcerative colitis is limited to the colonic mucosa. Immune cells including activated T cells, plasma cells, mast cells, macrophages, and dendritic cells (DCs) trigger the inflammation. Furthermore, dendritic cells are antigen presenting cells involved in maintaining intestinal immune homeostasis. It has been described an increment of number in DCs colonic mucosa of patients with ulcerative colitis. The immune cells such as antigen-presenting cells can act as autocrine or paracrine modulators. Recent studies showed that dendritic cells synthetized and released classical neurotransmitters as glutamate, dopamine, acetylcholine, and serotonin. Paraformaldehyde-fixed intestinal tissues, obtained from the stricture sites of ten patients with ulcerative colitis were analyzed by immunostaining for Langerin/CD207, serotonin and vesicular acetylcholine transporter. As controls, unaffected (normal) portions of five patients were also investigated. Aim of this study was to characterize for the first time the human gut dendritic cells of ulcerative colitis patients, with Langerin/CD207 that is a c-type lectin expressed by different types of DCs and to colocalize in the same cells the expression of serotonin and vesicular acetylcholine transporter, showing the link between dendritic cells, gut enterochromaffin cells or autonomic nerves in immune activation and generation of intestinal inflammation.
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28
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Giannoudaki E, Gargan S, Hussey S, Long A, Walsh PT. Opportunities to Target T Cell Trafficking in Pediatric Inflammatory Bowel Disease. Front Pediatr 2021; 9:640497. [PMID: 33816403 PMCID: PMC8012547 DOI: 10.3389/fped.2021.640497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
T cell subsets are considered central orchestrators of inflammation and homeostasis in the intestine and are established targets for the treatment of inflammatory bowel disease. While approaches aimed at the neutralization of T cell effector cytokines have provided significant benefits for pediatric and adult patients, more recent strategies aimed at inhibiting the infiltration of pathogenic T cell subsets have also emerged. In this review, we describe current knowledge surrounding the function of T cell subsets in pediatric inflammatory bowel disease and outline approaches aimed at targeting T cell trafficking to the intestine which may represent a new treatment option for pediatric inflammatory bowel disease.
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Affiliation(s)
- Eirini Giannoudaki
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Siobhan Gargan
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Seamus Hussey
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Department of Paediatrics, Royal College of Surgeons of Ireland, Dublin, Ireland
| | - Aideen Long
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Patrick T Walsh
- National Children's Research Center, Children's Health Ireland (CHI) Crumlin, Dublin, Ireland.,Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
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29
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Dickson K, Malitan H, Lehmann C. Imaging of the Intestinal Microcirculation during Acute and Chronic Inflammation. BIOLOGY 2020; 9:E418. [PMID: 33255906 PMCID: PMC7760140 DOI: 10.3390/biology9120418] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022]
Abstract
Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.
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Affiliation(s)
- Kayle Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Hajer Malitan
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Christian Lehmann
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Anesthesia, Pain and Perioperative Management, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
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30
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Hardesty JE, Warner JB, Song YL, Rouchka EC, Chen CY, Kang JX, McClain CJ, Warner DR, Kirpich IA. Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids. Sci Rep 2020; 10:19930. [PMID: 33199802 PMCID: PMC7670449 DOI: 10.1038/s41598-020-76959-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/04/2020] [Indexed: 12/19/2022] Open
Abstract
The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health. Previous studies showed that different types of dietary fats can modulate EtOH-induced changes in the intestine; however, mechanisms underlying these effects are not completely understood. Here, we examined intestinal transcriptional responses to EtOH in WT and transgenic fat-1 mice (which endogenously convert n6 to n3 polyunsaturated fatty acids [PUFAs]) to identify novel genes and pathways involved in EtOH-associated gut pathology and discern the impact of n3 PUFA enrichment. WT and fat-1 mice were chronically fed EtOH, and ileum RNA-seq and bioinformatic analyses were performed. EtOH consumption led to a marked down-regulation of genes encoding digestive and xenobiotic-metabolizing enzymes, and transcription factors involved in developmental processes and tissue regeneration. Compared to WT, fat-1 mice exhibited a markedly plastic transcriptome response to EtOH. Cell death, inflammation, and tuft cell markers were downregulated in fat-1 mice in response to EtOH, while defense responses and PPAR signaling were upregulated. This transcriptional reprogramming may contribute to the beneficial effects of n3 PUFAs on EtOH-induced intestinal pathology. In summary, our study provides a reference dataset of the intestinal mucosa transcriptional responses to chronic EtOH exposure for future hypothesis-driven mechanistic studies.
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Affiliation(s)
- Josiah E Hardesty
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jeffrey B Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Ying L Song
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
| | - Eric C Rouchka
- Department of Computer Science and Engineering, Speed School of Engineering, University of Louisville, Louisville, KY, USA
| | - Chih-Yu Chen
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jing X Kang
- Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA
- Robley Rex Veterans Medical Center, Louisville, KY, USA
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA
| | - Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, 505 Hancock St., Louisville, KY, 40202, USA.
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA.
- University of Louisville Hepatobiology and Toxicology Center, University of Louisville School of Medicine, Louisville, KY, USA.
