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1
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Yuan T, Xing J, Liu P. Identification of Crohn's Disease-Related Biomarkers and Pan-Cancer Analysis Based on Machine Learning. Mediators Inflamm 2025; 2025:6631637. [PMID: 40224483 PMCID: PMC11991868 DOI: 10.1155/mi/6631637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/14/2025] [Indexed: 04/15/2025] Open
Abstract
Background: In recent years, the incidence of Crohn's disease (CD) has shown a significant global increase, with numerous studies demonstrating its correlation with various cancers. This study aims to identify novel biomarkers for diagnosing CD and explore their potential applications in pan-cancer analysis. Methods: Gene expression profiles were retrieved from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified using the "limma" R package. Key biomarkers were selected through an integrative machine learning pipeline combining LASSO regression, neural network modeling, and Support Vector Machine-Recursive Feature Elimination (SVM-RFE). Six hub genes were identified and further validated using the independent dataset GSE169568. To assess the broader relevance of these biomarkers, a standardized pan-cancer dataset from the UCSC database was analyzed to evaluate their associations with 33 cancer types. Results: Among the identified biomarkers, S100 calcium binding protein P (S100P) and S100 calcium binding protein A8 (S100A8) emerged as key candidates for CD diagnosis, with strong validation in the independent dataset. Notably, S100P displayed significant associations with immune cell infiltration and patient survival outcomes in both liver and lung cancers. These findings suggest that chronic inflammation and immune imbalances in CD may not only contribute to disease progression but also elevate cancer risk. As an inflammation-associated biomarker, S100P holds particular promise for both CD diagnosis and potential cancer risk stratification, especially in liver and lung cancers. Conclusion: Our study highlights S100P and S100A8 as potential diagnostic biomarkers for CD. Moreover, the pan-cancer analysis underscores the broader clinical relevance of S100P, offering new insights into its role in immune modulation and cancer prognosis. These findings provide a valuable foundation for future research into the shared molecular pathways linking chronic inflammatory diseases and cancer development.
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Affiliation(s)
- Tangyu Yuan
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong, China
| | - Jiayin Xing
- School of Life Science and Technology, Shandong Second Medical University, Weifang, Shandong, China
| | - Pengtao Liu
- School of Basic Medical Science, Shandong Second Medical University, Weifang, Shandong, China
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2
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Chen T, Liu J, Hang R, Chen Q, Wang D. Neutrophils: From Inflammatory Bowel Disease to Colitis-Associated Colorectal Cancer. J Inflamm Res 2025; 18:925-947. [PMID: 39871958 PMCID: PMC11770381 DOI: 10.2147/jir.s497701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 01/06/2025] [Indexed: 01/29/2025] Open
Abstract
Inflammatory bowel disease (IBD) is a non-specific inflammatory disease of digestive tract, primarily manifesting as ulcerative colitis (UC) and Crohn's disease (CD). The precise etiology of IBD remains elusive. The interplay of genetic factors, environmental influences, and intestinal microbiota contributes to the establishment of an uncontrolled immune environment within the intestine, which can progressively lead to atypical hyperplasia and ultimately to malignancy over a long period. This colorectal malignant tumor that arises from chronic IBD is referred to as colitis-associated colorectal cancer (CAC). Dysregulation in the quantity and functionality of neutrophils plays a significant role in the onset, progression, and recurrence of IBD, as well as in the transition from IBD to CAC. Neutrophils affect the pathophysiology of IBD through various mechanisms, including the production of reactive oxygen species (ROS), degranulation, the release of inflammatory mediators and chemokines, and the formation of neutrophil extracellular traps (NETs). These processes can induce DNA mutations, thereby facilitating the development of colon cancer. Given the incomplete understanding of the disease mechanisms underlying IBD and CAC, effective treatment and prevention strategies remain challenging. Consequently, a comprehensive review of the functional roles of neutrophils in IBD and CAC is essential for advancing our understanding of IBD pathogenesis and identifying potential therapeutic targets.
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Affiliation(s)
- Tianyi Chen
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Jiachen Liu
- Radiology Department, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Ruyi Hang
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Qian Chen
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
| | - Dong Wang
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, People’s Republic of China
- Oncology Department of Qianjiang Center Hospital, Chongqing University, Chongqing, People’s Republic of China
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3
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Zheng C, Li J, Chen H, Ma X, Si T, Zhu W. Dual role of CD177 + neutrophils in inflammatory bowel disease: a review. J Transl Med 2024; 22:813. [PMID: 39223577 PMCID: PMC11370282 DOI: 10.1186/s12967-024-05539-3] [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: 04/12/2024] [Accepted: 07/25/2024] [Indexed: 09/04/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a group of recurrent chronic inflammatory disorders associated with autoimmune dysregulation, typically characterized by neutrophil infiltration and mucosal inflammatory lesions. Neutrophils, as the earliest immune cells to arrive at inflamed tissues, play a dual role in the onset and progression of mucosal inflammation in IBD. Most of these cells specifically express CD177, a molecule increasingly recognized for its critical role in the pathogenesis of IBD. Under IBD-related inflammatory stimuli, CD177 is highly expressed on neutrophils and promotes their migration. CD177 + neutrophils activate bactericidal and barrier-protective functions at IBD mucosal inflammation sites and regulate the release of inflammatory mediators highly correlated with the severity of inflammation in IBD patients, thus playing a dual role. However, mitigating the detrimental effects of neutrophils in inflammatory bowel disease remains a challenge. Based on these data, we have summarized recent articles on the role of neutrophils in intestinal inflammation, with a particular emphasis on CD177, which mediates the recruitment, transepithelial migration, and activation of neutrophils, as well as their functional consequences. A better understanding of CD177 + neutrophils may contribute to the development of novel therapeutic targets to selectively modulate the protective role of this class of cells in IBD.
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Affiliation(s)
- Chengli Zheng
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiekai Li
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailin Chen
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaolin Ma
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tianyu Si
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wenwei Zhu
- Department of Hematology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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4
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Shao Y, Li L, Yang Y, Ye Y, Guo Z, Liu L, Huang J, Chen Y, Gao X, Sun B. DNase aggravates intestinal microvascular injury in IBD patients by releasing NET-related proteins. FASEB J 2024; 38:e23395. [PMID: 38149880 DOI: 10.1096/fj.202301780r] [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: 09/02/2023] [Revised: 12/02/2023] [Accepted: 12/15/2023] [Indexed: 12/28/2023]
Abstract
Neutrophils accumulate in the inflammatory mucosa of patients with inflammatory bowel disease (IBD), and excessive release of NETs (neutrophil extracellular traps may be one of the important factors that cause IBD progression. However, the specific mechanism underlying vascular injury caused by NETs remains unclear. Immunofluorescence, ELISA, and flow cytometry were used in this study to detect the expression of NETs and DNase in the tissue and peripheral blood samples of patients with IBD. DSS mouse model was used to detect colon injury and vascular permeability. We found that NETs and DNase levels increased in the colon of patients with IBD. We found an increase in the activity of NET-related MPO released by DNase. DNase released NET-related proteins and damaged vascular endothelial cells in vitro. In DSS mouse model, the synchronous increase of DNase and NETs in the colon leads to an increase in vascular injury markers (CD44, sTM). DNase aggravated colon injury and increased vascular permeability in vivo, which was inhibited by gentamicin sulfate (GS). GS does not reduce the expression of DNase, but rather reduces the release of NET-related proteins to protect vascular endothelium by inhibiting DNase activity. MPO and histones synergistically damaged the vascular endothelium, and vascular injury can be improved by their active inhibitors. We further found that H2 O2 is an important substrate for MPO induced vascular damage. In conclusion, in IBD, DNase, and NET levels increased synchronously in the lesion area and released NET-related proteins to damage the vascular endothelium. Therefore, targeting DNase may be beneficial for the treatment of IBD.
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Affiliation(s)
- Yiming Shao
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jining Medical University, Jining, China
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Linbin Li
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yunxi Yang
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yulan Ye
- Department of Gastroenterology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Zaiwen Guo
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Lu Liu
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Jiamin Huang
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yi Chen
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Xi Gao
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Bingwei Sun
- Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
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Loh L, Orlicky D, Spengler A, Levens C, Celli S, Domenico J, Klarquist J, Onyiah J, Matsuda J, Kuhn K, Gapin L. MAIT cells drive chronic inflammation in a genetically diverse murine model of spontaneous colitis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.29.569225. [PMID: 38076996 PMCID: PMC10705467 DOI: 10.1101/2023.11.29.569225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/19/2024]
Abstract
Background & aims Lymphocytes that produce IL-17 can confer protective immunity during infections by pathogens, yet their involvement in inflammatory diseases is a subject of debate. Although these cells may perpetuate inflammation, resulting in tissue damage, they are also capable of contributing directly or indirectly to tissue repair, thus necessitating more detailed investigation. Mucosal-Associated-Invariant-T (MAIT) cells are innate-like T cells, acquiring a type III phenotype in the thymus. Here, we dissected the role of MAIT cells in vivo using a spontaneous colitis model in a genetically diverse mouse strain. Methods Multiparameter spectral flow cytometry and scRNAseq were used to characterize MAIT and immune cell dynamics and transcriptomic signatures respectively, in the collaborative-cross strain, CC011/Unc and CC011/Unc- Traj33 -/- . Results In contrast to many conventional mouse laboratory strains, the CC011 strain harbors a high baseline population of MAIT cells. We observed an age-related increase in colonic MAIT cells, Th17 cells, regulatory T cells, and neutrophils, which paralleled the development of spontaneous colitis. This progression manifested histological traits reminiscent of human IBD. The transcriptomic analysis of colonic MAIT cells from CC011 revealed an activation profile consistent with an inflammatory milieu, marked by an enhanced type-III response. Notably, IL-17A was abundantly secreted by MAIT cells in the colons of afflicted mice. Conversely, in the MAIT cell-deficient CC011-Traj33-/- mice, there was a notable absence of significant colonic histopathology. Furthermore, myeloperoxidase staining indicated a substantial decrease in colonic neutrophils. Conclusions Our findings suggest that MAIT cells play a pivotal role in modulating the severity of intestinal pathology, potentially orchestrating the inflammatory process by driving the accumulation of neutrophils within the colonic environment.
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Coletto LA, Rizzo C, Guggino G, Caporali R, Alivernini S, D’Agostino MA. The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations. Int J Mol Sci 2023; 24:4108. [PMID: 36835520 PMCID: PMC9959122 DOI: 10.3390/ijms24044108] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/14/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Spondyloarthritis (SpA) contemplates the inflammatory involvement of the musculoskeletal system, gut, skin, and eyes, delineating heterogeneous diseases with a common pathogenetic background. In the framework of innate and adaptive immune disruption in SpA, neutrophils are arising, across different clinical domains, as pivotal cells crucial in orchestrating the pro-inflammatory response, both at systemic and tissue levels. It has been suggested they act as key players along multiple stages of disease trajectory fueling type 3 immunity, with a significant impact in the initiation and amplification of inflammation as well as in structural damage occurrence, typical of long-standing disease. The aim of our review is to focus on neutrophils' role within the spectrum of SpA, dissecting their functions and abnormalities in each of the relevant disease domains to understand their rising appeal as potential biomarkers and therapeutic targets.
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Affiliation(s)
- Lavinia Agra Coletto
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
| | - Chiara Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, 90127 Palermo, Italy
| | - Giuliana Guggino
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, 90127 Palermo, Italy
| | - Roberto Caporali
- Division of Clinical Rheumatology, ASST Gaetano Pini-CTO Institute, 20122 Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
| | - Stefano Alivernini
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
| | - Maria Antonietta D’Agostino
- Division of Rheumatology, Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli IRCSS, 00168 Rome, Italy
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7
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Neutrophils in Intestinal Inflammation: What We Know and What We Could Expect for the Near Future. GASTROINTESTINAL DISORDERS 2022. [DOI: 10.3390/gidisord4040025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Neutrophils are short-lived cells that play a crucial role in inflammation. As in other tissues, these polymorphonuclear phagocytes are involved in the intestinal inflammatory response, on the one hand, contributing to the activation and recruitment of other immune cells, but on the other hand, facilitating intestinal mucosa repair by releasing mediators that aid in the resolution of inflammation. Even though these responses are helpful in physiological conditions, excessive recruitment of activated neutrophils in the gut correlates with increased mucosal damage and severe symptoms in patients with inflammatory bowel disease (IBD) and pre-clinical models of colitis. Thus, there is growing interest in controlling their biology to generate novel therapeutic approaches capable of reducing exacerbated intestinal inflammation. However, the beneficial and harmful effects of neutrophils on intestinal inflammation are still controversial. With this review, we summarise and discuss the most updated literature showing how neutrophils (and neutrophil extracellular traps) contribute to developing and resolving intestinal inflammation and their putative use as therapeutic targets.
