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Liu Y, Deng H, Yao J, He C, Zhang J. The role of neutrophil extracellular traps in Crohn's disease. Heliyon 2024; 10:e40577. [PMID: 39654789 PMCID: PMC11625251 DOI: 10.1016/j.heliyon.2024.e40577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/19/2024] [Accepted: 11/19/2024] [Indexed: 12/12/2024] Open
Abstract
Crohn's disease (CD) is an idiopathic and chronic inflammation of the gastrointestinal (GI) tract. The underlying pathogenesis of CD is multifaceted, with complex interactions between genetic predisposition, environmental triggers, and abnormalities within the immune system. Neutrophil extracellular traps (NETs) have gained significant attention as a novel component in the pathogenesis of CD. NETs are intricate structures fashioned from DNA, histones, and granule proteins, and are actively released by neutrophils to entangle and eliminate pathogenic microbes. This review article delves into the intricate role of NETs in the pathogenesis of CD. We examine how NETs may serve as a pivotal mechanism for the recruitment of immune cells to the site of inflammation. NETs are known to influence the function of epithelial cells, which line the GI tract, potentially contributing to the structural integrity and barrier dysfunction observed in CD. NETs stimulate inflammation, a hallmark of the disease, by releasing pro-inflammatory molecules and activating immune cells. We also investigate the promising therapeutic potential of targeting NETs in CD. By intercepting the formation or function of NETs, it may be possible to mitigate the chronic inflammation, reduce tissue damage, and alleviate the symptoms associated with CD. Strategies to inhibit NET formation, such as the use of DNase I and approaches to disrupt NET-mediated signaling pathways, are discussed in CD therapeutics. Understanding the detailed mechanisms of NETs is crucial for the development of targeted treatments that could potentially revolutionize the management of CD.
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Affiliation(s)
- Ying Liu
- College of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Heng Deng
- Department of Anorectal Surgery, The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jinfeng Yao
- Department of Internal Medicine, Anhui Hospital Affiliated Shanghai Shuguang Hospital, Hefei, Anhui, China
| | - Chunrong He
- Hefei Haiheng Health Service Center, Hefei, Anhui, China
| | - Jun Zhang
- College of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, China
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Shukrun R, Fidel V, Baron S, Unger N, Ben-Shahar Y, Cohen S, Elhasid R, Yerushalmy-Feler A. Neutrophil Extracellular Traps in Pediatric Inflammatory Bowel Disease: A Potential Role in Ulcerative Colitis. Int J Mol Sci 2024; 25:11126. [PMID: 39456908 PMCID: PMC11507660 DOI: 10.3390/ijms252011126] [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: 09/08/2024] [Revised: 10/06/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory condition of the gut affecting both adults and children. Neutrophil extracellular traps (NETs) are structures released by activated neutrophils, potentially contributing to tissue damage in various diseases. This study aimed to explore the presence and role of NETs in pediatric IBD. We compared intestinal biopsies and peripheral blood from 20 pediatric IBD patients (UC and CD) to controls. Biopsy staining and techniques for neutrophil activation were used to assess neutrophil infiltration and NET formation. We also measured the enzymatic activity of key NET proteins and evaluated NET formation in UC patients in remission. Both UC and CD biopsies showed significantly higher levels of neutrophils and NETs compared to controls (p < 0.01), with UC exhibiting the strongest association. Peripheral blood neutrophils from UC patients at diagnosis displayed increased NET formation compared to controls and CD patients. Interestingly, NET formation normalized in UC patients following remission-inducing treatment. This pilot study suggests a potential role for NETs in pediatric IBD, particularly UC. These findings warrant further investigation into the mechanisms of NET involvement and the potential for targeting NET formation as a therapeutic strategy.
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Affiliation(s)
- Rachel Shukrun
- Pediatric Hemato-Oncology Research Laboratory, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (R.S.); (V.F.); (S.B.)
- Department of Pediatric Hemato-Oncology, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; (N.U.); (S.C.); (A.Y.-F.)
| | - Victoria Fidel
- Pediatric Hemato-Oncology Research Laboratory, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (R.S.); (V.F.); (S.B.)
| | - Szilvia Baron
- Pediatric Hemato-Oncology Research Laboratory, Tel Aviv Medical Center, Tel Aviv 6423906, Israel; (R.S.); (V.F.); (S.B.)
| | - Noga Unger
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; (N.U.); (S.C.); (A.Y.-F.)
| | - Yoav Ben-Shahar
- Department of Pediatric Surgery, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel;
| | - Shlomi Cohen
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; (N.U.); (S.C.); (A.Y.-F.)
- Pediatric Gastroenterology Institute, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Ronit Elhasid
- Department of Pediatric Hemato-Oncology, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Anat Yerushalmy-Feler
- Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel; (N.U.); (S.C.); (A.Y.-F.)