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Leccese G, Bibi A, Mazza S, Facciotti F, Caprioli F, Landini P, Paroni M. Probiotic Lactobacillus and Bifidobacterium Strains Counteract Adherent-Invasive Escherichia coli (AIEC) Virulence and Hamper IL-23/Th17 Axis in Ulcerative Colitis, but Not in Crohn's Disease. Cells 2020; 9:cells9081824. [PMID: 32752244 PMCID: PMC7464949 DOI: 10.3390/cells9081824] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/21/2020] [Accepted: 07/31/2020] [Indexed: 02/07/2023] Open
Abstract
Hypersecretion of proinflammatory cytokines and dysregulated activation of the IL-23/Th17 axis in response to intestinal microbiota dysbiosis are key factors in the pathogenesis of inflammatory bowel diseases (IBD). In this work, we studied how Lactobacillus and Bifidobacterium strains affect AIEC-LF82 virulence mechanisms and the consequent inflammatory response linked to the CCR6–CCL20 and IL-23/Th17 axes in Crohn’s disease (CD) and ulcerative colitis (UC) patients. All Lactobacillus and Bifidobacterium strains significantly reduced the LF82 adhesion and persistence within HT29 intestinal epithelial cells, inhibiting IL-8 secretion while not affecting the CCR6–CCL20 axis. Moreover, they significantly reduced LF82 survival within macrophages and dendritic cells, reducing the secretion of polarizing cytokines related to the IL-23/Th17 axis, both in healthy donors (HD) and UC patients. In CD patients, however, only B. breve Bbr8 strain was able to slightly reduce the LF82 persistence within dendritic cells, thus hampering the IL-23/Th17 axis. In addition, probiotic strains were able to modulate the AIEC-induced inflammation in HD, reducing TNF-α and increasing IL-10 secretion by macrophages, but failed to do so in IBD patients. Interestingly, the probiotic strains studied in this work were all able to interfere with the IL-23/Th17 axis in UC patients, but not in CD patients. The different interaction mechanisms of probiotic strains with innate immune cells from UC and CD patients compared to HD suggest that testing on CD-derived immune cells may be pivotal for the identification of novel probiotic strains that could be effective also for CD patients.
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Affiliation(s)
- Gabriella Leccese
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Alessia Bibi
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Stefano Mazza
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.M.); (F.C.)
| | - Federica Facciotti
- Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, 20139 Milan, Italy;
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (S.M.); (F.C.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20135 Milan, Italy
| | - Paolo Landini
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
| | - Moira Paroni
- Department of Biosciences, Università degli Studi di Milano, 20133 Milan, Italy; (G.L.); (A.B.); (P.L.)
- Correspondence:
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32
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Risk of colorectal cancer in inflammatory bowel diseases. Semin Cancer Biol 2020; 64:51-60. [DOI: 10.1016/j.semcancer.2019.05.001] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/29/2019] [Accepted: 05/01/2019] [Indexed: 12/21/2022]
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Naumovska E, Aalderink G, Wong Valencia C, Kosim K, Nicolas A, Brown S, Vulto P, Erdmann KS, Kurek D. Direct On-Chip Differentiation of Intestinal Tubules from Induced Pluripotent Stem Cells. Int J Mol Sci 2020; 21:ijms21144964. [PMID: 32674311 PMCID: PMC7404294 DOI: 10.3390/ijms21144964] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/03/2020] [Accepted: 07/10/2020] [Indexed: 12/15/2022] Open
Abstract
Intestinal organoids have emerged as the new paradigm for modelling the healthy and diseased intestine with patient-relevant properties. In this study, we show directed differentiation of induced pluripotent stem cells towards intestinal-like phenotype within a microfluidic device. iPSCs are cultured against a gel in microfluidic chips of the OrganoPlate, in which they undergo stepwise differentiation. Cells form a tubular structure, lose their stem cell markers and start expressing mature intestinal markers, including markers for Paneth cells, enterocytes and neuroendocrine cells. Tubes develop barrier properties as confirmed by transepithelial electrical resistance (TEER). Lastly, we show that tubules respond to pro-inflammatory cytokine triggers. The whole procedure for differentiation lasts 14 days, making it an efficient process to make patient-specific organoid tubules. We anticipate the usage of the platform for disease modelling and drug candidate screening.
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Affiliation(s)
- Elena Naumovska
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
- Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; (C.W.V.); (S.B.)
| | - Germaine Aalderink
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
| | - Christian Wong Valencia
- Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; (C.W.V.); (S.B.)
| | - Kinga Kosim
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
- Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; (C.W.V.); (S.B.)
| | - Arnaud Nicolas
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
| | - Stephen Brown
- Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; (C.W.V.); (S.B.)
| | - Paul Vulto
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
| | - Kai S. Erdmann
- Department of Biomedical Sciences, University of Sheffield, Western Bank, Sheffield S10 2TN, UK; (C.W.V.); (S.B.)
- Correspondence: (K.S.E.); (D.K.)
| | - Dorota Kurek
- Mimetas BV, Model Development, J.H. Oortweg 16, 2333 CH Leiden, The Netherlands; (E.N.); (G.A.); (K.K.); (A.N.); (P.V.)
- Correspondence: (K.S.E.); (D.K.)
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Controlling leukocyte trafficking in IBD. Pharmacol Res 2020; 159:105050. [PMID: 32598943 DOI: 10.1016/j.phrs.2020.105050] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the accumulation of immune cells, myeloid cells and lymphocytes in the inflamed intestine. The presence and persistence of these cells, together with the production of pro-inflammatory mediators, perpetuate intestinal inflammation in both ulcerative colitis and Crohn's disease. Thus, blockade of leukocyte migration to the intestine is a main strategy used to control the disease and alleviate symptoms. Vedolizumab is the only anti-integrin drug approved for the treatment of IBD but several other drugs also targeting integrins, chemokines or receptors involved in leukocyte intestinal trafficking are under development and investigated for their efficacy and safety in IBD. The challenge now is to better understand the specific mechanism of action underlying each drug and to identify biomarkers that would guide drug selection in the individual patient.
