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López-Posadas R, Bagley DC, Pardo-Pastor C, Ortiz-Zapater E. The epithelium takes the stage in asthma and inflammatory bowel diseases. Front Cell Dev Biol 2024; 12:1258859. [PMID: 38529406 PMCID: PMC10961468 DOI: 10.3389/fcell.2024.1258859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 02/22/2024] [Indexed: 03/27/2024] Open
Abstract
The epithelium is a dynamic barrier and the damage to this epithelial layer governs a variety of complex mechanisms involving not only epithelial cells but all resident tissue constituents, including immune and stroma cells. Traditionally, diseases characterized by a damaged epithelium have been considered "immunological diseases," and research efforts aimed at preventing and treating these diseases have primarily focused on immuno-centric therapeutic strategies, that often fail to halt or reverse the natural progression of the disease. In this review, we intend to focus on specific mechanisms driven by the epithelium that ensure barrier function. We will bring asthma and Inflammatory Bowel Diseases into the spotlight, as we believe that these two diseases serve as pertinent examples of epithelium derived pathologies. Finally, we will argue how targeting the epithelium is emerging as a novel therapeutic strategy that holds promise for addressing these chronic diseases.
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Affiliation(s)
- Rocío López-Posadas
- Department of Medicine 1, University Hospital of Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-Universtiy Eralngen-Nürnberg, Erlangen, Germany
| | - Dustin C. Bagley
- Randall Centre for Cell and Molecular Biophysics, New Hunt’s House, School of Basic and Medical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Carlos Pardo-Pastor
- Randall Centre for Cell and Molecular Biophysics, New Hunt’s House, School of Basic and Medical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Elena Ortiz-Zapater
- Department of Biochemistry and Molecular Biology, Universitat de Valencia, Valencia, Spain
- Instituto Investigación Hospital Clínico-INCLIVA, Valencia, Spain
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Riaz B, Sohn S. Neutrophils in Inflammatory Diseases: Unraveling the Impact of Their Derived Molecules and Heterogeneity. Cells 2023; 12:2621. [PMID: 37998356 PMCID: PMC10670008 DOI: 10.3390/cells12222621] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 11/08/2023] [Accepted: 11/10/2023] [Indexed: 11/25/2023] Open
Abstract
Inflammatory diseases involve numerous disorders and medical conditions defined by an insufficient level of self-tolerance. These diseases evolve over the course of a multi-step process through which environmental variables play a crucial role in the emergence of aberrant innate and adaptive immunological responses. According to experimental data accumulated over the past decade, neutrophils play a significant role as effector cells in innate immunity. However, neutrophils are also involved in the progression of numerous diseases through participation in the onset and maintenance of immune-mediated dysregulation by releasing neutrophil-derived molecules and forming neutrophil extracellular traps, ultimately causing destruction of tissues. Additionally, neutrophils have a wide variety of functional heterogeneity with adverse effects on inflammatory diseases. However, the complicated role of neutrophil biology and its heterogeneity in inflammatory diseases remains unclear. Moreover, neutrophils are considered an intriguing target of interventional therapies due to their multifaceted role in a number of diseases. Several approaches have been developed to therapeutically target neutrophils, involving strategies to improve neutrophil function, with various compounds and inhibitors currently undergoing clinical trials, although challenges and contradictions in the field persist. This review outlines the current literature on roles of neutrophils, neutrophil-derived molecules, and neutrophil heterogeneity in the pathogenesis of autoimmune and inflammatory diseases with potential future therapeutic strategies.