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8
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Schroeder-Castagno M, Del Rio-Serrato A, Wilhelm A, Romero-Suárez S, Schindler P, Alvarez-González C, Duchow AS, Bellmann-Strobl J, Ruprecht K, Hastermann M, Grütz G, Wildemann B, Jarius S, Schmitz-Hübsch T, Paul F, Infante-Duarte C. Impaired response of blood neutrophils to cell-death stimulus differentiates AQP4-IgG-seropositive NMOSD from MOGAD. J Neuroinflammation 2022; 19:239. [PMID: 36183103 PMCID: PMC9526338 DOI: 10.1186/s12974-022-02600-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 09/17/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND In neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), neutrophils are found in CNS lesions. We previously demonstrated that NMOSD neutrophils show functional deficiencies. Thus, we hypothesized that neutrophil accumulation in the CNS may be facilitated by impairments affecting mechanisms of neutrophil death. OBJECTIVE To evaluate cell death in blood neutrophils from aquaporin-4 (AQP4)-IgG-seropositive NMOSD and MOGAD patients as well as matched healthy controls (HC) using in vitro assays. METHODS Twenty-eight AQP4 + NMOSD and 19 MOGAD patients in stable disease phase as well as 45 age- and sex-matched HC were prospectively recruited. To induce cell death, isolated neutrophils were cultured with/without phorbol 12-myristate 13-acetate (PMA). Spontaneous and PMA-induced NETosis and apoptosis were analyzed using 7-AAD and annexin-V by flow cytometry. Caspase-3 was assessed by western blot. Myeloperoxidase-DNA complexes (MPO-DNA), MPO and elastase were evaluated by ELISA, and cell-free DNA (cfDNA) by a fluorescence-based assay. Reactive oxygen species (ROS) were evaluated by a dihydrorhodamine 123-based cytometric assay. Serum GM-CSF, IL-6, IL-8, IL-15, TNF-ɑ and IL-10 were evaluated by multiplex assays, and neurofilament light chain (NfL) by single-molecule array assay. RESULTS In response to PMA, neutrophils from AQP4 + NMOSD but not from MOGAD patients showed an increased survival, and subsequent reduced cell death (29.6% annexin V+ 7-AAD+) when compared to HC (44.7%, p = 0.0006). However, AQP4 + NMOSD also showed a mild increase in annexin V+ 7-AAD- early apoptotic neutrophils (24.5%) compared to HC (20.8%, p = 0.048). PMA-induced reduction of caspase-3 activation was more pronounced in HC (p = 0.020) than in AQP4 + NMOSD neutrophils (p = 0.052). No differences were observed in neutrophil-derived MPO-DNA or serum levels of MPO, elastase, IL-6, IL-8 and TNF-ɑ. IL-15 levels were increased in both groups of patients. In AQP4 + NMOSD, an increase in cfDNA, GM-CSF and IL-10 was found in serum. A positive correlation among cfDNA and NfL was found in AQP4 + NMOSD. CONCLUSIONS AQP4 + NMOSD neutrophils showed an increased survival capacity in response to PMA when compared to matched HC neutrophils. Although the data indicate that the apoptotic but not the NETotic response is altered in these neutrophils, additional evaluations are required to validate this observation.
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Affiliation(s)
- Maria Schroeder-Castagno
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Campus Berlin-Buch GmbH, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Alba Del Rio-Serrato
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Campus Berlin-Buch GmbH, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Andreas Wilhelm
- BIH Center for Regenerative Therapies (BCRT) Charité- Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Core Unit Immunocheck-Biomarker Immunologisches Studienlabor (ISL), Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Silvina Romero-Suárez
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.,Department of Immunobiochemistry, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, 68167, Mannheim, Germany
| | - Patrick Schindler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Campus Berlin-Buch GmbH, Robert-Rössle-Straße 10, 13125, Berlin, Germany.,Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Cesar Alvarez-González
- Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.,Neurologic Clinic and Policlinic, Departments of Medicine, University Hospital Basel & RC2NB - Research Center for Clinical Neuroimmunology and Neuroscience, University of Basel, Basel, Switzerland
| | - Ankelien-Solveig Duchow
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Judith Bellmann-Strobl
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Klemens Ruprecht
- Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Maria Hastermann
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.,Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Gerald Grütz
- BIH Center for Regenerative Therapies (BCRT) Charité- Humboldt-Universität Zu Berlin and Berlin Institute of Health, Institute for Medical Immunology, Core Unit Immunocheck-Biomarker Immunologisches Studienlabor (ISL), Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Brigitte Wildemann
- Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
| | - Sven Jarius
- Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
| | - Tanja Schmitz-Hübsch
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.,Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Friedemann Paul
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, NeuroCure Clinical Research Center, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany.,Department of Neurology, Charité-Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117, Berlin, Germany
| | - Carmen Infante-Duarte
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, ECRC Experimental and Clinical Research Center, a Cooperation Between the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité-Universitätsmedizin Berlin, Lindenberger Weg 80, 13125, Berlin, Germany. .,Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Campus Berlin-Buch GmbH, Robert-Rössle-Straße 10, 13125, Berlin, Germany. .,Institute for Medical Immunology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.
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9
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Martin-Rodriguez O, Gauthier T, Bonnefoy F, Couturier M, Daoui A, Chagué C, Valmary-Degano S, Gay C, Saas P, Perruche S. Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease. Front Immunol 2021; 12:754475. [PMID: 35003066 PMCID: PMC8727348 DOI: 10.3389/fimmu.2021.754475] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 12/06/2021] [Indexed: 12/21/2022] Open
Abstract
Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.
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Affiliation(s)
- Omayra Martin-Rodriguez
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
| | - Thierry Gauthier
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
| | - Francis Bonnefoy
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
- MED’INN’Pharma, Besançon, France
| | - Mélanie Couturier
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
- MED’INN’Pharma, Besançon, France
| | - Anna Daoui
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
| | - Cécile Chagué
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
| | | | - Claire Gay
- Department of Gastroenterology, University Hospital of Besançon, Besançon, France
| | - Philippe Saas
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
| | - Sylvain Perruche
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098 RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Fédération Hospitalo-Universitaire INCREASE, LabEx LipSTIC, Besançon, France
- MED’INN’Pharma, Besançon, France
- *Correspondence: Sylvain Perruche,
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10
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Ren J, Yan D, Wang Y, Zhang J, Li M, Xiong W, Jing X, Li P, Zhao W, Xiong X, Wu M, Zhong G. Inhibitor of Differentiation-2 Protein Ameliorates DSS-Induced Ulcerative Colitis by Inhibiting NF-κB Activation in Neutrophils. Front Immunol 2021; 12:760999. [PMID: 34804049 PMCID: PMC8599958 DOI: 10.3389/fimmu.2021.760999] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
The loss of inhibitor of differentiation-2 (ID2) could lead to the development of colitis in mice, supplementation with exogenous ID2 protein might be a potential strategy to ameliorate colitis. In this study, the effects of ID2 protein supplementation on Dextran sodium sulfate (DSS)-induced colitis were investigated. Firstly, we confirmed that the expression of ID2 was reduced in the colon tissues of DSS-induced colitis mice and patients with ulcerative colitis (UC). Then, we constructed a recombinant plasmid containing the human Id2 gene and expressed it in Escherichia coli (E. coli) successfully. After purification and identification, purified hID2 could ameliorate DSS-induced colitis efficiently in mice by improving disease symptoms, decreasing the levels of proinflammatory cytokines in colon tissues, maintaining the integrity of intestinal barrier and reducing the infiltration of neutrophils and macrophages in the colon. Further study showed that hID2 could be endocytosed efficiently by neutrophils and macrophages, and hID2 lost its protection function against colitis when neutrophils were depleted with an anti-Gr-1 antibody. hID2 decreased the mRNA levels of IL-6, IL-1β and TNF-α in lipopolysaccharides (LPS)-stimulated neutrophils and efficiently inhibited the activation of NF-κB signalling pathway in neutrophils. Interestingly, hID2 showed a synergistic role in inhibition of NF-κB activation with pyrrolidine dithiocarbamic acid (PDTC), an inhibitor of NF-κB activation. Therefore, this study demonstrated the potential use of hID2 to treat UC, and hID2 protein might be a promising anti-inflammatory agent that targets the NF-κB signalling pathway in neutrophils.
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Affiliation(s)
- Jie Ren
- School of Basic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Dong Yan
- School of Basic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Yichun Wang
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Jiaojiao Zhang
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Min Li
- School of Basic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Wancheng Xiong
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Xueqian Jing
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Puze Li
- School of Basic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Weidong Zhao
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Xiwen Xiong
- School of Forensic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Minna Wu
- School of Basic Medicine, Xinxiang Medical University, Xinxiang, China
| | - Genshen Zhong
- Henan Key Laboratory of Immunology and Targeted Therapy, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
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11
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Fu W, Fu H, Ye W, Han Y, Liu X, Zhu S, Li H, Tang R, Wang Q. Peripheral blood neutrophil-to-lymphocyte ratio in inflammatory bowel disease and disease activity: A meta-analysis. Int Immunopharmacol 2021; 101:108235. [PMID: 34678692 DOI: 10.1016/j.intimp.2021.108235] [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: 06/26/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a valuable predictor of clinical disease activity in inflammatory bowel disease (IBD). Therefore, we conducted a meta-analysis to evaluate the clinical significance of peripheral blood NLR in IBD patients. METHODS A comprehensive literature search was conducted by searching PubMed, Embase, Web of Science, Cochrane Library, and Chinese databases from inception to May 10, 2021. We used the standard mean difference (SMD) with a 95% confidence interval (CI) to estimate the pooled effect and subgroup analysis to investigate heterogeneity. RESULTS Sixteen studies including 2185 IBD patients and 993 healthy controls (HCs) were enrolled in this study. The peripheral blood NLR values were significantly higher in 1,092 IBD patients than in 933 HCs (SMD = 1.54, 95% CI = 1.05-2.02, P < 0.001) and in 1,269 patients with active IBD than in 1,056 patients with remissive IBD (SMD = 1.55, 95% CI = 1.06-2.05, P < 0.001). Subgroup analysis of the major subtypes of IBD revealed significantly elevated peripheral blood NLR values in patients with active ulcerative colitis (UC) compared to HCs (SMD = 2.04), remissive UC than HCs (SMD = 0.63), and active UC than in those with remissive UC (SMD = 1.32) (P < 0.05). Both Crohn's disease (CD) patients and active CD patients had significantly elevated peripheral blood NLR values than HCs with the SMD of 0.52 and 3.53 (P < 0.001). CONCLUSIONS Peripheral blood NLR could serve as a valuable biomarker for predicting disease severity in IBD patients.
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Affiliation(s)
- Wei Fu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Hu Fu
- Department of Laboratory Medicine, Chengdu First People's Hospital, Chengdu 610000, Sichuan, PR China
| | - Weixia Ye
- Department of Gastroenterology, Luzhou People's Hospital, Luzhou 646000, Sichuan, PR China.
| | - Yinsuo Han
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Xianqiang Liu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Sirui Zhu
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Hongmin Li
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Rong Tang
- Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, PR China
| | - Qin Wang
- Sichuan Provincial Center for Gynecology and Breast Diseases (Gynecology), Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China.
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12
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The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells. Proc Natl Acad Sci U S A 2021; 118:2100594118. [PMID: 34548395 PMCID: PMC8488689 DOI: 10.1073/pnas.2100594118] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2021] [Indexed: 01/06/2023] Open
Abstract
Extracellular adenosine triphosphate (ATP) released by mucosal immune cells and by microbiota in the intestinal lumen elicits diverse immune responses that mediate the intestinal homeostasis via P2 purinergic receptors, while overactivation of ATP signaling leads to mucosal immune system disruption, which leads to pathogenesis of intestinal inflammation. In the small intestine, hydrolysis of luminal ATP by ectonucleoside triphosphate diphosphohydrolase (E-NTPD)7 in epithelial cells is essential for control of the number of T helper 17 (Th17) cells. However, the molecular mechanism by which microbiota-derived ATP in the colon is regulated remains poorly understood. Here, we show that E-NTPD8 is highly expressed in large-intestinal epithelial cells and hydrolyzes microbiota-derived luminal ATP. Compared with wild-type mice, Entpd8 -/- mice develop more severe dextran sodium sulfate-induced colitis, which can be ameliorated by either the depletion of neutrophils and monocytes by injecting with anti-Gr-1 antibody or the introduction of P2rx4 deficiency into hematopoietic cells. An increased level of luminal ATP in the colon of Entpd8 -/- mice promotes glycolysis in neutrophils through P2x4 receptor-dependent Ca2+ influx, which is linked to prolonged survival and elevated reactive oxygen species production in these cells. Thus, E-NTPD8 limits intestinal inflammation by controlling metabolic alteration toward glycolysis via the P2X4 receptor in myeloid cells.