- Pediatric Gastroenterology Institute, “Dana-Dwek” Children’s Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
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Lee JS, Yang B, Shin HS, Lee H, Chai HG, Choi H, Han JH, Yoon JH, Kim EG, Lee H. Increased bronchiectasis risk and related risk factors in inflammatory bowel disease: a 10-year Korean national cohort study. ERJ Open Res 2024; 10:00087-2024. [PMID: 39040586 PMCID: PMC11261352 DOI: 10.1183/23120541.00087-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/06/2024] [Indexed: 07/24/2024] Open
Abstract
Background The association between inflammatory bowel disease (IBD) and an increased risk of bronchiectasis, as well as contributing factors, remains unclear. Additionally, whether bronchiectasis increases disease burden in IBD remains unknown. Therefore, this study aimed to: 1) assess whether IBD increases the risk of incident bronchiectasis; 2) compare the risk of bronchiectasis between individuals with Crohn's disease (CD) and those with ulcerative colitis (UC); 3) identify risk factors for bronchiectasis in individuals with IBD; and 4) examine the disease burden in individuals with IBD and bronchiectasis versus those without. Methods We conducted a population-based matched cohort study involving adults aged ≥20 years with IBD, using data acquired from the Korean National Health Insurance Service-National Sample Cohort database between 2002 and 2012. Results During the mean follow-up of 9.6 years, the incidence rate of bronchiectasis was 419.63 out of 100 000 person-years (PY) and 309.65 out of 100 000 PY in the IBD and matched cohorts (adjusted hazard ratio (aHR) 1.21, 95% CI 1.05-1.39), respectively. UC was associated with increased bronchiectasis risk (aHR 1.42, 95% CI 1.19-1.69), but CD was not. Multivariate Cox regression analyses showed that age, male sex, medical aid, underweight status, COPD and diabetes mellitus were associated with an increased risk of bronchiectasis in the IBD cohort (p<0.05). The mortality, emergency department visit and hospitalisation rates were significantly higher for individuals with IBD and bronchiectasis compared with those without bronchiectasis (p<0.05). Conclusion IBD is associated with increased risk of bronchiectasis, which results in a greater disease burden in individuals with IBD.
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Affiliation(s)
- Jun Su Lee
- Division of Gastroenterology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
- J.S. Lee and B. Yang contributed equally to this work
| | - Bumhee Yang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
- J.S. Lee and B. Yang contributed equally to this work
| | - Hye Soon Shin
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Heajung Lee
- Department of Statistics and Data Science, Yonsei University, Seoul, Republic of Korea
| | | | - Hayoung Choi
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Republic of Korea
| | - Joung-Ho Han
- Division of Gastroenterology, Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Jai Hoon Yoon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Eung-Gook Kim
- Division of Biochemistry, College of Medicine, Chungbuk National University, Cheongju, Republic of Korea
| | - Hyun Lee
- Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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Yasuda H, Uno A, Tanaka Y, Koda S, Saito M, Sato EF, Matsumoto K, Kato S. Neutrophil extracellular trap induction through peptidylarginine deiminase 4 activity is involved in 2,4,6-trinitrobenzenesulfonic acid-induced colitis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:3127-3140. [PMID: 37878044 DOI: 10.1007/s00210-023-02800-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 10/16/2023] [Indexed: 10/26/2023]
Abstract
Neutrophil extracellular traps (NETs) are induced in the innate immune response against infectious agents and are also implicated in the pathogenesis of various cancers and autoimmune diseases. Peptidylarginine deiminase 4 (PAD4), an enzyme that converts arginine to citrulline, is also involved in NET formation. In this study, we investigated the pathogenic effect of PAD4 on NETs in inflammatory bowel disease using a trinitrobenzene sulfonic acid (TNBS)-induced murine colitis model. PAD4-deficient (PAD4KO) mice were generated by CRISPR-Cas9-mediated genomic editing. NETs were triggered in peritoneal neutrophils obtained from wild-type mice by A23187 (a calcium ionophore), but these responses were completely abolished in the PAD4KO mice. Experimental colitis was induced in wild-type and PAD4KO mice via an intrarectal injection of TNBS. TNBS injection resulted in body weight loss, extensive colonic erosion, and ulceration in wildtype mice. However, these responses were significantly attenuated following the administration of Cl-amidine (an inhibitor of pan-PADs) and DNase I (an inhibitor of NET formation), in combination with PAD4KO in mice. TNBS-induced increases in myeloperoxidase activity, inflammatory cytokine expression, and NET formation in the colon were significantly reduced following the administration of Cl-amidine, DNase I injection, and PAD4KO. These findings suggest that NET formation contributes to the pathogenesis of TNBS-induced colitis via PAD4. Thus, PAD4 is a promising target for the treatment of inflammatory bowel disease.