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Bottois H, Ngollo M, Hammoudi N, Courau T, Bonnereau J, Chardiny V, Grand C, Gergaud B, Allez M, Le Bourhis L. KLRG1 and CD103 Expressions Define Distinct Intestinal Tissue-Resident Memory CD8 T Cell Subsets Modulated in Crohn's Disease. Front Immunol 2020; 11:896. [PMID: 32477365 PMCID: PMC7235448 DOI: 10.3389/fimmu.2020.00896] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 04/17/2020] [Indexed: 12/14/2022] Open
Abstract
Intestinal tissue-resident memory CD8 T cells (Trm) are non-recirculating effector cells ideally positioned to detect and react to microbial infections in the gut mucosa. There is an emerging understanding of Trm cell differentiation and functions, but their implication in inflammatory bowel diseases, such as Crohn's disease (CD), is still unknown. Here, we describe CD8 cells in the human intestine expressing KLRG1 or CD103, two receptors of E-cadherin. While CD103 CD8 T cells are present in high numbers in the mucosa of CD patients and controls, KLRG1 CD8 T cells are increased in inflammatory conditions. Mucosal CD103 CD8 T cells are more responsive to TCR restimulation, but KLRG1 CD8 T cells show increased cytotoxic and proliferative potential. CD103 CD8 T cells originate mostly from KLRG1 negative cells after TCR triggering and TGFβ stimulation. Interestingly, mucosal CD103 CD8 T cells from CD patients display major changes in their transcriptomic landscape compared to controls. They express Th17 related genes including CCL20, IL22, and IL26, which could contribute to the pathogenesis of CD. Overall, these findings suggest that CD103 CD8 T cells in CD induce a tissue-wide alert increasing innate immune responses and recruitment of effector cells such as KLRG1 CD8 T cells.
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Affiliation(s)
- Hugo Bottois
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Marjolaine Ngollo
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Nassim Hammoudi
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France.,Gastroenterology Department, Hopital Saint Louis, AP-HP, Paris, France
| | - Tristan Courau
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Julie Bonnereau
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Victor Chardiny
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Céline Grand
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Brice Gergaud
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
| | - Matthieu Allez
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France.,Gastroenterology Department, Hopital Saint Louis, AP-HP, Paris, France
| | - Lionel Le Bourhis
- Université de Paris, INSERM U1160, EMiLy, Institut de Recherche Saint-Louis, Paris, France
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36
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Jia Y, Anwaar S, Li L, Yin Z, Ye Z, Huang Z. A new target for the treatment of inflammatory bowel disease: Interleukin-37. Int Immunopharmacol 2020; 83:106391. [PMID: 32208166 DOI: 10.1016/j.intimp.2020.106391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/22/2020] [Accepted: 03/08/2020] [Indexed: 12/19/2022]
Abstract
Interleukin (IL)-37 belongs to the IL-1 cytokine family. It has anti-inflammatory effects on numerous autoimmune diseases such as asthma, psoriasis, inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS) and rheumatoid arthritis (RA). Mechanistically, IL-37 plays an anti-inflammatory role by regulating the expression of inflammatory factors in two ways: binding extracellular receptors IL-18R or transferring into the nucleus with Smad3. IBD is a kind of idiopathic intestinal inflammatory disease with unknown etiology and pathogenesis. Recent researches had proved that IL-37 is negatively involved in the pathogenesis and development of IBD. Among various inflammatory diseases, IL-37 has been shown to regulate inflammatory development by acting on various immune cells such as neutrophils, macrophages (Mϕ), dendritic cells (DCs), T cells and intestinal epithelial cells. This review summarizes the biological role of IL-37, and its immunoregulatory effects on the immune cells, especially anti-inflammatory function in both human and experimental models of IBD.
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Affiliation(s)
- Yuning Jia
- Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Health Science Center, Shenzhen University, Shenzhen 518055, China
| | - Shoaib Anwaar
- Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Health Science Center, Shenzhen University, Shenzhen 518055, China
| | - Linyun Li
- Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Health Science Center, Shenzhen University, Shenzhen 518055, China
| | - Zhihua Yin
- Shenzhen City Futian Qu Rheumatology Specialist Hospital, Shenzhen 518089, China
| | - Zhizhon Ye
- Shenzhen City Futian Qu Rheumatology Specialist Hospital, Shenzhen 518089, China.
| | - Zhong Huang
- Biological Therapy Institute, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Immunology, Health Science Center, Shenzhen University, Shenzhen 518055, China.
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37
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deZoeten EF, Battista KD, Colson SB, Lovell MA, Kessler BE, Isfort RW, Fennimore BP, Onyiah JC, Kao DJ, Yeckes A, Keely S, Murray M, Hoffenberg EJ, Colgan SP, Gerich ME. Markers of Hypoxia Correlate with Histologic and Endoscopic Severity of Colitis in Inflammatory Bowel Disease. HYPOXIA (AUCKLAND, N.Z.) 2020; 8:1-12. [PMID: 32104717 PMCID: PMC7026141 DOI: 10.2147/hp.s219049] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 10/16/2019] [Indexed: 12/25/2022]
Abstract
BACKGROUND Inflammation results in significant shifts in tissue metabolism. Recent studies indicate that inflammation and hypoxia occur concomitantly. We examined whether circulating and tissue markers of hypoxia could serve as surrogate indicators of disease severity in adult and pediatric patients with inflammatory bowel disease (IBD). METHODS Serum and colonic biopsies were obtained from pediatric subjects with active IBD colitis and adult subjects with active and inactive ulcerative colitis, along with healthy non-colitis controls of all ages. Disease activity was evaluated by endoscopy and histopathology. Levels of serum hypoxia markers (macrophage inflammatory protein-3α [MIP-3α], vascular endothelial growth factor [VEGF], and erythropoietin [EPO]) were measured. RESULTS Children with active IBD colitis had higher levels of serum MIP-3α and VEGF compared to non-colitis controls (p<0.01 and p<0.05, respectively). In adult subjects with endoscopically active ulcerative colitis, serum MIP-3α and EPO were significantly elevated compared to non-colitis controls (both p<0.01). In parallel, analysis of colon tissue MIP-3α mRNA and protein in pediatric subjects revealed increased expression in those with IBD colitis compared to controls (p<0.05 and p<0.01 for mRNA and protein, respectively). Serum MIP-3α and VEGF significantly increased with histology grade. CONCLUSION Peripheral blood hypoxia markers may be useful indicators of disease activity for pediatric and adult IBD patients.