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13
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Ishiguro Y, Ohmori T, Umemura K, Iizuka M. Factors associated with the outcomes in ulcerative colitis patients undergoing granulocyte and monocyte adsorptive apheresis as remission induction therapy: A multicenter cohort study. Ther Apher Dial 2021; 25:502-512. [PMID: 33029920 DOI: 10.1111/1744-9987.13594] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/20/2020] [Accepted: 10/04/2020] [Indexed: 12/20/2022]
Abstract
Ulcerative colitis (UC) patients harbor activated myeloid leukocytes, which exacerbate and perpetuate UC by releasing inflammatory cytokines. Granulocyte and monocyte adsorptive apheresis (GMA) with an Adacolumn depletes elevated myeloid leukocytes, inducing efficacy with favorable safety. To understand how the clinical outcome with GMA is affected by prior corticosteroid treatment or concomitant immunomodulators, a retrospective multicenter study in 102 UC patients, who had not responded well to first-line medications was undertaken. The remission rates after a course of GMA therapy were significantly higher in corticosteroid-naïve patients compared with those with prior corticosteroid exposure. Absence of corticosteroid background was an independent predictive factor of response to GMA. Further, in corticosteroid-naïve patients, the 1-year cumulative sustained remission rate in patients who did not receive immunomodulators was significantly higher than in patients who received immunomodulators. Accordingly, multivariate analysis revealed that immunomodulator was associated with higher risk of relapse. In conclusion, GMA was an effective treatment for corticosteroid-naïve patients and the efficacy sustained longer in those not receiving immunomodulators during GMA. GMA fulfills the notion that apheresis is to induce disease remission by removing from the body factors known to perpetuate disease. In therapeutic settings, these findings should help better decision making and avoid futile use of medical resources.
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Affiliation(s)
- Yoh Ishiguro
- Department of Clinical Research, National Hirosaki Hospital, National Hospital Organization, Hirosaki, Japan
| | | | - Ken Umemura
- Department of Gastroenterology, South Miyagi Medical Center, Shibata-gun, Japan
| | - Masahiro Iizuka
- Akita Health Care Center, Akita Red Cross Hospital, Akita, Japan
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14
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Trilleaud C, Gauttier V, Biteau K, Girault I, Belarif L, Mary C, Pengam S, Teppaz G, Thepenier V, Danger R, Robert-Siegwald G, Néel M, Bruneau S, Glémain A, Néel A, Poupon A, Mosnier JF, Chêne G, Dubourdeau M, Blancho G, Vanhove B, Poirier N. Agonist anti-ChemR23 mAb reduces tissue neutrophil accumulation and triggers chronic inflammation resolution. SCIENCE ADVANCES 2021; 7:eabd1453. [PMID: 33811066 PMCID: PMC11057782 DOI: 10.1126/sciadv.abd1453] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 02/16/2021] [Indexed: 06/12/2023]
Abstract
Resolution of inflammation is elicited by proresolving lipids, which activate GPCRs to induce neutrophil apoptosis, reduce neutrophil tissue recruitment, and promote macrophage efferocytosis. Transcriptional analyses in up to 300 patients with Inflammatory Bowel Disease (IBD) identified potential therapeutic targets mediating chronic inflammation. We found that ChemR23, a GPCR targeted by resolvin E1, is overexpressed in inflamed colon tissues of severe IBD patients unresponsive to anti-TNFα or anti-α4β7 therapies and associated with significant mucosal neutrophil accumulation. We also identified an anti-ChemR23 agonist antibody that induces receptor signaling, promotes macrophage efferocytosis, and reduces neutrophil apoptosis at the site of inflammation. This ChemR23 mAb accelerated acute inflammation resolution and triggered resolution in ongoing chronic colitis models, with a significant decrease in tissue lesions, fibrosis and inflammation-driven tumors. Our findings suggest that failure of current IBD therapies may be associated with neutrophil infiltration and that ChemR23 is a promising therapeutic target for chronic inflammation.
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Affiliation(s)
- C Trilleaud
- OSE Immunotherapeutics, Nantes, France
- Université de Nantes
| | | | - K Biteau
- OSE Immunotherapeutics, Nantes, France
| | - I Girault
- OSE Immunotherapeutics, Nantes, France
| | - L Belarif
- OSE Immunotherapeutics, Nantes, France
| | - C Mary
- OSE Immunotherapeutics, Nantes, France
| | - S Pengam
- OSE Immunotherapeutics, Nantes, France
| | - G Teppaz
- OSE Immunotherapeutics, Nantes, France
| | | | - R Danger
- Université de Nantes
- [CHU Nantes], INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064
- [ITUN], 44000 Nantes, France
| | | | - M Néel
- Université de Nantes
- [CHU Nantes], INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064
- [ITUN], 44000 Nantes, France
| | - S Bruneau
- Université de Nantes
- [ITUN], 44000 Nantes, France
| | - A Glémain
- Université de Nantes
- [ITUN], 44000 Nantes, France
| | - A Néel
- Université de Nantes
- [CHU Nantes], INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064
- Service de Médecine Interne, CHU de Nantes, Nantes, France
| | | | - J F Mosnier
- Université de Nantes
- [CHU Nantes], INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064
- Service d'Anatomie et Cytologie Pathologiques, CHU Nantes, Nantes, France
| | - G Chêne
- Ambiotis, Canal Biotech 2, Toulouse, France
| | | | - G Blancho
- Université de Nantes
- [CHU Nantes], INSERM, Centre de Recherche en Transplantation et Immunologie, UMR 1064
- [ITUN], 44000 Nantes, France
| | - B Vanhove
- OSE Immunotherapeutics, Nantes, France
| | - N Poirier
- OSE Immunotherapeutics, Nantes, France.
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15
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Domènech E, Grífols JR, Akbar A, Dignass AU. Use of granulocyte/monocytapheresis in ulcerative colitis: A practical review from a European perspective. World J Gastroenterol 2021; 27:908-918. [PMID: 33776362 PMCID: PMC7968132 DOI: 10.3748/wjg.v27.i10.908] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/03/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Half of the patients with ulcerative colitis require at least one course of systemic corticosteroids in their lifetime. Approximately 75% of these patients will also require immunosuppressive drugs (i.e., thiopurines or biological agents) in the mid-term to avoid colectomy. Immunosuppressive drugs raise some concerns due to an increased risk of serious and opportunistic infections and cancer, particularly in elderly and co-morbid patients, underlining the unmet need for safer alternative therapies. Granulocyte/monocytapheresis (GMA), a CE-marked, non-pharmacological procedure for the treatment of ulcerative colitis (among other immune-mediated diseases), remains the only therapy targeting neutrophils, the hallmark of pathology in ulcerative colitis. GMA has proven its efficacy in different clinical scenarios and shows an excellent and unique safety profile. In spite of being a first line therapy in Japan, GMA use is still limited to a small number of centres and countries in Europe. In this article, we aim to give an overview from a European perspective of the mechanism of action, recent clinical data on efficacy and practical aspects for the use of GMA in ulcerative colitis.
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Affiliation(s)
- Eugeni Domènech
- Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona 08916, Catalonia, Spain
- Department of Medicine, Universitat Autònoma de Barcelona, Badalona 08916, Catalonia, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Badalona 08916, Catalonia, Spain
| | - Joan-Ramon Grífols
- Blood and Tissue Bank, Hospital Universitari Germans Trias i Pujol, Badalona 08916, Catalonia, Spain
| | - Ayesha Akbar
- IBD Unit, St. Mark’s Hospital and Academic Institute, London HA1 3UJ, United Kingdom
| | - Axel U Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Goethe-University, Frankfurt am Main 60431, Germany
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16
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Drury B, Hardisty G, Gray RD, Ho GT. Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathogenic Mechanisms and Clinical Translation. Cell Mol Gastroenterol Hepatol 2021; 12:321-333. [PMID: 33689803 PMCID: PMC8166923 DOI: 10.1016/j.jcmgh.2021.03.002] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 02/07/2023]
Abstract
The Inflammatory Bowel Diseases (IBD), Ulcerative Colitis (UC) and Crohn's Disease (CD) are characterised by chronic non-resolving gut mucosal inflammation involving innate and adaptive immune responses. Neutrophils, usually regarded as first responders in inflammation, are a key presence in the gut mucosal inflammatory milieu in IBD. Here, we review the role of neutrophil extracellular trap (NET) formation as a potential effector disease mechanism. NETs are extracellular webs of chromatin, microbicidal proteins and oxidative enzymes that are released by neutrophils to contain pathogens. NETs contribute to the pathogenesis of several immune-mediated diseases such as systemic lupus erythematosus and rheumatoid arthritis; and recently, as a major tissue damaging process involved in the host response to severe acute respiratory syndrome coronavirus 2 infection. NETs are pertinent as a defence mechanism at the gut mucosal interphase exposed to high levels of bacteria, viruses and fungi. On the other hand, NETs can also potentiate and perpetuate gut inflammation. In this review, we discuss the broad protective vs. pathogenic roles of NETs, explanatory factors that could lead to an increase in NET formation in IBD and how NETs may contribute to gut inflammation and IBD-related complications. Finally, we summarise therapeutic opportunities to target NETs in IBD.
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Affiliation(s)
- Broc Drury
- Centre for Inflammation Research, University of Edinburgh, Scotland, United Kingdom
| | - Gareth Hardisty
- Centre for Inflammation Research, University of Edinburgh, Scotland, United Kingdom
| | - Robert D Gray
- Centre for Inflammation Research, University of Edinburgh, Scotland, United Kingdom
| | - Gwo-Tzer Ho
- Centre for Inflammation Research, University of Edinburgh, Scotland, United Kingdom.
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17
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Camba-Gómez M, Gualillo O, Conde-Aranda J. New Perspectives in the Study of Intestinal Inflammation: Focus on the Resolution of Inflammation. Int J Mol Sci 2021; 22:ijms22052605. [PMID: 33807591 PMCID: PMC7962019 DOI: 10.3390/ijms22052605] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/25/2021] [Accepted: 03/02/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is an essential physiological process that is directed to the protection of the organism against invading pathogens or tissue trauma. Most of the existing knowledge related to inflammation is focused on the factors and mechanisms that drive the induction phase of this process. However, since the recognition that the resolution of the inflammation is an active and tightly regulated process, increasing evidence has shown the relevance of this process for the development of chronic inflammatory diseases, such as inflammatory bowel disease. For that reason, with this review, we aimed to summarize the most recent and interesting information related to the resolution process in the context of intestinal inflammation. We discussed the advances in the understanding of the pro-resolution at intestine level, as well as the new mediators with pro-resolutive actions that could be interesting from a therapeutic point of view.
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Affiliation(s)
- Miguel Camba-Gómez
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
| | - Oreste Gualillo
- SERGAS (Servizo Galego de Saúde) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, 15706 Santiago de Compostela, Spain;
| | - Javier Conde-Aranda
- Molecular and Cellular Gastroenterology, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Correspondence: ; Tel.: +34-981-955-091
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18
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Xie Y, Zhuang T, Ping Y, Zhang Y, Wang X, Yu P, Duan X. Elevated systemic immune inflammation index level is associated with disease activity in ulcerative colitis patients. Clin Chim Acta 2021; 517:122-126. [PMID: 33662359 DOI: 10.1016/j.cca.2021.02.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND It has been confirmed that high Systemic immune-inflammation index (SII) levels usually indicate poor outcomes in various diseases, especially on malignancies. However, the clinical significance of the SII in ulcerative colitis (UC) patients is remain unclear. Therefore, the purpose of our paper is to analyze the levels of SII in UC patients and assess the relationship between the SII and disease activity. MATERIALS AND METHODS We studied 187 consecutive patients with UC and 185 age- and sex-matched healthy controls retrospectively. The Mayo scoring system was adopted to evaluate disease activity in UC patients. We collected clinical characteristics and laboratory parameters from hospital electronic medical records. RESULTS The SII levels were significantly higher in UC patients than those in healthy subjects (P < 0.001). Higher SII levels were observed in moderate and severe UC subgroups compared to mild or remission subgroups. Correlation analysis displayed that the SII levels were positively relatived with Mayo score (r = 0.469, P < 0.001), C reactive protein (CRP) (r = 0.480, P < 0.001), and erythrocyte sedimentation rate (ESR) (r = 0.336, P < 0.001), but negatively with haemoglobin (Hb) (r = -0.271, P < 0.001). A multiple linear regression analysis suggested that there was an independent correlation between Mayo score and SII (beta = 0.324, t = 4.241, P < 0.001). The receiver operating characteristic (ROC) curve revealed that the maximum area under the curve (AUC) was 0.711 (95% CI, 0.630-0.791, P < 0.001), and the cut-off value for diagnosing active UC was 485.95, the sensitivity was 0.641, and the specificity was 0.75. CONCLUSIONS We demonstrated that the SII was elevated significantly in UC patients and was closely related to the UC disease activity. In addition, the SII had a high discriminative capacity for active UC.