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Affiliation(s)
- Bushra Riaz
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
| | - Seonghyang Sohn
- Department of Biomedical Science, Ajou University School of Medicine, Suwon 16499, Republic of Korea;
- Department of Microbiology, Ajou University School of Medicine, Suwon 16499, Republic of Korea
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Krawiec P, Pac-Kożuchowska E. Clinical Significance of Serum Elafin in Children with Inflammatory Bowel Disease. Biomedicines 2022; 10:3267. [PMID: 36552023 PMCID: PMC9775364 DOI: 10.3390/biomedicines10123267] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The role of elafin in the pathophysiology of inflammatory bowel disease (IBD) has not been not elucidated. We aimed to evaluate serum elafin in children with IBD and assess its relationship with disease activity. METHODS We enrolled children with IBD in the study group and children with functional abdominal pain in the control group. We evaluated serum elafin using enzyme-linked immunosorbent assay kits. RESULTS In children with IBD, serum elafin (mean ± SD: 4.192 ± 1.424 ng/mL) was significantly elevated compared with controls (mean ± SD: 3.029 ± 1.366 ng/mL) (p = 0.0005). Elafin was significantly increased in children in the active phase of IBD (mean ± SD: 4.424 ± 1.449 ng/mL) compared with the control group (p = 0.0003). In IBD remission, only children with ulcerative colitis (mean ± SD: 4.054 ± 1.536 ng/mL) had elevated elafin compared with controls (p = 0.004). ROC analysis revealed that the area under the curve (AUC) of serum elafin was 0.809 while discriminating patients with ulcerative colitis from the control group, and the AUC was 0.664 while differentiating patients with Crohn's disease from the control group. CONCLUSIONS Serum elafin was found to be elevated in our cohort of children with IBD, depending on disease activity. Serum elafin was increased in the active phases of both ulcerative colitis and Crohn's disease, but only in the remission of ulcerative colitis. Elafin appears to be a potential candidate for a biomarker of ulcerative colitis.
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Affiliation(s)
- Paulina Krawiec
- Department of Pediatrics and Gastroenterology, Medical University of Lublin, Al. Racławickie 1, 20-059 Lublin, Poland
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Acen EL, Kateete DP, Worodria W, Olum R, Joloba ML, Bbuye M, Biraro IA. Evaluation of circulating serum cathelicidin levels as a potential biomarker to discriminate between active and latent tuberculosis in Uganda. PLoS One 2022; 17:e0272788. [PMID: 36018845 PMCID: PMC9416991 DOI: 10.1371/journal.pone.0272788] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 07/26/2022] [Indexed: 01/08/2023] Open
Abstract
Background
Tuberculosis remains a major public health problem worldwide accounting for 1.4 million deaths annually. LL-37 is an effector molecule involved in immunity with both antimicrobial and immunomodulatory properties. The purpose of this study was to compare LL-37 circulatory levels among participants with active and latent tuberculosis and to determine its ability to discriminate between the two infectious states.
Methods
A cross-sectional study was performed among 56 active tuberculosis patients, 49 latent tuberculosis individuals, and 43 individuals without tuberculosis infection. The enzyme-linked immunosorbent assay was used to assess LL-37 levels. Data analysis was performed using STATA software and Graph pad Prism version 8. Mann-Whitney U test was used for correlation between variables with two categories and the Kruskal-Wallis test for three or more categories.
Results
The study had more female participants than males, with similar median ages across the three groups, 29.5, 25.0, and 23.0 years respectively. Active tuberculosis patients had significantly higher LL-37 levels compared to those with latent tuberculosis and without tuberculosis. The median/interquartile ranges were 318.8 ng/ml (157.9–547.1), 242.2 ng/ml (136.2–579.3), 170.9 ng/ml (129.3–228.3); p = 0.002 respectively. Higher LL-37 was found in the male participant with median/interquartile range, 424.8 ng/ml (226.2–666.8) compared to the females 237.7 ng/ml (129.6–466.6); p = 0.045. LL-37 had better discriminatory potential between active tuberculosis and no tuberculosis (AUC = 0.71, sensitivity 71.4% specificity = 69.8%) than with latent tuberculosis (AUC = 0.55, sensitivity = 71.4%, specificity = 44.9%). There was moderate differentiation between latent tuberculosis and no tuberculosis (AUC = 0.63, sensitivity = 44.9% specificity = 90.7%).
Conclusion
Significantly higher LL-37 levels were observed among active tuberculosis patients than those without tuberculosis infection and were, therefore able to discriminate between active tuberculosis and other tuberculosis infectious states, especially with no tuberculosis. Further assessment of this biomarker as a screening tool to exclude tuberculosis is required.