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Affiliation(s)
- Hiroyuki Yasuda
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan.
| | - Ayaka Uno
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
| | - Yoshiya Tanaka
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
| | - Saya Koda
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
| | - Michiko Saito
- Bio-Science Research Center, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
| | - Eisuke F Sato
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, 3500-3, Minamitamagaki, Suzuka-City, Mie, 513-8670, Japan
| | - Kenjiro Matsumoto
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
| | - Shinichi Kato
- Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, 6078414, Japan
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Hafner S, Seufferlein T, Kleger A, Müller M. Symptoms and Management of Aseptic Liver Abscesses. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:208-217. [PMID: 37827501 DOI: 10.1055/a-2075-5082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/14/2023]
Abstract
Aseptic liver abscesses occur very rarely. Clinical guidelines on the management of the disease do not exist, and the diagnosis is challenging.We screen MEDLINE and PUBMED databases for relevant case reports from inception to November 2022. Information on patient age, sex, initial symptoms, the extent of abscess formation, further diagnoses, treatment, and course of the disease is analyzed.Thirty cases with sterile hepatic abscess formation are identified. In most patients (n=18), the spleen is affected as well. Patients typically present with fever, abdominal pain, and increased inflammatory values. Comorbidity with inflammatory bowel disease is very common (n=18) and is associated with a significantly younger age at the time of hepatic abscess development. In addition, many patients show autoimmune-mediated cutaneous, ocular, or arthritic rheumatoid manifestations. Histological examination of abscess material reveals neutrophilic infiltration. The majority of patients initially receive corticosteroid therapy. Furthermore, response to azathioprine, anti-TNF-α antibodies, and other immunomodulatory drugs is reported. Ten out of fourteen patients with a long-term follow-up (≥ 36 months) have at least one relapse of hepatic abscess formation.Aseptic hepatic abscesses should be considered in the case of sterile punctures and non-response to antibiotics. Patients with aseptic liver abscesses have a high risk of recurrence warranting immunomodulatory maintenance therapy.
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Affiliation(s)
- Susanne Hafner
- Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, University Ulm Medical Centre, Ulm, Germany
| | | | - Alexander Kleger
- Internal Medicine I, University Ulm Medical Centre, Ulm, Germany
| | - Martin Müller
- Internal Medicine I, University Ulm Medical Centre, Ulm, Germany
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Li Z, Yuan T. Neutrophil extracellular traps in adult diseases and neonatal bacterial infectious diseases: A review. Heliyon 2024; 10:e23559. [PMID: 38173520 PMCID: PMC10761809 DOI: 10.1016/j.heliyon.2023.e23559] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024] Open
Abstract
Neutrophils, the most abundant type of white blood cells, are pivotal in fighting bacterial infections due to their immunological and anti-infection capabilities. In recent years, scientists have discovered a novel mechanism known as neutrophil extracellular traps, which are fibrous networks primarily released by neutrophils that combat bacterial infections. There is a growing interest in studying NETs and their role in human infectious diseases, particularly in neonates susceptible to bacterial infections. NETs and their components have been found in various samples from neonatal-infected patients, providing a new route for early diagnosis of neonatal infectious diseases. This paper aims to summarize the studies on NETs in adult diseases and mainly discuss NETs in neonatal sepsis, necrotizing enterocolitis, and purulent meningitis, to provide scientific evidence for early monitoring, diagnosis, and treatment of neonatal infections.
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Affiliation(s)
- Ziheng Li
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, China
| | - Tianming Yuan
- Department of Neonatology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang, China
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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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Cao D, Qian K, Yang N, Xu G, Wang X, Zhu M, Wang Y, Li H, Shen J, Zhang Y, Cui Z. Thymopentin ameliorates experimental colitis via inhibiting neutrophil extracellular traps. Int Immunopharmacol 2023; 124:110898. [PMID: 37696141 DOI: 10.1016/j.intimp.2023.110898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 07/30/2023] [Accepted: 09/01/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND The long-term prognosis of Crohn's disease (CD) remains unsatisfactory. Therefore, we assessed the therapeutic effect of thymopentin (TP5) in a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, which mimics CD, and analyzed its impact on neutrophil extracellular traps (NETs). METHODS NET markers, including myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (CitH3), peptidyl arginine deiminase IV (PAD4), and double-stranded DNA (dsDNA) were assessed by immunostaining and enzyme-linked immunosorbent assay. NET formation was evaluated in vitro. Neoseptin 3, a specific NET agonist, was used to reverse the effect of TP5 on TNBS-induced colitis. The action mechanism of TP5 was investigated using RNA-seq. RESULTS TP5 ameliorated weight loss (P < 0.001), disease activity index (DAI) (P = 0.05), colon shrinkage (P = 0.04), and elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and neutrophils in the TNBS group. The TNBS group exhibited increased MPO, NE, CitH3, PAD4, dsDNA and MPO-DNA levels (all P < 0.001), which decreased after TP5 administration (P = 0.01, P < 0.001, P < 0.001, P < 0.001, P = 0.02, and P = 0.02 respectively). Tissue CitH3 levels were positively correlated with DAI and TNF-α levels (P < 0.05). Furthermore, phorbol 12-myristate 13-acetate-stimulated NET formation increased by 1.8-, 2.8-, and 2.3-fold in vitro in the control, TNBS + saline, and TNBS + TP5 groups, respectively. Neoseptin 3 significantly reversed the effect of TP5. RNA-seq revealed potential pathways underlying the effect of TP5. CONCLUSION TP5 effectively ameliorated colitis by suppressing NETs in the experimental CD model.