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Affiliation(s)
- Yiyi Xie
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
| | - Tingting Zhuang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Ping
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yingzhi Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xuchu Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Pan Yu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Xiuzhi Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
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19
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Dobosz E, Wadowska M, Kaminska M, Wilamowski M, Honarpisheh M, Bryzek D, Potempa J, Jura J, Lech M, Koziel J. MCPIP-1 Restricts Inflammation via Promoting Apoptosis of Neutrophils. Front Immunol 2021; 12:627922. [PMID: 33717148 PMCID: PMC7952515 DOI: 10.3389/fimmu.2021.627922] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/08/2021] [Indexed: 11/13/2022] Open
Abstract
Monocyte chemoattractant protein-induced protein-1 (MCPIP-1) is a potent inhibitor of inflammatory response to pathogens. Acting as endonuclease against transcripts of inflammatory cytokines or transcription factors MCPIP-1 can significantly reduce the cytokine storm, thus limiting the tissue damage. As the adequate resolution of inflammation depends also on the efficient clearance of accumulated neutrophils, we focused on the role of MCPIP-1 in apoptosis and retention of neutrophils. We used peritoneal neutrophils from cell-specific MCPIP-1 knockout mice and showed prolonged survival of these cells. Moreover, we confirmed that MCPIP-1-dependent degradation of transcripts of antiapoptotic genes, including BCL3, BCL2A1, BCL2L1, and for the first time MCL-1, serves as an early event in spontaneous apoptosis of primary neutrophils. Additionally, we identified previously unknown miRNAs as potential binding partners to the MCPIP-1 transcript and their regulation suggest a role in MCPIP-1 half-life and translation. These phenomena may play a role as a molecular switch that balances the MCPIP-1-dependent apoptosis. Besides that, we determined these particular miRNAs as integral components of the GM-CSF-MCPIP-1 axis. Taken together, we identified the novel anti-inflammatory role of MCPIP-1 as a regulator of accumulation and survival of neutrophils that simultaneously promotes an adequate resolution of inflammation.
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Affiliation(s)
- Ewelina Dobosz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Marta Wadowska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Marta Kaminska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Mateusz Wilamowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Mohsen Honarpisheh
- Ludwig-Maximilians University Hospital, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians University, Munich, Germany
| | - Danuta Bryzek
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland.,Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, University of Louisville, Louisville, KY, United States
| | - Jolanta Jura
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
| | - Maciej Lech
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland.,Ludwig-Maximilians University Hospital, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians University, Munich, Germany
| | - Joanna Koziel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, Krakow, Poland
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20
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Noseykina EM, Schepetkin IA, Atochin DN. Molecular Mechanisms for Regulation of Neutrophil Apoptosis under Normal and Pathological Conditions. J EVOL BIOCHEM PHYS+ 2021; 57:429-450. [PMID: 34226754 PMCID: PMC8245921 DOI: 10.1134/s0022093021030017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/10/2021] [Accepted: 02/23/2021] [Indexed: 02/04/2023]
Abstract
Neutrophils are one of the main cells of innate immunity that perform a key effector and regulatory function in the development of the human inflammatory response. Apoptotic forms of neutrophils are important for regulating the intensity of inflammation and restoring tissue homeostasis. This review summarizes current data on the molecular mechanisms of modulation of neutrophil apoptosis by the main regulatory factors of the inflammatory response-cytokines, integrins, and structural components of bacteria. Disturbances in neutrophil apoptosis under stress are also considered, molecular markers of changes in neutrophil lifespan associated with various diseases and pathological conditions are presented, and data on pharmacological agents for modulating apoptosis as potential therapeutics are also discussed.
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Affiliation(s)
| | - I. A. Schepetkin
- Tomsk Polytechnic University, Tomsk, Russia ,Department of Microbiology
and Immunology, Montana State University, Bozeman, MT, USA
| | - D. N. Atochin
- Tomsk Polytechnic University, Tomsk, Russia ,Cardiovascular Research Center,
Cardiology Division, Massachusetts General Hospital, Charlestown, MA, USA
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21
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Yuyun X, Fan Y, Weiping W, Qing Y, Bingwei S. Metabolomic analysis of spontaneous neutrophil apoptosis reveals the potential involvement of glutathione depletion. Innate Immun 2020; 27:31-40. [PMID: 32910715 PMCID: PMC7780355 DOI: 10.1177/1753425920951985] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Spontaneous apoptosis of neutrophils plays a key role in maintaining immune homeostasis and resolving inflammation. However, the mechanism triggering this apoptosis remains obscure. In the present study, we performed a global metabolomics analysis of neutrophils undergoing spontaneous apoptosis by using hydrophilic interaction chromatography ultra-high-performance liquid chromatography-tandem quadrupole/time-of-flight mass spectrometry and found 23 metabolites and 42 related pathways that were altered in these cells. Among them, glutathione, which is known to be involved in apoptosis, was particularly interesting. We found that L-pyroglutamic acid, glutamate, and their glutathione-mediated embolic pathways were all changed. Our findings confirmed the glutathione levels decreased in apoptotic neutrophils. Exogenous glutathione and LPS treatment delayed neutrophil apoptosis and decreased the levels of pro-apoptotic protein caspase-3. γ-glutamylcyclotransferase, 5-oxoprolinase, and ChaC1, which participated in glutathione degradation, were all activated. At the same time, the down-regulation of ATP production suggested the activity of glutathione biosynthesis may be attenuated even if glutamate-cysteine ligase and glutathione synthase, which are two ATP-dependent enzymes participating in glutathione biosynthesis, were enhanced. To our knowledge, this is the first report highlighting a global metabolomics analysis using hydrophilic interaction chromatography ultra-high-performance liquid chromatography-tandem quadrupole/time-of-flight mass spectrometry and the potential involvement of glutathione depletion in spontaneous apoptosis of neutrophils demonstrating that LPS could delay this process.
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Affiliation(s)
- Xiong Yuyun
- Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, People's Republic of China
| | - Yu Fan
- Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, People's Republic of China
| | - Wei Weiping
- Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, People's Republic of China
| | - Yin Qing
- Department of Clinical Laboratory, Affiliated Hospital of Jiangsu University, People's Republic of China
| | - Sun Bingwei
- Department of Burn and Plastic Surgery, Affiliated Suzhou Hospital of Nanjing Medical University, People's Republic of China
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22
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Solis CJ, Hamilton MK, Caruffo M, Garcia-Lopez JP, Navarrete P, Guillemin K, Feijoo CG. Intestinal Inflammation Induced by Soybean Meal Ingestion Increases Intestinal Permeability and Neutrophil Turnover Independently of Microbiota in Zebrafish. Front Immunol 2020; 11:1330. [PMID: 32793187 PMCID: PMC7393261 DOI: 10.3389/fimmu.2020.01330] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 05/26/2020] [Indexed: 12/18/2022] Open
Abstract
Intestinal inflammation is a condition shared by several intestinal chronic diseases, such as Crohn's disease and ulcerative colitis, with severely detrimental consequences in the long run. Current mammalian models have considerably increased understanding of this pathological condition, highlighting the fact that, in most of the cases, it is a highly complex and multifactorial problem and difficult to deal with. Thus, there is an increasingly evident need for alternative animal models that could offer complementary approaches that have not been exploited in rodents, thereby contributing to a different view on the disease. Here, we report the effects of a soybean meal-induced intestinal inflammation model on intestinal integrity and function as well as on neutrophil recruitment and microbiota composition in zebrafish. We find that the induced intestinal inflammation process is accompanied by an increase in epithelial permeability in addition to changes in the mRNA levels of different tight junction proteins. Conversely, there was no evidence of damage of epithelial cells nor an increase in their proliferation. Of note, our results show that this intestinal inflammatory model is induced independently of the presence of microbiota. On the other hand, this inflammatory process affects intestinal physiology by decreasing protein absorption, increasing neutrophil replacement, and altering microbiota composition with a decrease in the diversity of cultivable bacteria.
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Affiliation(s)
- Camila J. Solis
- Fish Immunology Laboratory, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Nucleus in the Biology of Intestinal Microbiota, Santiago, Chile
| | | | - Mario Caruffo
- Fish Immunology Laboratory, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Escuela de Biotecnología, Facultad de Ciencias, Universidad Santo Tomás, Santiago, Chile
| | - Juan P. Garcia-Lopez
- Fish Immunology Laboratory, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Paola Navarrete
- Millennium Nucleus in the Biology of Intestinal Microbiota, Santiago, Chile
- Laboratory of Microbiology and Probiotics, Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago, Chile
| | - Karen Guillemin
- Institute of Molecular Biology, University of Oregon, Eugene, OR, United States
- Humans and the Microbiome Program, Canadian Institute for Advanced Research, Toronto, ON, Canada
| | - Carmen G. Feijoo
- Fish Immunology Laboratory, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Nucleus in the Biology of Intestinal Microbiota, Santiago, Chile
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23
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Li N, Mao J, Tang H, Zhu L, Tan X, Bi J, Wu H, Chen X, Wang Y. Efficacy and safety of adsorptive granulomonocytapheresis in Chinese patients with ulcerative colitis: A retrospective analysis of 50 cases with focus on factors impacting clinical efficacy. J Clin Apher 2020; 35:271-280. [PMID: 32378240 PMCID: PMC7496385 DOI: 10.1002/jca.21787] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 03/22/2020] [Accepted: 04/21/2020] [Indexed: 12/12/2022]
Abstract
Background Myeloid‐derived leucocytes, a major source of inflammatory cytokines, play an important role in the exacerbation of ulcerative colitis (UC). Selective depletion of myeloid leucocytes by adsorptive granulomonocytapheresis (GMA) with an Adacolumn should alleviate inflammation and promote remission. However, there are discrepancies among the reported efficacy outcomes. This study aimed to evaluate the efficacy and safety of GMA in UC patients with a focus on factors affecting clinical efficacy. Methods This was a retrospective analysis of 50 patients with active UC who had received GMA therapy. GMA efficacy was evaluated based on the Rachmilewitz's clinical activity index (CAI) and Mayo endoscopic score for mucosal healing. Laboratory findings were analyzed to demonstrate any relationship with the GMA‐responder or nonresponder feature. Adverse events were recorded during and after GMA therapy. Results The overall clinical remission rate (CAI ≤4) was 79.2%, and among these, the mucosal healing rate was 59.2%. The clinical remission rate was 69.2% in patients who received 5 GMA sessions and 82.3% in patients who received 10 sessions. Significantly higher baseline CAIs and lower albumin and hemoglobin levels were observed in nonremission cases compared with those who achieved remission. Four patients (8%) experienced transient adverse events, but none were severe. Conclusions GMA was favored by patients because of its safety and nonpharmacological treatment options. Accordingly, UC patients were spared from pharmaceuticals after applying GMA therapy.