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Affiliation(s)
- Ester Lilian Acen
- Department of Physiology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
- * E-mail:
| | - David Patrick Kateete
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - William Worodria
- Pulmonary Division, Department of Medicine, Mulago National Referral Hospital, Kampala, Uganda
| | - Ronald Olum
- Department of Medicine, School of Medicine, College of Health Sciences Unit, Makerere University, Kampala, Uganda
| | - Moses L. Joloba
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Mudarshiru Bbuye
- Makerere Lung Institute College of Health Sciences, Makerere University, Kampala, Uganda
| | - Irene Andia Biraro
- Department of Medicine, School of Medicine, College of Health Sciences Unit, Makerere University, Kampala, Uganda
- Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
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Gubatan J, Holman DR, Puntasecca CJ, Polevoi D, Rubin SJS, Rogalla S. Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World J Gastroenterol 2021; 27:7402-7422. [PMID: 34887639 PMCID: PMC8613745 DOI: 10.3748/wjg.v27.i43.7402] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/13/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.
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Affiliation(s)
- John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
| | - Derek R Holman
- Department of Radiology, Molecular Imaging Program at Stanford , Stanford University, Stanford , CA 94305, United States
| | | | - Danielle Polevoi
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Samuel JS Rubin
- Stanford University School of Medicine, Stanford University, Stanford, CA 94063, United States
| | - Stephan Rogalla
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Redwood City, CA 94063, United States
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Liver Pathology in Children with Diagnosed Inflammatory Bowel Disease-A Single Center Experience. J Clin Med 2021; 10:jcm10225359. [PMID: 34830641 PMCID: PMC8621401 DOI: 10.3390/jcm10225359] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) in children is frequently associated with liver pathology manifested as transient elevation of liver enzymes or specified liver diseases. The aim of the study was to evaluate the prevalence and the type of liver pathology in children with IBD within 2 years' follow-up after the IBD diagnosis. METHODS We retrospectively reviewed records of children with IBD. Liver pathology was defined as elevated activity of liver enzymes (alanine transaminase (ALT) and/or gamma-glutamyl transpeptidase (GGT)) and bilirubin concentration in serum and/or as pathological changes of the organ on imaging tests (abdominal ultrasound and/or magnetic resonance cholangiopancreatography) or on liver histology performed when indicated. RESULTS Liver pathology was detected in 21 from 119 children (18%), including 7 (17%) with Crohn's disease (CD) and 14 (18%) with ulcerative colitis (UC). Specified diagnosis for liver abnormality was found in 14 of 21 children (67%), including primary sclerosing cholangitis (PSC, 19%), non-alcoholic fatty liver disease (NAFLD, 19%), autoimmune sclerosing cholangitis (ASC, 5%), autoimmune hepatitis (AIH, 5%), cholelithiasis (5%), drug-induced liver disease (9%) and viral infection (herpes simplex virus, 5%). Most patients manifested mild IBD or were in clinical remission at the time of liver pathology diagnosis. 14% of patients with liver disease (including only cases with PSC) were diagnosed before IBD, 33% at the same time, and 52% in the later period. Patients with the specified diagnosis of liver pathology were younger, had higher ALT activity and more often demonstrated liver abnormalities on imaging tests. UC patients with idiopathic elevation of liver enzymes had higher pediatric ulcerative colitis activity index scores compared to children with specified liver disease. CONCLUSIONS Liver pathology was observed in a significant percentage of children with IBD in our study. The majority of cases of hepatobiliary abnormalities were detected after diagnosis of IBD; therefore, children with IBD should undergo routine monitoring of liver enzymes.
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Kvedaraite E. Neutrophil-T cell crosstalk in inflammatory bowel disease. Immunology 2021; 164:657-664. [PMID: 34240423 PMCID: PMC8561100 DOI: 10.1111/imm.13391] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/30/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
Neutrophils are the most abundant leucocytes in human blood, promptly recruited to the site of tissue injury, where they orchestrate inflammation and tissue repair. The multifaceted functions of neutrophils have been more appreciated during the recent decade, and these cells are now recognized as sophisticated and essential players in infection, cancer and chronic inflammatory diseases. Consequently, our understanding of the role of neutrophils in inflammatory bowel disease (IBD), their immune responses and their ability to shape adaptive immunity in the gut have been recognized. Here, current knowledge on neutrophil responses in IBD and their capacity to influence T cells are summarized with an emphasis on the role of these cells in human disease.
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Affiliation(s)
- Egle Kvedaraite
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.,Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.,Department of Clinical Pathology, Karolinska University Hospital, Stockholm, Sweden
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