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Affiliation(s)
- Dongxing Cao
- Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China; Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Keyu Qian
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China.
| | - Nailin Yang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Gang Xu
- Laboratory Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China.
| | - Xiaohui Wang
- Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China.
| | - Mingming Zhu
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Yangyang Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
| | - Han Li
- Department of Otolaryngology, Eye Ear Nose and Throat Hospital of Fudan University, Shanghai 200031, China.
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China.
| | - Ye Zhang
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China.
| | - Zhe Cui
- Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China; Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
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Zhang D, Duan S, He Z, Zhu Z, Li Z, Yi Q, Cai T, Li J, Chen N, Guo S. Sijunzi Decoction Targets IL1B and TNF to Reduce Neutrophil Extracellular Traps (NETs) in Ulcerative Colitis: Evidence from Silicon Prediction and Experiment Validation. Drug Des Devel Ther 2023; 17:3103-3128. [PMID: 37868820 PMCID: PMC10590142 DOI: 10.2147/dddt.s428814] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/07/2023] [Indexed: 10/24/2023] Open
Abstract
Purpose This study was conducted to explore the mechanism of Sijunzi Decoction (SJZ) in the treatment of ulcerative colitis (UC). Methods The study aimed to investigate the active components and targets of SJZ in the treatment of UC by screening databases such as TCMSP, GeneCards, OMIM, Distinct, TTD, and Drugbank. An online Venn tool, Cytoscape 3.7.2, and Autodock Tools were used to analyze the components and targets. The study also used a mouse model of UC to further investigate the effects of SJZ. HE staining, immunofluorescence, ELISA, qPCR, and Western blot were used to detect various indices. Results Eighty-three active components and 112 action targets were identified from SJZ, including 67 targets for treating UC-related NETs. The five core targets identified were AKT1, JUN, IL1B, PTGS2, and TNF, and molecular docking studies indicated that the five targets were well-docked with ginsenoside Rh2, isoflavones, and formononetin. Animal experiments demonstrated that SJZ could alleviate various parameters such as weight, colon length, spleen index, disease activity index, and intestinal pathology of the UC mice. Immunofluorescence and Western blot showed that SJZ could reduce the expression of IL1B and TNF in intestinal neutrophils while increasing the expression of Occludin. Cellular immunofluorescence suggests that SJZ can reduce the expression of TNF and IL1B in NETs. The qPCR results also suggested that SJZ could inhibit TNF signal. Furthermore, ELISA results suggested that SJZ could inhibit the expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) while promoting the expression of anti-inflammatory cytokines (IL-10, IL-37, TGF-β). Conclusion SJZ treats UC by reducing the content of intestinal NETs, with primary targets on the NETs being IL1B and TNFand suppress TNF signal. The practical components of SJZ may be ginsenoside Rh2, isoflavones, and formononetin.
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Affiliation(s)
- Dong Zhang
- Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China
| | - Siwei Duan
- Institute of Gastroenterology, Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Zhangyou He
- Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Zeming Zhu
- Institute of Gastroenterology, Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Zhiping Li
- Institute of Gastroenterology, Science and Technology Innovation Center of Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Qincheng Yi
- Institute of Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China
| | - Tiantian Cai
- Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China
| | - Juanjuan Li
- Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China
| | - Nan Chen
- Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China
| | - Shaoju Guo
- Gastrointestinal Ward, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, People’s Republic of China
- Gastrointestinal Ward, Shenzhen Hospital of Traditional Chinese Medicine, Shenzhen, People’s Republic of China
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Lai HJ, Doan HT, Lin EY, Chiu YL, Cheng YK, Lin YH, Chiang HS. Histones of Neutrophil Extracellular Traps Directly Disrupt the Permeability and Integrity of the Intestinal Epithelial Barrier. Inflamm Bowel Dis 2023; 29:783-797. [PMID: 36617175 DOI: 10.1093/ibd/izac256] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Indexed: 01/09/2023]
Abstract
BACKGROUND Increased neutrophil extracellular trap (NET) formation and abundant NET-associated proteins are frequently found in the inflamed colon of patients with inflammatory bowel disease. Peptidyl arginine deiminase 4 (PAD4) activation is essential for the generation of NET and NET-mediated pathogenesis. However, the role of PAD4-dependent NET formation in murine inflammatory bowel disease models and the molecular mechanisms responsible for the altered gut barrier function are unknown. METHODS Wild-type and Pad4 knockout (Pad4-/-) mice were administrated 3% dextran sulfate sodium (DSS) in their drinking water. Caco-2 monolayers were used to test the effect of NETs on intestinal barrier function and cytotoxicity. Histones were intrarectally administrated to wild-type mice to determine their effects on intestinal barrier function and cytotoxicity in vivo. RESULTS PAD4 deficiency reduced the severity of DSS-induced colitis with decreased intestinal NET formation and enhanced gut barrier function and integrity in mice. NETs disrupted the barrier function in intestinal epithelial Caco-2 monolayers through their protein, rather than DNA, components. Pretreatment of NETs with histone inhibitors abrogated the effects on epithelial permeability. Consistent with these observations, adding purified histone proteins to Caco-2 monolayers significantly damaged epithelial barrier function, which was associated with the abnormal distribution and integrity of tight junctions as well as with increased cell death. Furthermore, intrarectal administration of histones damaged the intestinal barrier integrity and induced cytotoxicity in the mouse colon epithelium. CONCLUSIONS PAD4-mediated NET formation has a detrimental role in acute colitis. NET-associated histones directly inhibit intestinal barrier function, resulting in cytotoxicity in vitro and in vivo.