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Affiliation(s)
- Na Li
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Jingwei Mao
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Haiying Tang
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Lei Zhu
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xiaoyan Tan
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Jian Bi
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Hao Wu
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Xiuli Chen
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
| | - Yingde Wang
- Department of GastroenterologyFirst Affiliated Hospital of Dalian Medical UniversityDalianChina
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24
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Wang W, Zhang F, Li X, Luo J, Sun Y, Wu J, Li M, Wen Y, Liang H, Wang K, Niu J, Miao Y. Heat shock transcription factor 2 inhibits intestinal epithelial cell apoptosis through the mitochondrial pathway in ulcerative colitis. Biochem Biophys Res Commun 2020; 527:173-179. [PMID: 32446363 DOI: 10.1016/j.bbrc.2020.04.103] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/20/2020] [Indexed: 12/29/2022]
Abstract
UC is a chronic inflammatory disease of the colonic mucosa and lacks effective treatments because of unclear pathogenesis. Excessive apoptosis of IECs damages the intestinal epithelial barrier and is involved in the progression of UC, but the mechanism is unknown. HSPs are important in maintaining homeostasis and regulate apoptosis through the mitochondrial pathway. In our previous studies, HSF2, an important regulator of HSPs, was highly expressed in UC patients and negatively correlated with inflammation in mice and IECs. Therefore, we hypothesized that HSF2 may protect against intestinal mucositis by regulating the apoptosis of IECs. In this study, a DSS-induced colitis model of hsf2-/- mice was used to explore the relationship between HSF2 and apoptosis in IECs for the first time. The expression of HSF2 increased in the WT + DSS group compared with that in the WT + H2O group. Moreover, the extent of apoptosis was more severe in the KO + DSS group than in the WT + DSS group. The results showed that HSF2 was negatively correlated with apoptosis in vivo. The expression of HSF2 in Caco-2 cells was changed by lentiviral transfection, and the expression of Bax, cytoplasmic Cyto-C, Cleaved Caspase-9 and Cleaved Caspase-3 were negatively correlated with the different levels of HSF2. These results suggest that HSF2 negatively regulates apoptosis of IECs through the mitochondrial pathway. This may be one of the potential mechanisms to explain the protective role of HSF2 in UC.
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Affiliation(s)
- Wen Wang
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Fengrui Zhang
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Xiaoyu Li
- Department of Respiration, The First Hospital of Changsha, Changsha, Hunan, 410005, China
| | - Juan Luo
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Yang Sun
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Jing Wu
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Maojuan Li
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Yunling Wen
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Hao Liang
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Kunhua Wang
- Department of General Surgery, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China
| | - Junkun Niu
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China.
| | - Yinglei Miao
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Diseases, Kunming, Yunnan, 650032, China.
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25
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Yu T, Wang Z, Jie W, Fu X, Li B, Xu H, Liu Y, Li M, Kim E, Yang Y, Cho JY. The kinase inhibitor BX795 suppresses the inflammatory response via multiple kinases. Biochem Pharmacol 2020; 174:113797. [DOI: 10.1016/j.bcp.2020.113797] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/07/2020] [Indexed: 02/06/2023]
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26
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Ryan JJ, Hanes DA, Bradley RD, Contractor N. Effect of a Nutrition Support Formula in Adults With Inflammatory Bowel Disease: A Pilot Study. Glob Adv Health Med 2019; 8:2164956119867251. [PMID: 31384513 PMCID: PMC6664624 DOI: 10.1177/2164956119867251] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 06/11/2019] [Accepted: 07/09/2019] [Indexed: 12/19/2022] Open
Abstract
Background Due to the high prevalence of nutrient deficiencies in patients
with inflammatory bowel disease (IBD), routine monitoring of
nutrient status and supplementation are recommended. Objective This preliminary study was implemented to prospectively identify
potential effects of a nutrition support formula on blood
nutrient parameters in adults with IBD. Methods Ten adults with Crohn’s disease or ulcerative colitis were
recruited from the Portland, Oregon, metropolitan area into a
single-arm, open-label pilot study. Participants consumed a
nutrition support beverage twice daily for 12 weeks. The formula
contained a mixture of micronutrients (including methylated
forms of folate and vitamin B12), macronutrients, and
phytonutrients (including curcumin, xanthohumol, ginger
compounds, and quercetin). Primary measures were the following
parameters: folate, vitamin B12, red blood cell (RBC) count,
hemoglobin, hematocrit, electrolytes, and albumin. Exploratory
measures included a food frequency questionnaire, circulating
blood cell counts, and inflammatory markers. Results Nine participants completed the study and one withdrew. Adherence
was 98%. Serum folate increased 48.7%
(P = .029), serum vitamin B12 increased 17.4%
but did not reach statistical significance
(P = .053), and red cell distribution width
(RDW) decreased 9.2% (P = .012) over the
12-week study period. There were minimal shifts in total white
blood cell (WBC) counts (−1.0%, P = .845), but
percent neutrophils decreased 10.4% (P = .042)
and absolute lymphocyte count increased 18.6%
(P = .048). RBC count, hemoglobin,
hematocrit, electrolytes, albumin, and inflammatory markers did
not change significantly. Post hoc analysis demonstrated that
neutrophil–lymphocyte ratio (NLR) decreased 18.4% (not
significant, P = .061). Conclusion Serum folate and RDW improved in adults with IBD after 12 weeks.
Modulation of leukocyte subtypes was also observed, including a
decrease in neutrophils and an increase in lymphocytes, with no
change in total WBC count. A randomized, controlled study to
further examine effects of the nutrition support formula will be
initiated to follow up on this promising, but preliminary
investigation.
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Affiliation(s)
- Jennifer J Ryan
- Helfgott Research Institute, National University of Natural Medicine, Portland, Oregon
| | - Douglas A Hanes
- Helfgott Research Institute, National University of Natural Medicine, Portland, Oregon
| | - Ryan D Bradley
- Helfgott Research Institute, National University of Natural Medicine, Portland, Oregon.,Family Medicine and Public Health, University of California, San Diego, La Jolla, California
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27
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Abstract
Inflammatory bowel disease is a chronic nonspecific inflammatory disease of the intestine. Its pathogenesis is not yet fully understood. It may be related to heredity, environmental triggers, infection, immune dysfunction and other factors. Purinergic receptor (P2X7R) ligand-gated ion channel is closely related to inflammation and widely expressed in intestinal cells. Previous studies have shown that ATP/P2X7R signal is involved in the pathogenesis of intestinal inflammation, but its specific mechanism needs further study. This article reviews the research progress of P2X7 receptor in inflammatory bowel disease.
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Affiliation(s)
- Yajun Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
| | - Xiaowei Liu
- a Department of Gastroenterology , Xiangya Hospital, Central South University , Changsha , China
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28
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Manuka Honey Modulates the Inflammatory Behavior of a dHL-60 Neutrophil Model under the Cytotoxic Limit. Int J Biomater 2019; 2019:6132581. [PMID: 30936919 PMCID: PMC6415307 DOI: 10.1155/2019/6132581] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 01/28/2019] [Indexed: 01/04/2023] Open
Abstract
Recent work has shown that Manuka honey, an increasingly popular wound additive with potent antibacterial properties, also has anti-inflammatory properties. However, little research has been done examining its effect on neutrophils. This study investigates the hypothesis that Manuka honey reduces neutrophil superoxide release and chemotaxis and reduces the activation of the inflammatory nuclear factor-κB (NF-κB) signaling pathway under honey's cytotoxic limit. A differentiated HL-60 cell line was used as a neutrophil model and cultured in various concentrations of Manuka honey for 3 and 24 hours to measure cytotoxicity via mitochondrial activity and visual trypan-exclusion count. Cytochrome C and Boyden chamber assays were used to measure the effect of Manuka honey on superoxide release and chemotaxis toward fMLP, respectively. Additionally, a Western blot for NF-κB inhibitor α (IκBα) was performed to measure Manuka honey's effect on the NF-κB pathway via IκBα phosphorylation. The results indicate a cytotoxic limit of 3-5% v/v. The presence of 1% honey decreased superoxide release at 24 hours. The 0.5, 1, and 3% honey concentrations reduced chemotaxis and IκBα phosphorylation in a dose-dependent fashion. These results suggest that Manuka honey significantly reduces neutrophil recruitment and inflammatory behavior in the wound site in a dose-dependent fashion under the cytotoxic limit.
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29
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Anti-TNF- α Therapy Suppresses Proinflammatory Activities of Mucosal Neutrophils in Inflammatory Bowel Disease. Mediators Inflamm 2018; 2018:3021863. [PMID: 30595666 PMCID: PMC6282128 DOI: 10.1155/2018/3021863] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/05/2018] [Accepted: 09/13/2018] [Indexed: 12/28/2022] Open
Abstract
Neutrophils have been found to play an important role in the pathogenesis of inflammatory bowel disease (IBD), and anti-TNF-α mAb (i.e., infliximab) therapy is demonstrated to be effective in the induction of clinical remission and mucosal healing in these patients. However, how anti-TNF-α mAb regulates the functions of neutrophils is still unknown. Herein, we found that anti-TNF-α therapy significantly downregulated infiltration of neutrophils in inflamed mucosa of IBD patients. Importantly, anti-TNF-α mAb could inhibit neutrophils to produce proinflammatory mediators, such as ROS, calprotectin, IL-8, IL-6, and TNF-α. These data indicate that TNF-α plays a critical role in the induction of mucosal inflammatory response, and that blockade of TNF-α modulates intestinal homeostasis through balancing immune responses of neutrophils.
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30
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Saniabadi AR, Tanaka T, Yamamoto T, Kruis W, Sacco R. Granulomonocytapheresis as a cell-dependent treatment option for patients with inflammatory bowel disease: Concepts and clinical features for better therapeutic outcomes. J Clin Apher 2018; 34:51-60. [PMID: 30407662 DOI: 10.1002/jca.21670] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 05/25/2018] [Accepted: 10/02/2018] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are major phenotypes of the chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms. The chronic nature of IBD means that patients require life-long medications, and this may lead to drug dependency, loss of response together with adverse side effects as additional morbidity factors. The efficacy of antitumour necrosis factor (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation and perpetuation of IBD. However, cytokines are released by myeloid lineage leucocytes like the CD14+ CD16+ monocyte phenotype. Additionally in IBD, myeloid leucocytes are elevated with activation behavior, while lymphocytes are compromised. Therefore, patients' leucocytes appear logical targets of therapy. Adsorptive granulomonocytapheresis (GMA) with an Adacolumn uses carriers, which interact with the Fcγ receptor expressing leucocytes and deplete the elevated myeloid leucocytes, while the neutrophils, which re-enter the circulation via the Adacolumn outflow (≥40%) are phagocytosed by CD19 B-cells to become interleukin (IL)-10 producing Bregs or CD19high CD1Dhigh B-cells. IL-10 is an anti-inflammatory cytokine. GMA has been applied to treat patients with IBD. The efficacy outcomes have been impressive as well as disappointing, the clinical response to GMA defines the patients' disease course and severity at entry. Efficacy outcomes in patients with deep ulcers together with extensive loss of the mucosal tissue are not encouraging, while patients without these features respond well and attain a favorable long-term disease course. Accordingly, for responder patients, GMA fulfills a desire to be treated without drugs.
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Affiliation(s)
| | - Tomotaka Tanaka
- Department of Gastroenterology, Akitsu Prefectural Hospital, Hiroshima, Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Hazu Medical Centre, Yokkaichi, Japan
| | - Wolfgang Kruis
- Evangelisches Krankenhaus Kalk, Cologen University, Cologne, Germany
| | - Rodolfo Sacco
- Department of Gastroenterology, Pisa University Hospital, Pisa, Italy
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Chami B, Martin NJJ, Dennis JM, Witting PK. Myeloperoxidase in the inflamed colon: A novel target for treating inflammatory bowel disease. Arch Biochem Biophys 2018; 645:61-71. [PMID: 29548776 DOI: 10.1016/j.abb.2018.03.012] [Citation(s) in RCA: 174] [Impact Index Per Article: 24.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 03/08/2018] [Accepted: 03/12/2018] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is a debilitating disorder involving inflammation of the gastrointestinal tract. The incidence of IBD is increasing worldwide. Immunological responses in the gastrointestinal (GI) tract to altered gut microbiota, mucosal injury and loss of intestinal epithelial cell function all contribute to a complex mechanism underlying IBD pathogenesis. Immune cell infiltration, particularly neutrophils, is a histological feature of IBD. This innate immune response is aimed at resolving intestinal damage however, neutrophils and monocytes that are recruited and accumulate in the GI wall, participate in IBD pathogenesis by producing inflammatory cytokines and soluble mediators such as reactive oxygen species (ROS; one- and two-electron oxidants). Unregulated ROS production in host tissue is linked to oxidative damage and inflammation and may potentiate mucosal injury. Neutrophil-myeloperoxidase (MPO) is an abundant granule enzyme that catalyses production of potent ROS; biomarkers of oxidative damage (and MPO protein) are increased in the mucosa of patients with IBD. Targeting MPO may mitigate oxidative damage to host tissue and ensuing inflammation. Here we identify mechanisms by which MPO activity perpetuates inflammation and contributes to host-tissue injury in patients with IBD and discuss MPO as a potential therapeutic target to protect the colon from inflammatory injury.