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Affiliation(s)
- Edwin F deZoeten
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Steven B Colson
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Mark A Lovell
- Department of Pathology, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Brittelle E Kessler
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Robert W Isfort
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Joseph C Onyiah
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Daniel J Kao
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Alyson Yeckes
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Simon Keely
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
- School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
| | - Monica Murray
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Edward J Hoffenberg
- Department of Pediatrics and the Digestive Health Institute, University of Colorado School of Medicine/Children’s Hospital Colorado, Aurora, CO, USA
| | - Sean P Colgan
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Mark E Gerich
- Department of Medicine and Mucosal Inflammation Program, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, USA
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38
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Chen W, Fan H, Liang R, Zhang R, Zhang J, Zhu J. Taraxacum officinale extract ameliorates dextran sodium sulphate-induced colitis by regulating fatty acid degradation and microbial dysbiosis. J Cell Mol Med 2019; 23:8161-8172. [PMID: 31565850 PMCID: PMC6850927 DOI: 10.1111/jcmm.14686] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/31/2019] [Accepted: 06/17/2019] [Indexed: 12/15/2022] Open
Abstract
Numerous data show that taraxacum officinale extract (TOE) exerts protective effects on inflammatory diseases. However, the underlying mechanisms by which TOE affects dextran sulphate sodium (DSS)-induced colitis remain unclear. After DSS-induced colitis were treated with different concentrations of TOE for 8 days, the bodyweight, disease activity index (DAI), colon lengths and pathological scoring were assessed, and histopathological examination was confirmed by HE staining. Furthermore, a transcriptome sequencing was performed by using the colon tissues between TOE and DSS groups, and the differentially expressed genes were conducted for the Kyoto Encyclopaedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) and were validated by qRT-PCR and immunohistochemistry analysis. In addition, a 16S rDNA sequencing was carried out to distinguish the differential gut microbiota by using the mouse faecal samples between TOE and DSS groups. We found that TOE attenuated the clinical symptoms, lowered the inflammatory scoring and inhibited the secretion of proinflammatory factors TNF-α, IL-1β and IL-6 in DSS-induced colitis. KEGG and GSEA analysis demonstrated that fatty acid degradation and cytokine-receptor signalling were predominantly enriched in TOE-treated colitis as compared with the DSS group. Further investigations revealed that TOE increased the expression levels of Adh5, Aldh3a2 and Acox3, but decreased those of CCL20, CCR6 and CXCL1/5 in DSS-induced colitis, where TOE also induced the enrichment of S24-7 and adlercreutzia, but decreased the amount of anaerostipes, enterococcus, enterobacteriaceae and peptostreptococcaceae. In conclusion, TOE ameliorated DSS-induced colitis by regulating fatty acid degradation and microbial dysbiosis.
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Affiliation(s)
- Wei Chen
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Huining Fan
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rui Liang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Rui Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jinshui Zhu
- Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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39
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Nelson DS, Marano RL, Joo Y, Tian SY, Patel B, Kaplan DH, Shlomchik MJ, Stevenson K, Bronson RT, Rollins BJ. BRAF V600E and Pten deletion in mice produces a histiocytic disorder with features of Langerhans cell histiocytosis. PLoS One 2019; 14:e0222400. [PMID: 31527903 PMCID: PMC6748438 DOI: 10.1371/journal.pone.0222400] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 08/28/2019] [Indexed: 12/28/2022] Open
Abstract
Langerhans cell histiocytosis (LCH) is characterized by the accumulation of Langerin (CD207)-expressing histiocytes. Mutational activation of mitogen-activated protein kinase pathway genes, in particular BRAF, drives most cases. To test whether activated BRAF is sufficient for the development of LCH, we engineered mice to express BRAF V600E under the control of the human Langerin promoter. These mice have shortened survivals, smaller lymphoid organs, absent Leydig cells, and fewer epidermal LCs than controls, but do not accumulate histiocytes. To test whether the absence of histiocyte proliferation could be due to oncogene-induced senescence, we engineered homozygous Pten loss in the same cells that expressed BRAF V600E. Like mice with intact Pten, these mice have shortened survivals, smaller thymi, and absent Leydig cells. However, loss of Pten also leads to the accumulation of CD207+ histiocytes in spleen, thymus, and some lymph nodes. While many CD207+ histiocytes in the thymus are CD8-, reminiscent of LCH cells, the CD207+ histiocytes in the spleen and lymph nodes are CD8+. These mice also accumulate large numbers of CD207- cells in the lamina propria (LP) of the small intestine. Both the lymphoid and LP phenotypes are likely due to human Langerin promoter-driven BRAF V600E expression in resident CD8+ dendritic cells in the former and LP dendritic cells in the latter and confirm that Pten loss is required to overcome inhibitory pathways induced by BRAF V600E expression. The complex phenotype of these mice is a consequence of the multiple murine cell types in which the human Langerin promoter is active.