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Affiliation(s)
- Hsuan-Ju Lai
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Ha T Doan
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Elliot Y Lin
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yi-Ling Chiu
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yuan-Kai Cheng
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yi-He Lin
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Hao-Sen Chiang
- Department of Life Science, National Taiwan University, Taipei, Taiwan.,Genome and Systems Biology Degree Program, National Taiwan University, Taipei, Taiwan
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11
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Song YH, Wang ZJ, Kang L, He ZX, Zhao SB, Fang X, Li ZS, Wang SL, Bai Y. PADs and NETs in digestive system: From physiology to pathology. Front Immunol 2023; 14:1077041. [PMID: 36761761 PMCID: PMC9902375 DOI: 10.3389/fimmu.2023.1077041] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Peptidylarginine deiminases (PADs) are the only enzyme class known to deiminate arginine residues into citrulline in proteins, a process known as citrullination. This is an important post-translational modification that functions in several physiological and pathological processes. Neutrophil extracellular traps (NETs) are generated by NETosis, a novel cell death in neutrophils and a double-edged sword in inflammation. Excessive activation of PADs and NETs is critically implicated in their transformation from a physiological to a pathological state. Herein, we review the physiological and pathological functions of PADs and NETs, in particular, the involvement of PAD2 and PAD4 in the digestive system, from inflammatory to oncological diseases, along with related therapeutic prospects.
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Affiliation(s)
- Yi-Hang Song
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhi-Jie Wang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Le Kang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zi-Xuan He
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Sheng-Bing Zhao
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xue Fang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
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12
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Citrullination: A modification important in the pathogenesis of autoimmune diseases. Clin Immunol 2022; 245:109134. [DOI: 10.1016/j.clim.2022.109134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/13/2022] [Accepted: 09/19/2022] [Indexed: 11/18/2022]
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13
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Huang J, Hong W, Wan M, Zheng L. Molecular mechanisms and therapeutic target of NETosis in diseases. MedComm (Beijing) 2022; 3:e162. [PMID: 36000086 PMCID: PMC9390875 DOI: 10.1002/mco2.162] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 07/03/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Evidence shows that neutrophils can protect the host against pathogens in multiple ways, including the formation and release of neutrophil extracellular traps (NETs). NETs are web-like structures composed of fibers, DNA, histones, and various neutrophil granule proteins. NETs can capture and kill pathogens, including bacteria, viruses, fungi, and protozoa. The process of NET formation is called NETosis. According to whether they depend on nicotinamide adenine dinucleotide phosphate (NADPH), NETosis can be divided into two categories: "suicidal" NETosis and "vital" NETosis. However, NET components, including neutrophil elastase, myeloperoxidase, and cell-free DNA, cause a proinflammatory response and potentially severe diseases. Compelling evidence indicates a link between NETs and the pathogenesis of a number of diseases, including sepsis, systemic lupus erythematosus, rheumatoid arthritis, small-vessel vasculitis, inflammatory bowel disease, cancer, COVID-19, and others. Therefore, targeting the process and products of NETosis is critical for treating diseases linked with NETosis. Researchers have discovered that several NET inhibitors, such as toll-like receptor inhibitors and reactive oxygen species scavengers, can prevent uncontrolled NET development. This review summarizes the mechanism of NETosis, the receptors associated with NETosis, the pathology of NETosis-induced diseases, and NETosis-targeted therapy.