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Affiliation(s)
- Belal Chami
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Nathan J J Martin
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Joanne M Dennis
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia
| | - Paul K Witting
- Redox Biology Group, Discipline of Pathology, Sydney Medical School, Charles Perkins Centre, The University of Sydney NSW 2006 Australia.
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32
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Peng YJ, Shen TL, Chen YS, Mersmann HJ, Liu BH, Ding ST. Adiponectin and adiponectin receptor 1 overexpression enhance inflammatory bowel disease. J Biomed Sci 2018; 25:24. [PMID: 29540173 PMCID: PMC5851065 DOI: 10.1186/s12929-018-0419-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 02/06/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Adiponectin (ADN) is an adipokine derived from adipocytes. It binds to adiponectin receptor 1 and 2 (AdipoR1 and R2) to exert its function in regulating whole-body energy homeostasis and inflammatory responses. However, the role of ADN-AdipoR1 signaling in intestinal inflammation is controversial, and its role in the regulation of neutrophils is still unclear. Our goal was to clarify the role of AdipoR1 signaling in colitis and the effects on neutrophils. METHODS We generated porcine AdipoR1 transgenic mice (pAdipoR1 mice) and induced murine colitis using dextran sulfate sodium (DSS) to study the potential role of AdipoR1 in inflammatory bowel disease. We also treated a THP-1 macrophage and a HT-29 colon epithelial cell line with ADN recombinant protein to study the effects of ADN on inflammation. RESULTS After inducing murine colitis, pAdipoR1 mice developed more severe symptoms than wild-type (WT) mice. Treatment with ADN increased the expression of pro-inflammatory factors in THP-1 and HT-29 cells. Moreover, we also observed that the expression of cyclooxygenase2 (cox2), neutrophil chemokines (CXCL1, CXCL2 and CXCL5), and the infiltration of neutrophils were increased in the colon of pAdipoR1 mice. CONCLUSIONS Our study showed that ADN-AdipoR1 signaling exacerbated colonic inflammation through two possible mechanisms. First, ADN-AdipoR1 signaling increased pro-inflammatory factors. Second, AdipoR1 enhanced neutrophil chemokine expression and recruited neutrophils into the colonic tissue to increase inflammation.
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Affiliation(s)
- Yu-Ju Peng
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Tang-Long Shen
- Department of Plant Pathology and Microbiology, National Taiwan University, No.1, Sec.4, Roosevelt Road, Taipei, 10617 Taiwan
| | - Yu-Shan Chen
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Harry John Mersmann
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Bing-Hsien Liu
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
| | - Shih-Torng Ding
- Department of Animal Science and Technology, National Taiwan University, No. 50, Ln. 155, Sec. 3, Keelung Rd., Da’an Dist, Taipei City, 10617 Taiwan
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33
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Sun J, Li Y, Nguyen DN, Mortensen MS, van den Akker CHP, Skeath T, Pors SE, Pankratova S, Rudloff S, Sørensen SJ, Burrin DG, Thymann T, Sangild PT. Nutrient Fortification of Human Donor Milk Affects Intestinal Function and Protein Metabolism in Preterm Pigs. J Nutr 2018; 148:336-347. [PMID: 29462356 DOI: 10.1093/jn/nxx033] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 10/31/2017] [Indexed: 02/02/2023] Open
Abstract
Background Nutrient fortification of human milk is often required to secure adequate growth and organ development for very preterm infants. There is concern that formula-based fortifiers (FFs) induce intestinal dysfunction, feeding intolerance, and necrotizing enterocolitis (NEC). Bovine colostrum (BC) may be an alternative nutrient fortifier, considering its high content of protein and milk bioactive factors. Objective We investigated whether BC was superior to an FF product based on processed bovine milk and vegetable oil to fortify donor human milk (DHM) for preterm pigs, used as a model for infants. Methods Sixty preterm pigs from 4 sows (Danish Landrace × Large White × Duroc, birth weight 944 ± 29 g) received decreasing volumes of parenteral nutrition (96-72 mL ⋅ kg-1 ⋅ d-1) and increasing volumes of enteral nutrition (24-132 mL ⋅ kg-1 ⋅ d-1) for 8 d. Pigs were fed donor porcine milk (DPM) and DHM with or without FF or BC fortification (+4.6 g protein ⋅ kg-1 ⋅ d-1). Results DPM-fed pigs showed higher growth (10-fold), protein synthesis (+15-30%), villus heights, lactase and peptidase activities (+30%), and reduced intestinal cytokines (-50%) relative to DHM pigs (all P < 0.05). Fortification increased protein synthesis (+20-30%), but with higher weight gain and lower urea and cortisol concentrations for DHM+BC compared with DHM+FF pigs (2- to 3-fold differences, all P ≤ 0.06). DHM+FF pigs showed more diarrhea and reduced lactase and peptidase activities, hexose uptake, and villus heights relative to DHM+BC or DHM pigs (30-90% differences, P < 0.05). Fortification did not affect NEC incidence but DHM+BC pigs had lower colonic interleukin (IL)-6 and IL-8 concentrations relative to the remaining pigs (-30%, P = 0.06). DHM+FF pigs had higher stomach bacterial load than did DHM, and higher bacterial density along intestinal villi than did DHM and DHM+BC pigs (2- to 3-fold, P < 0.05). Conclusions The FF product investigated in this study reduced growth, intestinal function, and protein utilization in DHM-fed preterm pigs, relative to BC as fortifier. The relevance of BC as an alternative nutrient fortifier for preterm infants should be tested.
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Affiliation(s)
- Jing Sun
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences
| | - Yanqi Li
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences
| | - Duc Ninh Nguyen
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences
| | | | | | - Tom Skeath
- Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
| | - Susanne E Pors
- Department of Veterinary and Animal Sciences; and Laboratory of Neural Plasticity, Center for Neuroscience, University of Copenhagen, Copenhagen, Denmark
| | - Stanislava Pankratova
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences.,Department of Laboratory of Neural Plasticity, Center for Neuroscience, University of Copenhagen, Copenhagen, Denmark.,Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Silvia Rudloff
- Institute of Nutritional Science, Justus-Liebig-University Giessen, Giessen, Germany
| | | | - Douglas G Burrin
- USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX
| | - Thomas Thymann
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences
| | - Per T Sangild
- Section of Comparative Pediatrics and Nutrition, Faculty of Health and Medical Sciences.,Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark
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Prame Kumar K, Nicholls AJ, Wong CHY. Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res 2018; 371:551-565. [PMID: 29387942 PMCID: PMC5820413 DOI: 10.1007/s00441-017-2753-2] [Citation(s) in RCA: 276] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
Neutrophils are becoming recognized as highly versatile and sophisticated cells that display de novo synthetic capacity and potentially prolonged lifespan. Emerging concepts such as neutrophil heterogeneity and plasticity have revealed that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional characteristics. Indeed, these newly described neutrophil subsets will undoubtedly add to the already complex interactions between neutrophils and other immune cell types for an effective immune response. The interactions between neutrophils and monocytes/macrophages enable the host to efficiently defend against and eliminate foreign pathogens. However, it is also becoming increasingly clear that these interactions can be detrimental to the host if not tightly regulated. In this review, we will explore the functional cooperation of neutrophil and monocytes/macrophages in homeostasis, during acute inflammation and in various disease settings. We will discuss this in the context of cardiovascular disease in the form of atherosclerosis, an autoimmune disease mainly occurring in the kidneys, as well as the unique intestinal immune response of the gut that does not conform to the norms of the typical immune system.
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Affiliation(s)
- Kathryn Prame Kumar
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, VIC, 3168, Australia
| | - Alyce J Nicholls
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, VIC, 3168, Australia
| | - Connie H Y Wong
- Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Sciences, Monash Medical Centre, Monash University, Clayton, VIC, 3168, Australia.
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Loss of BID Delays FASL-Induced Cell Death of Mouse Neutrophils and Aggravates DSS-Induced Weight Loss. Int J Mol Sci 2018; 19:ijms19030684. [PMID: 29495595 PMCID: PMC5877545 DOI: 10.3390/ijms19030684] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 02/21/2018] [Accepted: 02/25/2018] [Indexed: 02/06/2023] Open
Abstract
Neutrophils are key players in the early defense against invading pathogens. Due to their potent effector functions, programmed cell death of activated neutrophils has to be tightly controlled; however, its underlying mechanisms remain unclear. Fas ligand (FASL/CD95L) has been shown to induce neutrophil apoptosis, which is accelerated by the processing of the BH3-only protein BH3 interacting domain death agonist (BID) to trigger mitochondrial apoptotic events, and been attributed a regulatory role during viral and bacterial infections. Here, we show that, in accordance with previous works, mouse neutrophils underwent caspase-dependent apoptosis in response to FASL, and that this cell death was significantly delayed upon loss of BID. However, pan-caspase inhibition failed to protect mouse neutrophils from FASL-induced apoptosis and caused a switch to RIPK3-dependent necroptotic cell death. Intriguingly, such a switch was less evident in the absence of BID, particularly under inflammatory conditions. Delayed neutrophil apoptosis has been implicated in several auto-inflammatory diseases, including inflammatory bowel disease. We show that neutrophil and macrophage driven acute dextran sulfate sodium (DSS) induced colitis was slightly more aggravated in BID-deficient mice, based on significantly increased weight loss compared to wild-type controls. Taken together, our data support a central role for FASL > FAS and BID in mouse neutrophil cell death and further underline the anti-inflammatory role of BID.
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36
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Zhang S, Wu Z, Li J, Wen X, Li L, Liu C, Zhang F, Qian J, Li Y. Peripheral differentials by Cytodiff flow cytometric system predict disease activity in Chinese patients with inflammatory bowel disease. Clin Chim Acta 2017; 471:17-22. [PMID: 28522249 DOI: 10.1016/j.cca.2017.05.018] [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: 02/21/2017] [Revised: 05/03/2017] [Accepted: 05/14/2017] [Indexed: 01/02/2023]
Abstract
BACKGROUND This study aimed at evaluating whether leukocyte differentials could serve as effective biomarkers for disease activity in IBD. METHODS A total of 100 subjects were prospectively enrolled, including 36 patients with CD, 34 patients with UC, and 30 healthy controls (HC). Leukocyte differentials were determined by CytoDiff Flow Cytometry analysis. RESULTS Total neutrophil counts, monocyte/lymphocyte ratio (M/L), and CD16- monocyte/lymphocyte ratio (CD16- M/L) were significantly higher in active UC patients compared with quiescent UC patients and HC. A cut-off value of 0.25 in M/L exhibited the best overall accuracy of 82.4% with an AUC of 0.846 in differentiating active UC from quiescent UC. Total leukocyte counts were significantly decreased in active CD patients, while total monocyte counts and total CD16- monocyte counts were significantly increased in active CD patients compared with quiescent CD patients and HC. A cut-off value of 0.25 in CD16- M/L displayed the best AUC of 0.886 (overall accuracy of 86.1%) in differentiating active CD from quiescent CD. CONCLUSIONS Our data suggest that CD16- M/L could serve as promising biomarkers for distinguishing active disease from quiescent disease in both UC and CD. In addition, they could be used as supplements to other disease activity indicators, such as hsCRP and ESR.
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Affiliation(s)
- Shulan Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Ziyan Wu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, No. 1 Shuai Fu Yuan, Eastern District, Beijing 100730, China
| | - Xiaoting Wen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Liubing Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Chenxi Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Jiaming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, No. 1 Shuai Fu Yuan, Eastern District, Beijing 100730, China.
| | - Yongzhe Li
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China.
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Loss of T-cell protein tyrosine phosphatase in the intestinal epithelium promotes local inflammation by increasing colonic stem cell proliferation. Cell Mol Immunol 2017; 15:367-376. [PMID: 28287113 PMCID: PMC6052838 DOI: 10.1038/cmi.2016.72] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 12/20/2016] [Accepted: 12/21/2016] [Indexed: 12/27/2022] Open
Abstract
T-cell protein tyrosine phosphatase (TC-PTP) has a critical role in the development of the immune system and has been identified as a negative regulator of inflammation. Single-nucleotide polymorphisms in the TC-PTP locus have been associated with increased susceptibility to inflammatory bowel diseases (IBDs) in patients. To further understand how TC-PTP is related to IBDs, we investigated the role of TC-PTP in maintaining the intestinal epithelial barrier using an in vivo genetic approach. Intestinal epithelial cell (IEC)-specific deletion of TC-PTP was achieved in a mouse model at steady state and in the context of dextran sulphate sodium (DSS)-induced colitis. Knockout (KO) of TC-PTP in IECs did not result in an altered intestinal barrier. However, upon DSS treatment, IEC-specific TC-PTP KO mice displayed a more severe colitis phenotype with a corresponding increase in the immune response and inflammatory cytokine profile. The absence of TC-PTP caused an altered turnover of IECs, which is further explained by the role of the tyrosine phosphatase in colonic stem cell (CoSC) proliferation. Our results suggest a novel role for TC-PTP in regulating the homeostasis of CoSC proliferation. This supports the protective function of TC-PTP against IBDs, independently of its previously demonstrated role in intestinal immunity.