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Affiliation(s)
- David S. Nelson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
| | - Ryan L. Marano
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
| | - Yechaan Joo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
| | - Sara Y. Tian
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
| | - Bhumi Patel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
| | - Daniel H. Kaplan
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
- Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Mark J. Shlomchik
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America
| | - Kristen Stevenson
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, United States of America
| | - Roderick T. Bronson
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, United States of America
| | - Barrett J. Rollins
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States of America
- Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, United States of America
- * E-mail:
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Cheluvappa R. Identification of New Potential Therapies for Colitis Amelioration Using an Appendicitis-Appendectomy Model. Inflamm Bowel Dis 2019; 25:436-444. [PMID: 30329049 DOI: 10.1093/ibd/izy332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Indexed: 12/18/2022]
Abstract
The appendix contains copious lymphoid tissue and is constantly exposed to gut flora. Appendicitis followed by appendectomy (AA), when done at a young age, prevents or significantly ameliorates inflammatory bowel diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our unique murine AA model is the only existing experimental model of AA. Herein, the appendiceal pathology closely resembles the pathological features of human appendicitis. Our AA model protects against experimental colitis in an age-, bacteria- and antigen-dependent manner. Appendicitis-appendectomy performed in the most proximal colon curbs T helper 17 (Th17) cell activity, diminishes autophagy, modulates interferon activity-associated molecules, and suppresses endothelin vasoactivity-mediated immunopathology in the most distal colon. These changes induced by AA contribute to limiting colitis pathology. Manipulating and modulating various aspects of these pathways, pathophysiology, and molecular interactions will assist the development of novel therapeutic options to manage IBD. Competitive inhibition of the Th17 cell recruitment factor CCL20 or the chemokine CCL17 with antibodies, combinatorial peptides, or small molecules may limit colitic pathology. The chemokines CCL5 and CXCL11 could be investigated as potential therapies. Inhibition of the autophagy-associated molecules VPS15, LAMP2, LC3A, XBP1, or ULK1 may decrease colitic pathology. Curtailing endothelin-activity may decrease colitic impact. The antiproliferative, immunomodulatory molecules IFIT1, IFIT2, IFIT3, and IFI44 may have direct therapeutic value in ameliorating colitis. The molecules IRF4, IRF8, IRF2BP1, IFRD1, and IFRD2 are potentially good target molecules to competitively inhibit towards curbing colitis.
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Affiliation(s)
- Rajkumar Cheluvappa
- Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, NSW, Australia
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Zhang L, Kang Y, Chen S, Wang L, Jiang M, Xiang L. Circulating CCL20: A potential biomarker for active vitiligo together with the number of Th1/17 cells. J Dermatol Sci 2019; 93:92-100. [PMID: 30655106 DOI: 10.1016/j.jdermsci.2018.12.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 12/27/2018] [Accepted: 12/28/2018] [Indexed: 11/25/2022]
Abstract
BACKGROUND Vitiligo is an autoimmune disease with varying pathological features. Activation of the CCL20-CCR6 axis plays an important role in chronic inflammatory diseases. However, whether CCL20-CCR6 and Th1/17 cells are indicative of active vitiligo is unclear. OBJECTIVE To investigate the potential role of CCL20 and the involvement of Th1/17 and Tc1/17 cells in the mechanism in vitiligo. METHODS One hundred patients with vitiligo, and 20 healthy controls were included. The serum and blister fluid IL-17, IFN-γ, CCL20, and CXCL10 were studied using enzyme-linked immunosorbent assays. The numbers of Th1/17 cells and Tc1/17 cells in circulation were quantified using flow cytometry. CCR6 mRNA in peripheral blood mononuclear cells (PBMCs) was analyzed by real-time polymerase chain reaction and the protein level was confirmed by western blotting. CCR6 and CCL20 expression in lesions was analyzed by immunohistochemistry. RESULTS The serum CCL20 level was significantly elevated in patients with vitiligo. The level of serum CCL20 was higher in active than in the stable stage, which correlated positively with the Vitiligo European Task Force spreading score and the Vitiligo Area Scoring Index score. Patients with active vitiligo had elevated numbers of circulating Th1/17 cells and Tc1/17 cells, and upregulated expression of CCR6 in PBMCs and lesions. After effective treatment, the level of CCL20 in sera and blister fluid was significantly decreased, as were the numbers of circulating Th1/17 cells and Tc1/17 cells. CONCLUSION CCL20 might be a vital biomarker of active vitiligo, and circulating Th1/17 and Tc1/17 cells are involved in the pathogenesis of vitiligo.
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Affiliation(s)
- Li Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China
| | - Yuli Kang
- Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China
| | - Shujun Chen
- Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China
| | - Li Wang
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China
| | - Min Jiang
- Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China.
| | - Leihong Xiang
- Department of Dermatology, Huashan Hospital, Fudan University, 12 Wulumuqi Zhong Road, Shanghai, 200040, PR China.