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Affiliation(s)
- Jiayu Huang
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug TargetState Key Laboratory of BiotherapyNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengduChina
| | - Meihua Wan
- Department of Integrated Traditional Chinese and Western MedicineWest China HospitalSichuan UniversityChengduSichuanChina
| | - Limin Zheng
- Guangdong Province Key Laboratory of Pharmaceutical Functional GenesMOE Key Laboratory of Gene Function and RegulationSchool of Life SciencesSun Yat‐Sen UniversityGuangzhouChina
- State Key Laboratory of Oncology in Southern ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐Sen University Cancer CenterGuangzhouChina
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14
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Schroder AL, Chami B, Liu Y, Doyle CM, El Kazzi M, Ahlenstiel G, Ahmad G, Pathma-Nathan N, Collins G, Toh J, Harman A, Byrne S, Ctercteko G, Witting PK. Neutrophil Extracellular Trap Density Increases With Increasing Histopathological Severity of Crohn's Disease. Inflamm Bowel Dis 2022; 28:586-598. [PMID: 34724042 PMCID: PMC9036391 DOI: 10.1093/ibd/izab239] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Indexed: 12/30/2022]
Abstract
BACKGROUND Intestinal neutrophil recruitment is a characteristic feature of the earliest stages of inflammatory bowel disease (IBD). Neutrophil elastase (NE) and myeloperoxidase (MPO) mediate the formation of neutrophil extracellular traps (NETs); NETs produce the bactericidal oxidant hypochlorous acid (HOCl), causing host tissue damage when unregulated. The project aim was to investigate the relationship between NET formation and clinical IBD in humans. METHODS Human intestinal biopsies were collected from Crohn's disease (CD) patients, endoscopically categorized as unaffected, transitional, or diseased, and assigned a histopathological score. RESULTS A significant linear correlation was identified between pathological score and cell viability (TUNEL+). Immunohistochemical analysis revealed the presence of NET markers NE, MPO, and citrullinated histone (CitH3) that increased significantly with increasing histopathological score. Diseased specimens showed greater MPO+-immunostaining than control (P < .0001) and unaffected CD (P < .0001), with transitional CD specimens also showing greater staining than controls (P < .05) and unaffected CD (P < .05). Similarly, NE+-immunostaining was elevated significantly in diseased CD than controls (P < .0001) and unaffected CD (P < .0001) and was significantly higher in transitional CD than in controls (P < .0001) and unaffected CD (P < .0001). The CitH3+-immunostaining of diseased CD was significantly higher than controls (P < .05), unaffected CD (P < .0001) and transitional CD (P < .05), with transitional CD specimens showing greater staining than unaffected CD (P < .01). Multiplex immunohistochemistry with z-stacking revealed colocalization of NE, MPO, CitH3, and DAPI (cell nuclei), confirming the NET assignment. CONCLUSION These data indicate an association between increased NET formation and CD severity, potentially due to excessive MPO-mediated HOCl production in the extracellular domain, causing host tissue damage that exacerbates CD.
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Affiliation(s)
- Angie L Schroder
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Belal Chami
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Yuyang Liu
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Chloe M Doyle
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
| | - Mary El Kazzi
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Golo Ahlenstiel
- Western Sydney University, Westmead Clinical School and The Westmead Institute for Medical Research, Blacktown Hospital, Blacktown, NSW, Australia
| | - Gulfam Ahmad
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
| | - Nimalan Pathma-Nathan
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW,Australia
| | - Geoff Collins
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW,Australia
| | - James Toh
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW,Australia
- Department of Colorectal Surgery, Westmead Hospital, NSW,Australia
| | - Andrew Harman
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
| | - Scott Byrne
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
| | - Grahame Ctercteko
- Westmead Institute for Medical Research, Centre for Immunology and Allergy Research, Westmead, NSW, Australia
- Centre for Virus Research, The Westmead Institute for Medical Research, Westmead, NSW,Australia
- Department of Colorectal Surgery, Westmead Hospital, NSW,Australia
| | - Paul K Witting
- The University of Sydney, School of Medical Sciences, Faculty of Medicine and Health, NSW, Australia
- Charles Perkins Centre, The University of Sydney, NSW, Australia
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15
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Maronek M, Gardlik R. The Citrullination-Neutrophil Extracellular Trap Axis in Chronic Diseases. J Innate Immun 2022; 14:393-417. [PMID: 35263752 PMCID: PMC9485962 DOI: 10.1159/000522331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 01/25/2022] [Indexed: 11/19/2022] Open
Abstract
Citrullination of proteins is crucial for the formation of neutrophil extracellular traps (NETs) − strands of nuclear DNA expulsed in the extracellular environment along with antimicrobial proteins in order to halt the spread of pathogens. Paradoxically, NETs may be immunogenic and contribute to inflammation. It is known that for the externalization of DNA, a group of enzymes called peptidyl arginine deiminases (PADs) is required. Current research often looks at citrullination, NET formation, PAD overexpression, and extracellular DNA (ecDNA) accumulation in chronic diseases as separate events. In contrast, we propose that citrullination can be viewed as the primary mechanism of autoimmunity, for instance by the formation of anti-citrullinated protein antibodies (ACPAs) but also as a process contributing to chronic inflammation. Therefore, citrullination could be at the center, connecting and impacting multiple inflammatory diseases in which ACPAs, NETs, or ecDNA have already been documented. In this review, we aimed to highlight the importance of citrullination in the etiopathogenesis of a number of chronic diseases and to explore the diagnostic, prognostic, and therapeutic potential of the citrullination-NET axis.