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Muthas D, Reznichenko A, Balendran CA, Böttcher G, Clausen IG, Kärrman Mårdh C, Ottosson T, Uddin M, MacDonald TT, Danese S, Berner Hansen M. Neutrophils in ulcerative colitis: a review of selected biomarkers and their potential therapeutic implications. Scand J Gastroenterol 2017; 52:125-135. [PMID: 27610713 DOI: 10.1080/00365521.2016.1235224] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.
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Affiliation(s)
- Daniel Muthas
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Anna Reznichenko
- b Department of Cardiovascular and Metabolic Diseases , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Clare A Balendran
- c Department of Personalised HealthCare & Biomarkers , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Gerhard Böttcher
- d Department of Drug Safety and Metabolism , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Ib Groth Clausen
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Carina Kärrman Mårdh
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Tomas Ottosson
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Mohib Uddin
- c Department of Personalised HealthCare & Biomarkers , AstraZeneca R&D Gothenburg , Mölndal , Sweden
| | - Thomas T MacDonald
- e Blizard Institute, Barts and the London School of Medicine and Dentistry, QMUL , London , UK
| | - Silvio Danese
- f Department of Gastroenterology , IBD Center, Humanitas Research Hospital , Milan , Italy
| | - Mark Berner Hansen
- a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden.,g Digestive Disease Center K, Bispebjerg Hospital, University of Copenhagen , Copenhagen , Denmark
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Maeda T, Sakiyama T, Kanmura S, Hashimoto S, Ibusuki K, Tanoue S, Komaki Y, Arima S, Nasu Y, Sasaki F, Taguchi H, Numata M, Uto H, Tsubouchi H, Ido A. Low concentrations of human neutrophil peptide ameliorate experimental murine colitis. Int J Mol Med 2016; 38:1777-1785. [PMID: 27840892 PMCID: PMC5117768 DOI: 10.3892/ijmm.2016.2795] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 10/18/2016] [Indexed: 12/19/2022] Open
Abstract
Human neutrophil peptides (HNPs) not only have antimicrobial properties, but also exert multiple immunomodulatory effects depending on the concentration used. We have previously demonstrated that the intraperitoneal administration of high-dose HNP-1 (100 µg/day) aggravates murine dextran sulfate sodium (DSS)-induced colitis, suggesting a potential pro-inflammatory role for HNPs at high concentrations. However, the role of low physiological concentrations of HNPs in the intestinal tract remains largely unknown. The aim of this study was to examine the effects of low concentrations of HNPs on intestinal inflammation. We first examined the effects of the mild transgenic overexpression of HNP-1 in DSS-induced colitis. HNP-1 transgenic mice have plasma HNP-1 levels similar to the physiological concentrations in human plasma. Compared to wild-type mice treated with DSS, HNP-1 transgenic mice treated with DSS had significantly lower clinical and histological scores, and lower colonic mRNA levels of pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. We then injected low-dose HNP-1 (5 µg/day) or phosphate-buffered saline (PBS) intraperitoneally into C57BL/6N and BALB/c mice administered DSS. The HNP-1-treated mice exhibited significantly milder colitis with reduced expression levels of pro-inflammatory cytokines compared with the PBS-treated mice. Finally, we examined the in vitro effects of HNP-1 on the expression of cytokines associated with macrophage activation. Low physiological concentrations of HNP-1 did not significantly affect the expression levels of IL-1β, TNF-α, IL-6 or IL-10 in colonic lamina propria mononuclear cells activated with heat-killed Escherichia coli, suggesting that the anti-inflammatory effects of HNP-1 on murine colitis may not be exerted by direct action on intestinal macrophages. Collectively, our data demonstrated a biphasic dose-dependent effect of HNP-1 on DSS-induced colitis: an amelioration at low concentrations and an aggravation at high concentrations. Low concentrations of HNPs may contribute to the maintenance of intestinal homeostasis.
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Affiliation(s)
- Takuro Maeda
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Toshio Sakiyama
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shuji Kanmura
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shinichi Hashimoto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Kazunari Ibusuki
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shiroh Tanoue
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yuga Komaki
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Shiho Arima
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yuichiro Nasu
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Fumisato Sasaki
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hiroki Taguchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Masatsugu Numata
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hirofumi Uto
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hirohito Tsubouchi
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
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Espaillat MP, Kew RR, Obeid LM. Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. Adv Biol Regul 2016; 63:140-155. [PMID: 27866974 DOI: 10.1016/j.jbior.2016.11.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 11/10/2016] [Accepted: 11/12/2016] [Indexed: 02/06/2023]
Abstract
Bioactive sphingolipids are regulators of immune cell function and play critical roles in inflammatory conditions including ulcerative colitis. As one of the major forms of inflammatory bowel disease, ulcerative colitis pathophysiology is characterized by an aberrant intestinal inflammatory response that persists causing chronic inflammation and tissue injury. Innate immune cells play an integral role in normal intestinal homeostasis but their dysregulation is thought to contribute to the pathogenesis of ulcerative colitis. In particular, neutrophils are key effector cells and are first line defenders against invading pathogens. While the activity of neutrophils in the intestinal mucosa is required for homeostasis, regulatory mechanisms are equally important to prevent unnecessary activation. In ulcerative colitis, unregulated neutrophil inflammatory mechanisms promote tissue injury and loss of homeostasis. Aberrant neutrophil function represents an early checkpoint in the detrimental cycle of chronic intestinal inflammation; thus, dissecting the mechanisms by which these cells are regulated both before and during disease is essential for understanding the pathogenesis of ulcerative colitis. We present an analysis of the role of sphingolipids in the regulation of neutrophil function and the implication of this relationship in ulcerative colitis.
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Affiliation(s)
- Mel Pilar Espaillat
- Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Richard R Kew
- Department of Pathology, Stony Brook University, Stony Brook, NY 11794, USA
| | - Lina M Obeid
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Northport Veterans Affairs Medical Center, Northport, NY 11768, USA.
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Aydemir Y, Pınar A, Hızal G, Demir H, Saltık Temizel İN, Özen H, Akbıyık F, Yüce A. Neutrophil volume distribution width as a new marker in detecting inflammatory bowel disease activation. Int J Lab Hematol 2016; 39:51-57. [PMID: 27808471 DOI: 10.1111/ijlh.12574] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 07/29/2016] [Indexed: 01/07/2023]
Affiliation(s)
- Y. Aydemir
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
| | - A. Pınar
- Department of Medical Biochemistry; Hacettepe University School of Medicine; Ankara Turkey
| | - G. Hızal
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
| | - H. Demir
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
| | - İ. N. Saltık Temizel
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
| | - H. Özen
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
| | - F. Akbıyık
- Department of Medical Biochemistry; Hacettepe University School of Medicine; Ankara Turkey
| | - A. Yüce
- Department of Pediatric Gastroenterology, Hepatology and Nutrition; Hacettepe University School of Medicine; Ankara Turkey
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Perrone G, Brunelli R, Marcoccia E, Zannini I, Candelieri M, Gozzer M, Stefanutti C. Therapeutic Apheresis in Pregnancy: Three Differential Indications With Positive Maternal and Fetal Outcome. Ther Apher Dial 2016; 20:677-685. [DOI: 10.1111/1744-9987.12422] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 01/14/2016] [Accepted: 03/01/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Giuseppina Perrone
- Department of Obstetrical and Gynecological Sciences and Urological Sciences
| | - Roberto Brunelli
- Department of Obstetrical and Gynecological Sciences and Urological Sciences
| | - Eleonora Marcoccia
- Department of Obstetrical and Gynecological Sciences and Urological Sciences
| | - Ilaria Zannini
- Department of Obstetrical and Gynecological Sciences and Urological Sciences
| | - Miriam Candelieri
- Department of Obstetrical and Gynecological Sciences and Urological Sciences
| | | | - Claudia Stefanutti
- Extracorporeal Therapeutic Techniques Unit, Immunohematology and Transfusion Medicine, Lipid Clinic and Atherosclerosis Prevention Centre, Department of Molecular Medicine; ‘Umberto I’ Hospital, ‘Sapienza’ University of Rome; Rome Italy
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43
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The role of neutrophils in inflammation resolution. Semin Immunol 2016; 28:137-45. [DOI: 10.1016/j.smim.2016.03.007] [Citation(s) in RCA: 170] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 03/11/2016] [Accepted: 03/15/2016] [Indexed: 01/29/2023]
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Hashiguchi K, Takeshima F, Akazawa Y, Matsushima K, Minami H, Machida H, Yamaguchi N, Shiozawa K, Ohba K, Ohnita K, Ichikawa T, Isomoto H, Nakao K. Advantages of fecal lactoferrin measurement during granulocyte and monocyte adsorptive apheresis therapy in ulcerative colitis. Digestion 2015; 91:208-17. [PMID: 25823500 DOI: 10.1159/000375301] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 01/16/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Fecal lactoferrin has been introduced as a useful tool for the diagnosis and monitoring of inflammatory bowel disease (IBD). The aim of this study was to assess if fecal lactoferrin can be employed to predict or estimate the effect of granulocyte and monocyte adsorptive apheresis (GMA) in ulcerative colitis (UC). METHODS This was a prospective study involving 21 patients with UC. Patients with moderately-to-severely active UC who were scheduled to undergo GMA were recruited. Changes in fecal lactoferrin concentration were compared between the GMA-responder and -nonresponder groups. RESULTS In the GMA-responder group, fecal lactoferrin significantly increased 1 week after the introduction of GMA and then significantly decreased after GMA sessions. Fecal lactoferrin concentrations were significantly higher in the GMA-responder group than in the GMA-nonresponder group at 1 and 2 weeks after the introduction of GMA. Multivariate logistic regression analysis revealed that fecal lactoferrin concentration 1 week after the introduction of GMA was the most contributing factor for the effectiveness of GMA in patients with UC. CONCLUSIONS In the GMA-responder group, fecal lactoferrin concentration significantly increased 1 week after the introduction of GMA. Fecal lactoferrin may be beneficial for predicting clinical response of GMA in patients with UC at an early stage of GMA treatment.
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Affiliation(s)
- Keiichi Hashiguchi
- Department of Gastroenterology and Hepatology, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Japan
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Yoshimura N, Yokoyama Y, Matsuoka K, Takahashi H, Iwakiri R, Yamamoto T, Nakagawa T, Fukuchi T, Motoya S, Kunisaki R, Kato S, Hirai F, Ishiguro Y, Tanida S, Hiraoka S, Mitsuyama K, Ishihara S, Tanaka S, Otaka M, Osada T, Kagaya T, Suzuki Y, Nakase H, Hanai H, Watanabe K, Kashiwagi N, Hibi T. An open-label prospective randomized multicenter study of intensive versus weekly granulocyte and monocyte apheresis in active crohn's disease. BMC Gastroenterol 2015; 15:163. [PMID: 26585569 PMCID: PMC4653849 DOI: 10.1186/s12876-015-0390-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 10/31/2015] [Indexed: 02/07/2023] Open
Abstract
Background Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active Crohn’s disease (CD). However, with routine weekly therapy, it may take several weeks to achieve remission. This study was performed to assess clinical efficacy and safety of intensive GMA in patients with active CD. Methods In an open-label, prospective, randomized multicentre setting, 104 patients with CD activity index (CDAI) of 200 to 450 received intensive GMA, at two sessions per week (n = 55) or one session per week (n = 49). Clinical remission was defined as a CDAI score <150. Patients in each arm could receive up to 10 GMA sessions. However, GMA treatment could be discontinued when CDAI decreased to <150 (clinical remission level). Results Of the 104 patients, 99 were available for efficacy evaluation as per protocol, 45 in the weekly GMA group, and 54 in the intensive GMA group. Remission was achieved in 16 of 45 patients (35.6 %) in the weekly GMA and in 19 of 54 (35.2 %) in the intensive GMA (NS). Further, the mean time to remission was 35.4 ± 5.3 days in the weekly GMA and 21.7 ± 2.7 days in the intensive GMA (P = 0.0373). Elevated leucocytes and erythrocyte sedimentation rate were significantly improved by intensive GMA, from 8005/μL to 6950/μL (P = 0.0461) and from 54.5 mm/hr to 30.0 mm/hr (P = 0.0059), respectively. In both arms, GMA was well tolerated and was without safety concern. Conclusions In this study, with respect to remission rate, intensive GMA was not superior to weekly GMA, but the time to remission was significantly shorter in the former without increasing the incidence of side effects. UMIN registration # 000003666. Electronic supplementary material The online version of this article (doi:10.1186/s12876-015-0390-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Naoki Yoshimura
- Department of internal medicine, Division of IBD, Tokyo Yamate Medical Centre, Tokyo, Japan.
| | - Yoko Yokoyama
- Division of Internal Medicine, Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan.
| | - Katsuyoshi Matsuoka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Hiroki Takahashi
- Department of General Medicine, National Hospital Organization, Sendai Medical Centre, Miyagi, Japan.
| | - Ryuichi Iwakiri
- Division of Gastroenterology, Department of Internal Medicine, Saga Medical School, Saga, Japan.