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Shi Z, Fultz RS, Engevik MA, Gao C, Hall A, Major A, Mori-Akiyama Y, Versalovic J. Distinct roles of histamine H1- and H2-receptor signaling pathways in inflammation-associated colonic tumorigenesis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G205-G216. [PMID: 30462522 PMCID: PMC6383385 DOI: 10.1152/ajpgi.00212.2018] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel disease (IBD) is a well-known risk factor for the development of colorectal cancer. Prior studies have demonstrated that microbial histamine can ameliorate intestinal inflammation in mice. We tested the hypothesis whether microbe-derived luminal histamine suppresses inflammation-associated colon cancer in Apcmin/+ mice. Mice were colonized with the human-derived Lactobacillus reuteri. Chronic inflammation was induced by repeated cycles of low-dose dextran sulfate sodium (DSS). Mice that were given histamine-producing L. reuteri via oral gavage developed fewer colonic tumors, despite the presence of a complex mouse gut microbiome. We further demonstrated that administration of a histamine H1-receptor (H1R) antagonist suppressed tumorigenesis, while administration of histamine H2-receptor (H2R) antagonist significantly increased both tumor number and size. The bimodal functions of histamine include protumorigenic effects through H1R and antitumorigenic effects via H2R, and these results were supported by gene expression profiling studies on tumor specimens of patients with colorectal cancer. Greater ratios of gene expression of H2R ( HRH2) vs. H1R ( HRH1) were correlated with improved overall survival outcomes in patients with colorectal cancer. Additionally, activation of H2R suppressed phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited chemokine gene expression induced by H1R activation in colorectal cancer cells. Moreover, the combination of a H1R antagonist and a H2R agonist yielded potent suppression of lipopolysaccharide-induced MAPK signaling in macrophages. Given the impact on intestinal epithelial and immune cells, simultaneous modulation of H1R and H2R signaling pathways may be a promising therapeutic target for the prevention and treatment of inflammation-associated colorectal cancer. NEW & NOTEWORTHY Histamine-producing Lactobacillus reuteri can suppress development of inflammation-associated colon cancer in an established mouse model. The net effects of histamine may depend on the relative activity of H1R and H2R signaling pathways in the intestinal mucosa. Our findings suggest that treatment with H1R or H2R antagonists could yield opposite effects. However, by harnessing the ability to block H1R signaling while stimulating H2R signaling, novel strategies for suppression of intestinal inflammation and colorectal neoplasia could be developed.
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Affiliation(s)
- Zhongcheng Shi
- 1Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas,2Department of Pathology, Texas Children’s Hospital, Houston, Texas
| | - Robert S. Fultz
- 2Department of Pathology, Texas Children’s Hospital, Houston, Texas,3Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas
| | - Melinda A. Engevik
- 1Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas,2Department of Pathology, Texas Children’s Hospital, Houston, Texas
| | - Chunxu Gao
- 4Alkek Center for Metagenomics and Microbiome Research, Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Anne Hall
- 2Department of Pathology, Texas Children’s Hospital, Houston, Texas,5Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas
| | - Angela Major
- 2Department of Pathology, Texas Children’s Hospital, Houston, Texas
| | - Yuko Mori-Akiyama
- 1Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas,2Department of Pathology, Texas Children’s Hospital, Houston, Texas
| | - James Versalovic
- 1Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas,2Department of Pathology, Texas Children’s Hospital, Houston, Texas
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Skovdahl HK, Damås JK, Granlund AVB, Østvik AE, Doseth B, Bruland T, Mollnes TE, Sandvik AK. C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release. Int J Mol Sci 2018; 19:ijms19103257. [PMID: 30347808 PMCID: PMC6214005 DOI: 10.3390/ijms19103257] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 09/21/2018] [Accepted: 10/12/2018] [Indexed: 12/16/2022] Open
Abstract
The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6+ cells in circulation, indicating chemoattraction of CCR6+ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.
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Affiliation(s)
- Helene Kolstad Skovdahl
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
| | - Jan Kristian Damås
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Infectious Diseases, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Atle van Beelen Granlund
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
| | - Ann Elisabet Østvik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Berit Doseth
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Clinic of Medicine, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Torunn Bruland
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Clinic of Medicine, St. Olav's University Hospital, 7030 Trondheim, Norway.
| | - Tom Eirik Mollnes
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Immunology, Oslo University Hospital and University of Oslo, 0372 Oslo, Norway.
- Research Laboratory, Department of Laboratory Medicine, Nordland Hospital, 8005 Bodo, Norway.
- K.G. Jebsen TREC, University of Tromsø, 9037 Tromsø, Norway.
| | - Arne Kristian Sandvik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology (NTNU), 7030 Trondheim, Norway.
- Department of Clinical and Molecular Medicine, NTNU, 7030 Trondheim, Norway.
- Department of Gastroenterology and Hepatology, St. Olav's University Hospital, 7030 Trondheim, Norway.
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Abstract
CC chemokine receptor 6 (CCR6) and its specific partner CC chemokine ligand 20 (CCL20) are known to play a pivotal role in intestinal inflammation. CCR6-associated inflammatory bowel disease (IBD) is already at the forefront of experimental inflammatory disease models, being the subject of numerous analytical studies. IBD is associated with two sub phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC). Both these disease entities produce potent immune dysregulation followed by intense tissue damage within the gut mucosal system, initiating symptoms that are severely debilitating. Multiple causative factors are said to be responsible for IBD, but direct immune dysfunction is kindled by overplay of innate and adaptive immune responses produced against the luminal contents through the weakened or leaky gut epithelial barrier. Once immune homeostasis is not achieved by endogenous protective mechanisms, the self-assertive adaptive immunity mobilizes its various T and B cell cohorts, initializing their immune mechanisms by deploying the immune cells towards the site of infection. CCR6 and its unique solitary ligand CCL20 are small protein molecules that are abundantly expressed by T and B lymphocytes and act as chemotactic immune-modulatory envoys that help in the deployment of the effector lymphocyte arm of the immune system and produce two directly opposing outcomes in IBD. This dichotomous immunity consists of either immune tolerance or inflammation which then develops into a chronic state, remaining unresponsive to inherent immunity or targeted clinical therapy. In this review, we have identified large numbers of experimental studies that have employed both mouse models and clinical subjects spanning a period of nearly two decades and we have clustered these into 13 different groups. This review will provide greater understanding of the CCR6–CCL20 axis in IBD and identify gaps in the literature that can be filled in the future.