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Affiliation(s)
- Martin Maronek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Roman Gardlik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University in Bratislava, Bratislava, Slovakia
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16
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Role of NETosis in Central Nervous System Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3235524. [PMID: 35028005 PMCID: PMC8752220 DOI: 10.1155/2022/3235524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 11/18/2021] [Indexed: 11/17/2022]
Abstract
Central nervous system (CNS) injury is divided into brain injury and spinal cord injury and remains the most common cause of morbidity and mortality worldwide. Previous reviews have defined numerous inflammatory cells involved in this process. In the human body, neutrophils comprise the largest numbers of myeloid leukocytes. Activated neutrophils release extracellular web-like DNA amended with antimicrobial proteins called neutrophil extracellular traps (NETs). The formation of NETs was demonstrated as a new method of cell death called NETosis. As the first line of defence against injury, neutrophils mediate a variety of adverse reactions in the early stage, and we consider that NETs may be the prominent mediators of CNS injury. Therefore, exploring the specific role of NETs in CNS injury may help us shed some light on early changes in the disease. Simultaneously, we discovered that there is a link between NETosis and other cell death pathways by browsing other research, which is helpful for us to establish crossroads between known cell death pathways. Currently, there is a large amount of research concerning NETosis in various diseases, but the role of NETosis in CNS injury remains unknown. Therefore, this review will introduce the role of NETosis in CNS injury, including traumatic brain injury, cerebral ischaemia, CNS infection, Alzheimer's disease, and spinal cord injury, by describing the mechanism of NETosis, the evidence of NETosis in CNS injury, and the link between NETosis and other cell death pathways. Furthermore, we also discuss some agents that inhibit NETosis as therapies to alleviate the severity of CNS injury. NETosis may be a potential target for the treatment of CNS injury, so exploring NETosis provides a feasible therapeutic option for CNS injury in the future.
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17
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Therapeutic Targeting of Intestinal Fibrosis in Crohn's Disease. Cells 2022; 11:cells11030429. [PMID: 35159238 PMCID: PMC8834168 DOI: 10.3390/cells11030429] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Intestinal fibrosis is one of the most threatening complications of Crohn’s disease. It occurs in more than a third of patients with this condition, is associated with increased morbidity and mortality, and surgery often represents the only available therapeutic option. The mechanisms underlying intestinal fibrosis are partly known. Studies conducted so far have shown a relevant pathogenetic role played by mesenchymal cells (especially myofibroblasts), cytokines (e.g., transforming growth factor-β), growth factors, microRNAs, intestinal microbiome, matrix stiffness, and mesenteric adipocytes. Further studies are still necessary to elucidate all the mechanisms involved in intestinal fibrosis, so that targeted therapies can be developed. Although several pre-clinical studies have been conducted so far, no anti-fibrotic therapy is yet available to prevent or reverse intestinal fibrosis. The aim of this review is to provide an overview of the main therapeutic targets currently identified and the most promising anti-fibrotic therapies, which may be available in the near future.
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18
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Chen Y, Han L, Qiu X, Wang G, Zheng J. Neutrophil Extracellular Traps in Digestive Cancers: Warrior or Accomplice. Front Oncol 2021; 11:766636. [PMID: 34868992 PMCID: PMC8639597 DOI: 10.3389/fonc.2021.766636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/03/2021] [Indexed: 12/24/2022] Open
Abstract
Characterized as a complex of extracellular DNA fibers and granule proteins, neutrophil extracellular traps (NETs) are generated specifically by neutrophils which play a critical role in host defense and immune regulation. NETs have been initially found crucial for neutrophil anti-microbial function. Recent studies suggest that NETs are involved in tumorigenesis and cancer progression. However, the function of NETs in cancer remains unclear, which might be due to the variation of research models and the heterogeneity of cancers. Although most of malignant tumors have similar biological behaviors, significant differences indeed exist in various systems. Malignant tumors of the digestive system cause the most incidence and mortality of cancer worldwide. In this review, we would focus on research developments on NETs in digestive cancers to provide insights on their role in digestive cancer progression and future research directions.
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Affiliation(s)
- Yuxin Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Lulu Han
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiaoyan Qiu
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Junnian Zheng
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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19
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Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5541222. [PMID: 34712384 PMCID: PMC8548149 DOI: 10.1155/2021/5541222] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 07/04/2021] [Accepted: 09/29/2021] [Indexed: 12/26/2022]
Abstract
Many gut disease etiologies are attributed to the presence of robust inflammatory cell recruitment. The recruitment of neutrophils plays a vital role in inflammatory infiltration. Neutrophils have various antimicrobial effector mechanisms, including phagocytosis, oxidative burst, and degranulation. It is suggested that neutrophils could release neutrophil extracellular traps (NETs) to kill pathogens. However, recent evidence indicates that neutrophil infiltration within the gut is associated with disrupted local immunological microenvironment and impaired epithelial barrier. Growing evidence implies that NETs are involved in the progression of many diseases, including cancer, diabetes, thrombosis, and autoimmune disease. Increased NET formation was found in acute or chronic conditions, including infection, sterile inflammation, cancer, and ischemia/reperfusion injury (IRI). Here, we present a comprehensive review of recent advances in the understanding of NETs, focusing on their effects in gut disease. We also discuss NETs as a potential therapeutic target in gut disease.