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Centre, Yokkaichi Hazu Medical Centre, Mie, Japan.
| | - Tomoo Nakagawa
- Department of Gastroenterology and Hepatology, Chiba University Hospital, Chiba, Japan.
| | - Takumi Fukuchi
- Department of Gastroenterology and Hepatology, Osakafu Saiseikai Nakatsu Hospital, Osaka, Japan.
| | - Satoshi Motoya
- IBD Center, Sapporo Kosei General Hospital, Hokkaido, Japan.
| | - Reiko Kunisaki
- Inflammatory Bowel Centre, Yokohama City University Medical Centre, Kanagawa, Japan.
| | - Shingo Kato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saitama Medical Centre, Saitama Medical University, Saitama, Japan.
| | - Fumihito Hirai
- Department of Gastroenterology Fukuoka University Chikushi Hospital, Fukuoka, Japan.
| | - Yoh Ishiguro
- Department of Gastroenterology and Hematology, Hirosaki National Hospital, Aomori, Japan.
| | - Satoshi Tanida
- Department of Gastroenterology and Metabolism, Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan.
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan.
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Centre, Kurume University School of Medicine, Fukuoka, Japan.
| | - Shunji Ishihara
- Department of Internal Medicine II, Faculty of Medicine, Shimane University, Izumo, Japan.
| | - Shinji Tanaka
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
| | - Michiro Otaka
- Division of Gastroenterology, Kobari General Hospital & Juntendo University, Chiba, Japan.
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
| | - Takashi Kagaya
- Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Japan.
| | - Yasuo Suzuki
- Internal Medicine, Toho University Sakura Medical Centre, Chiba, Japan.
| | - Hiroshi Nakase
- Department of Gastroenterology and Endoscopic Medicine, Kyoto University Hospital, Kyoto, Japan.
| | - Hiroyuki Hanai
- Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Shizuoka, Japan.
| | - Kenji Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | | | - Toshifumi Hibi
- Kitasato Institute Hospital, Centre for Advanced IBD Research and Treatment, Kitasato University, 108-8642 Minato-ku, Tokyo, Japan.
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Sacco R, Tanaka T, Yamamoto T, Bresci G, Saniabadi AR. Adacolumn leucocytapheresis for ulcerative colitis: clinical and endoscopic features of responders and unresponders. Expert Rev Gastroenterol Hepatol 2015; 9:327-33. [PMID: 25160857 DOI: 10.1586/17474124.2014.953060] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Cytokines such as TNF-α have a validated role in the immunopathogensis of ulcerative colitis (UC), and intercepting inflammatory cytokines is currently the best option for maximizing treatment efficacy. One of the major sources of inflammatory cytokines are myeloid linage leucocytes (granulocytes, monocytes), which are present in great numbers in the colonic tissue. Their selective depletion by adsorptive granulocyte, monocyte apheresis (GMA), should be therapeutic in patients with UC, although until now efficacy outcomes have been both encouraging and disappointing. The authors' view is that in patients with UC, there is an evolving scope for therapeutic opportunity based on taking away the sources of inflammatory cytokines, also considering the favorable safety profile of GMA.
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Affiliation(s)
- Rodolfo Sacco
- Department of Gastroenterology-Pisa University Hospital, Pisa, Italy
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Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel disease by adsorptive leucocytapheresis: A desire to treat without drugs. World J Gastroenterol 2014; 20:9699-9715. [PMID: 25110409 PMCID: PMC4123360 DOI: 10.3748/wjg.v20.i29.9699] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms, impairing function and quality of life. Current medications are aimed at reducing the symptoms or suppressing exacerbations. However, patients require life-long medications, and this can lead to drug dependency, loss of response together with adverse side effects. Indeed, drug side effects become additional morbidity factor in many patients on long-term medications. Nonetheless, the efficacy of anti-tumour necrosis factors (TNF)-α biologics has validated the role of inflammatory cytokines notably TNF-α in the exacerbation of IBD. However, inflammatory cytokines are released by patients’ own cellular elements including myeloid lineage leucocytes, which in patients with IBD are elevated with activation behaviour and prolonged survival. Accordingly, these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis (GMA) with an Adacolumn. Based on this background, recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries. Efficacy rates have been impressive as well as disappointing. In fact the clinical response to GMA seems to define the patients’ disease course, response to medications, duration of active disease, and severity at entry. The best responders have been first episode cases (up to 100%) followed by steroid naïve and patients with a short duration of active disease prior to GMA. Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA. It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD. Additionally, GMA is very much favoured by patients for its good safety profile. GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates. However, in patients with IBD, there is a scope for removing from the body the sources of pro-inflammatory cytokines and achieve disease remission. The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications, many patients should respond to GMA and avoid pharmacologics. This should fulfill the desire to treat without drugs.
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Yamamoto T, Shiraki M, Bamba T, Umegae S, Matsumoto K. Fecal calprotectin and lactoferrin as predictors of relapse in patients with quiescent ulcerative colitis during maintenance therapy. Int J Colorectal Dis 2014; 29:485-91. [PMID: 24343276 DOI: 10.1007/s00384-013-1817-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/04/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE This prospective study was to evaluate the significance of fecal calprotectin and lactoferrin for the prediction of ulcerative colitis (UC) relapse. METHODS Eighty UC patients in remission for ≥3 months on mesalamine as maintenance therapy were included. At entry, stool samples were collected for the measurement of calprotectin and lactoferrin. All patients were followed up for the following 12 months. To identify predictive factors for relapse, time-dependent analyses using the Kaplan-Meier graphs and Cox's proportional hazard model were applied. RESULTS During the 12 months, 21 patients relapsed. Mean calprotectin and lactoferrin levels were significantly higher in patients with relapse than those in remission (calprotectin-173.7 vs 135.5 μg/g, P = 0.02; lactoferrin-165.1 vs 130.7 μg/g, P = 0.03). A cutoff value of 170 μg/g for calprotectin had a sensitivity of 76 % and a specificity of 76 % to predict relapse, while a cutoff value of 140 μg/g for lactoferrin had a sensitivity of 67 % and a specificity of 68 %. In a multivariate analysis, calprotectin (≥170 μg/g) was a predictor of relapse (hazard ratio, 7.23; P = 0.002). None of the following parameters were significantly associated with relapse: age, gender, duration of UC, number of UC episode, severity of the previous episode, extent of UC, extraintestinal manifestation, and lactoferrin level. CONCLUSIONS Fecal calprotectin showed a higher sensitivity and specificity than fecal lactoferrin for predicting UC relapse. Fecal calprotectin level appeared to be a significant predictor of relapse in patients with quiescent UC on mesalamine as maintenance therapy.
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Affiliation(s)
- Takayuki Yamamoto
- Inflammatory Bowel Disease Center, Yokkaichi Social Insurance Hospital, 10-8 Hazuyamacho, Yokkaichi, Mie, 510-0016, Japan,
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Luissint AC, Nusrat A, Parkos CA. JAM-related proteins in mucosal homeostasis and inflammation. Semin Immunopathol 2014; 36:211-26. [PMID: 24667924 DOI: 10.1007/s00281-014-0421-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 02/25/2014] [Indexed: 02/06/2023]
Abstract
Mucosal surfaces are lined by epithelial cells that form a physical barrier protecting the body against external noxious substances and pathogens. At a molecular level, the mucosal barrier is regulated by tight junctions (TJs) that seal the paracellular space between adjacent epithelial cells. Transmembrane proteins within TJs include junctional adhesion molecules (JAMs) that belong to the cortical thymocyte marker for Xenopus family of proteins. JAM family encompasses three classical members (JAM-A, JAM-B, and JAM-C) and related molecules including JAM4, JAM-like protein, Coxsackie and adenovirus receptor (CAR), CAR-like membrane protein and endothelial cell-selective adhesion molecule. JAMs have multiple functions that include regulation of endothelial and epithelial paracellular permeability, leukocyte recruitment during inflammation, angiogenesis, cell migration, and proliferation. In this review, we summarize the current knowledge regarding the roles of the JAM family members in the regulation of mucosal homeostasis and leukocyte trafficking with a particular emphasis on barrier function and its perturbation during pathological inflammation.
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Affiliation(s)
- Anny-Claude Luissint
- Epithelial pathobiology and mucosal inflammation research unit, Department of Pathology and Laboratory Medicine, Emory University, 615 Michael Street, 30306, Atlanta, GA, USA
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50
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Burgon J, Robertson AL, Sadiku P, Wang X, Hooper-Greenhill E, Prince LR, Walker P, Hoggett EE, Ward JR, Farrow SN, Zuercher WJ, Jeffrey P, Savage CO, Ingham PW, Hurlstone AF, Whyte MKB, Renshaw SA. Serum and glucocorticoid-regulated kinase 1 regulates neutrophil clearance during inflammation resolution. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2014; 192:1796-805. [PMID: 24431232 PMCID: PMC3921102 DOI: 10.4049/jimmunol.1300087] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The inflammatory response is integral to maintaining health by functioning to resist microbial infection and repair tissue damage. Large numbers of neutrophils are recruited to inflammatory sites to neutralize invading bacteria through phagocytosis and the release of proteases and reactive oxygen species into the extracellular environment. Removal of the original inflammatory stimulus must be accompanied by resolution of the inflammatory response, including neutrophil clearance, to prevent inadvertent tissue damage. Neutrophil apoptosis and its temporary inhibition by survival signals provides a target for anti-inflammatory therapeutics, making it essential to better understand this process. GM-CSF, a neutrophil survival factor, causes a significant increase in mRNA levels for the known anti-apoptotic protein serum and glucocorticoid-regulated kinase 1 (SGK1). We have characterized the expression patterns and regulation of SGK family members in human neutrophils and shown that inhibition of SGK activity completely abrogates the antiapoptotic effect of GM-CSF. Using a transgenic zebrafish model, we have disrupted sgk1 gene function and shown this specifically delays inflammation resolution, without altering neutrophil recruitment to inflammatory sites in vivo. These data suggest SGK1 plays a key role in regulating neutrophil survival signaling and thus may prove a valuable therapeutic target for the treatment of inflammatory disease.
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Affiliation(s)
- Joseph Burgon
- Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
| | - Anne L. Robertson
- Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom
| | - Pranvera Sadiku
- Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom
| | - Xingang Wang
- Institute of Molecular and Cellular Biology, 61, Biopolis Drive, Proteos, Singapore
| | - Edward Hooper-Greenhill
- Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development Ltd., Stevenage, United Kingdom
| | - Lynne R. Prince
- Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom
| | - Paul Walker
- Faculty of Life Sciences, Michael Smith Building, Oxford Road, The University of Manchester, Manchester, United Kingdom
| | - Emily E. Hoggett
- Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
| | - Jonathan R. Ward
- Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
| | - Stuart N. Farrow
- Respiratory Therapy Area, GlaxoSmithKline Research and Development Ltd., Stevenage, United Kingdom
| | - William J. Zuercher
- Department of Chemical Biology, GlaxoSmithKline, Research Triangle Park, North Carolina, USA
| | - Philip Jeffrey
- Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development Ltd., Stevenage, United Kingdom
| | - Caroline O. Savage
- Immuno-Inflammation Therapy Area Unit, GlaxoSmithKline Research and Development Ltd., Stevenage, United Kingdom
| | - Philip W. Ingham
- Institute of Molecular and Cellular Biology, 61, Biopolis Drive, Proteos, Singapore
| | - Adam F. Hurlstone
- Faculty of Life Sciences, Michael Smith Building, Oxford Road, The University of Manchester, Manchester, United Kingdom
| | - Moira K. B. Whyte
- Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
- Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom
| | - Stephen A. Renshaw
- Medical Research Council Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, United Kingdom
- Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom
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