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Noguchi K, Kamiyama N, Hidano S, Gendo Y, Sonoda A, Ozaki T, Hirose H, Sachi N, Saechue B, Ozaka S, Eshita Y, Mizukami K, Kawano K, Kobayashi T. Autoimmune sialadenitis is associated with the upregulation of chemokine/chemokine receptor pairs in T cell-specific TRAF6-deficient mice. Biochem Biophys Res Commun 2018; 504:245-250. [PMID: 30190125 DOI: 10.1016/j.bbrc.2018.08.162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 08/27/2018] [Indexed: 12/14/2022]
Abstract
Sialadenitis is an inflammatory condition affecting the salivary glands including the parotid, submandibular, and sublingual glands. There are several different types of sialadenitis, each with different sites of predilection. However, the pathogenic mechanism underlying the tissue specificity of sialadenitis is largely unknown. TRAF6 is a cytoplasmic adaptor protein that is necessary for the activation of dendritic cells in response to Toll-like receptor ligands, thereby regulating innate immune responses. We previously demonstrated that T cell-specific TRAF6-deficient mice (TRAF6ΔT mice) spontaneously develop systemic inflammatory disease. Here, we show that salivary secretion is reduced in TRAF6ΔT mice due to sialadenitis that occurs in the parotid and submandibular glands, but not the sublingual glands. Consistent with pathological findings, both CD4+ and CD8+ T cells predominantly infiltrated the submandibular glands; however, sublingual infiltration was rare in TRAF6ΔT mice. The TH1 cytokine IFN-γ, the TH1 cell attractant chemokine CCL2, and its cognate receptor CCR2 were upregulated concomitantly in both the submandibular and sublingual glands. Interestingly, the TH17 cell attractant chemokine CCL20 and its cognate receptor CCR6 were selectively increased in the submandibular glands, but not in the sublingual glands of TRAF6ΔT mice. Thus, the expression of TRAF6 in T cells might be implicated in tissue-specific sialadenitis by regulating the chemokine-chemokine receptor system.
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Affiliation(s)
- Kaori Noguchi
- Department of Infectious Disease Control, Japan; Department of Oral and Maxillofacial Surgery, Japan
| | | | | | | | | | | | | | | | | | | | - Yuki Eshita
- Department of Infectious Disease Control, Japan
| | - Kazuhiro Mizukami
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Kenji Kawano
- Department of Oral and Maxillofacial Surgery, Japan
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Lamb CA, O'Byrne S, Keir ME, Butcher EC. Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. J Crohns Colitis 2018; 12:S653-S668. [PMID: 29767705 DOI: 10.1093/ecco-jcc/jjy060] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between α4β7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by αEβ7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti-integrin therapeutics, including gut-selective antibodies against the β7 integrin subunit [etrolizumab] and the α4β7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-α4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules.
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Affiliation(s)
- Christopher A Lamb
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sharon O'Byrne
- Global Medical Affairs, Takeda Pharmaceuticals International AG, Zurich, Switzerland
| | - Mary E Keir
- Genentech Research & Early Development, South San Francisco, CA, USA
| | - Eugene C Butcher
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, CA, USA
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Trivedi PJ, Adams DH. Chemokines and Chemokine Receptors as Therapeutic Targets in Inflammatory Bowel Disease; Pitfalls and Promise. J Crohns Colitis 2018; 12:S641-S652. [PMID: 30137309 PMCID: PMC6104621 DOI: 10.1093/ecco-jcc/jjx145] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The principal targets for anti-chemokine therapy in inflammatory bowel disease (IBD) have been the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10. More recently CCR6 and its ligand CCL20 have also received attention, the expression of the latter in enterocytes being manipulated through Smad7 signalling. These pathways, selected based on their fundamental role in regulating mucosal immunity, have led to the development of several therapeutic candidates that have been tested in early phase clinical trials with variable clinical efficacy. In this article, we appraise the status of chemokine-directed therapy in IBD, review recent developments, and nominate future areas for therapeutic focus.
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health Research (NIHR) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK
- Department of Gastroenterology, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK
- Centre for Rare Diseases, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
| | - David H Adams
- National Institute for Health Research (NIHR) Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK
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Cheluvappa R, Thomas DG, Selvendran S. The Role of Specific Chemokines in the Amelioration of Colitis by Appendicitis and Appendectomy. Biomolecules 2018; 8:biom8030059. [PMID: 30037025 PMCID: PMC6165111 DOI: 10.3390/biom8030059] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 07/03/2018] [Accepted: 07/16/2018] [Indexed: 01/07/2023] Open
Abstract
The appendix contains abundant lymphoid tissue and is constantly exposed to gut flora. When completed at a young age, appendicitis followed by appendectomy (AA) prevents or significantly ameliorates Inflammatory Bowel Diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn’s disease and ulcerative colitis. Our murine AA model is the only existing experimental model of AA. In our unique model, AA performed in the most proximal colon limits colitis pathology in the most distal colon by curbing T-helper 17 cell activity, diminishing autophagy, modulating interferon activity-associated molecules, and suppressing endothelin vaso-activity-mediated immunopathology. In the research presented in this paper, we have examined the role of chemokines in colitis pathology with our murine AA model. Chemokines are a family of small cytokines with four conserved cysteine residues. Chemokines induce chemotaxis in adjacent cells with corresponding receptors. All 40 known chemokine genes and 24 chemokine receptor genes were examined for gene expression levels in distal colons three days post-AA and 28 days post-AA. At 28 days post-AA, the chemokine gene CCL5 was significantly upregulated. Furthermore, Gene Set Enrichment Analysis (GSEA) showed upregulation of seven CCL5-associated gene-sets 28 days post-AA in contrast to just one gene-set downregulated at the same time-point. The chemokine gene CXCL11 was significantly upregulated three days post-AA and 28 days post-AA. Evaluation using GSEA showed upregulation of six CXCL11-associated gene sets but no downregulation of any gene set. At 28 days post-AA, CCL17 gene expression was significantly downregulated. There was no expression of any chemokine receptor gene three days post-AA, but CCR10 was the only chemokine receptor gene that displayed differential gene expression (upregulation) 28 days post-AA. No CCR10-associated gene set was upregulated in GSEA in contrast to one downregulated gene set. Our analysis resulted in identifying three new therapeutic targets towards ameliorating colitis: CCL5, CXCL11, and CCL17. While CCL5 and CXCL11 are good therapeutic chemokine candidates to be exogenously administered, CCL17 is a good candidate chemokine to competitively inhibit or limit colitis pathology.
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Affiliation(s)
- Rajkumar Cheluvappa
- Department of Medicine, St. George Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
| | - Dennis G Thomas
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99352, USA.
| | - Selwyn Selvendran
- Department of Surgery, St. George Hospital, Kogarah, NSW 2217, Australia.
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Means AL, Freeman TJ, Zhu J, Woodbury LG, Marincola-Smith P, Wu C, Meyer AR, Weaver CJ, Padmanabhan C, An H, Zi J, Wessinger BC, Chaturvedi R, Brown TD, Deane NG, Coffey RJ, Wilson KT, Smith JJ, Sawyers CL, Goldenring JR, Novitskiy SV, Washington MK, Shi C, Beauchamp RD. Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer. Cell Mol Gastroenterol Hepatol 2018; 6:257-276. [PMID: 30109253 PMCID: PMC6083016 DOI: 10.1016/j.jcmgh.2018.05.006] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 05/18/2018] [Indexed: 02/08/2023]
Abstract
Background & Aims Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells. Methods The Smad4 gene was deleted specifically in adult murine intestinal epithelium. Colitis was induced by 3 rounds of dextran sodium sulfate in drinking water, after which mice were observed for up to 3 months. Nontransformed mouse colonocyte cell lines and colonoid cultures and human colorectal cancer cell lines were analyzed for responses to TGFβ1 and bone morphogenetic protein 2. Results Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic Smad4 expression, with resulting tumors bearing striking resemblance to human colitis-associated carcinoma. Loss of SMAD4 protein was observed in 48% of human colitis-associated carcinoma samples as compared with 19% of sporadic colorectal carcinomas. Loss of Smad4 increased the expression of inflammatory mediators within nontransformed mouse colon epithelial cells in vivo. In vitro analysis of mouse and human colonic epithelial cell lines and organoids indicated that much of this regulation was cell autonomous. Furthermore, TGFβ signaling inhibited the epithelial inflammatory response to proinflammatory cytokines. Conclusions TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.
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Key Words
- AOM, azoxymethane
- APC, adenomatous polyposis coli
- BMP, bone morphogenetic protein
- CAC, colitis-associated carcinoma
- CCL20, Chemokine (C-C motif) ligand 20
- CRC, colorectal cancer
- CRISPR/Cas9, Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9
- Colitis-Associated Carcinoma
- DMEM, Dulbecco's modified Eagle medium
- DSS, dextran sodium sulfate
- FBS, fetal bovine serum
- FDR, false discovery rate
- GFP, green fluorescent protein
- HBSS, Hank's balanced salt solution
- IBD, inflammatory bowel disease
- IL, interleukin
- IMCS4fl/fl, immortalized mouse colonoctye cell line with loxP-flanked Smad4 alleles
- IMCS4null, immortalized mouse colonocyte cell line with deletion of the Smad4 alleles
- LPS, lipopolysaccharide
- PBS, phosphate-buffered saline
- PE, phycoerythrin
- R-SMAD, Receptor-SMAD
- SFG, retroviral vector
- STAT3, signal transducer and activator of transcription 3
- TGFβ
- TGFβ, transforming growth factor β
- TNF, tumor necrosis factor
- Tumor Necrosis Factor
- UC, ulcerative colitis
- WNT, wingless-type mouse mammary tumor virus integration site
- YAMC, young adult mouse colon epithelial cells
- mRNA, messenger RNA
- sgRNA, single-guide RNA
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Affiliation(s)
- Anna L. Means
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Tanner J. Freeman
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jing Zhu
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Luke G. Woodbury
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Chao Wu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anne R. Meyer
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Connie J. Weaver
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Hanbing An
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jinghuan Zi
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Bronson C. Wessinger
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Rupesh Chaturvedi
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Tasia D. Brown
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Natasha G. Deane
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Robert J. Coffey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Keith T. Wilson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
| | - J. Joshua Smith
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Charles L. Sawyers
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - James R. Goldenring
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Sergey V. Novitskiy
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - M. Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Chanjuan Shi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - R. Daniel Beauchamp
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
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Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res 2018; 16:26-42. [PMID: 29422795 PMCID: PMC5797268 DOI: 10.5217/ir.2018.16.1.26] [Citation(s) in RCA: 380] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 04/18/2017] [Accepted: 04/19/2017] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory state of the gastrointestinal tract and can be classified into 2 main clinical phenomena: Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD, including CD and UC, involves the presence of pathogenic factors such as abnormal gut microbiota, immune response dysregulation, environmental changes, and gene variants. Although many investigations have tried to identify novel pathogenic factors associated with IBD that are related to environmental, genetic, microbial, and immune response factors, a full understanding of IBD pathogenesis is unclear. Thus, IBD treatment is far from optimal, and patient outcomes can be unsatisfactory. As result of massive studying on IBD, T helper 17 (Th17) cells and innate lymphoid cells (ILCs) are investigated on their effects on IBD. A recent study of the plasticity of Th17 cells focused primarily on colitis. ILCs also emerging as novel cell family, which play a role in the pathogenesis of IBD. IBD immunopathogenesis is key to understanding the causes of IBD and can lead to the development of IBD therapies. The aim of this review is to explain the pathogenesis of IBD, with a focus on immunological factors and therapies.
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Affiliation(s)
- Seung Hoon Lee
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Jeong eun Kwon
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
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