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20
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Mutua V, Gershwin LJ. A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clin Rev Allergy Immunol 2021; 61:194-211. [PMID: 32740860 PMCID: PMC7395212 DOI: 10.1007/s12016-020-08804-7] [Citation(s) in RCA: 334] [Impact Index Per Article: 83.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Activated neutrophils release neutrophil extracellular traps (NETs) in response to a variety of stimuli. NETosis is driven by protein-arginine deiminase type 4, with the release of intracellular granule components that function by capturing and destroying microbes, including viral, fungal, bacterial, and protozoal pathogens. The positive effects of pathogen control are countered by pro-inflammatory effects as demonstrated in a variety of diseases. Components of NETS are non-specific, and other than controlling microbes, they cause injury to surrounding tissue by themselves or by increasing the pro-inflammatory response. NETs can play a role in enhancement of the inflammation seen in autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosis. In addition, autoinflammatory diseases such as gout have been associated with NETosis. Inhibition of NETs may decrease the severity of many diseases improving survival. Herein, we describe NETosis in different diseases focusing on the detrimental effect of NETs and outline possible therapeutics that can be used to mitigate netosis. There is a need for more studies and clinical trials on these and other compounds that could prevent or destroy NETs, thereby decreasing damage to patients.
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Affiliation(s)
- Victoria Mutua
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA.
| | - Laurel J Gershwin
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA
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21
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Bettiol A, Becatti M, Silvestri E, Argento FR, Fini E, Mannucci A, Galora S, Mattioli I, Urban ML, Malandrino D, Palermo A, Taddei N, Emmi G, Prisco D, Fiorillo C. Neutrophil-mediated mechanisms of damage and in-vitro protective effect of colchicine in non-vascular Behçet's syndrome. Clin Exp Immunol 2021; 206:410-421. [PMID: 34562315 PMCID: PMC8561698 DOI: 10.1111/cei.13664] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/17/2021] [Accepted: 09/22/2021] [Indexed: 12/11/2022] Open
Abstract
Behçet’s syndrome (BS) is a systemic vasculitis with several clinical manifestations. Neutrophil hyperactivation mediates vascular BS pathogenesis, via both a massive reactive oxygen species (ROS) production and neutrophil extracellular traps (NETs) release. Here, we investigated neutrophil‐mediated mechanisms of damage in non‐vascular BS manifestations and explored the in‐vitro effects of colchicine in counteracting these mechanisms. NETs and intracellular ROS production was assessed in blood samples from 80 BS patients (46 with active non‐vascular BS, 34 with inactive disease) and 80 healthy controls. Moreover, isolated neutrophils were incubated for 1 h with an oxidating agent [2,2′‐azobis (2‐amidinopropane) dihydrochloride; 250 nM] and the ability of pure colchicine pretreatment (100 ng/ml) to counteract oxidation‐induced damage was assessed. Patients with active non‐vascular BS showed remarkably increased NET levels [21.2, interquartile range (IQR) = 18.3–25.9 mU/ml] compared to patients with inactive disease (16.8, IQR = 13.3–20.2 mU/ml) and to controls (7.1, IQR = 5.1–8.7 mU/ml, p < 0.001]. Also, intracellular ROS tended to increase in active BS, although not significantly. In active non‐vascular BS, NETs correlated with neutrophil ROS production (p < 0.001) and were particularly increased in patients with active mucosal (p < 0.001), articular (p = 0.004) and gastrointestinal symptoms (p = 0.006). In isolated neutrophils, colchicine significantly reduced oxidation‐induced NET production and cell apoptosis, although not via an anti‐oxidant activity. Neutrophil‐mediated mechanisms might be directly involved in non‐vascular BS, and NETs, more than ROS, might drive the pathogenesis of mucosal, articular and intestinal manifestations. Colchicine might be effective in counteracting neutrophils‐mediated damage in BS, although further studies are needed.
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Affiliation(s)
- Alessandra Bettiol
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Elena Silvestri
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Flavia Rita Argento
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Eleonora Fini
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Amanda Mannucci
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Silvia Galora
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Irene Mattioli
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Maria Letizia Urban
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Danilo Malandrino
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Adalgisa Palermo
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
| | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Domenico Prisco
- Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
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22
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Shao BZ, Yao Y, Li JP, Chai NL, Linghu EQ. The Role of Neutrophil Extracellular Traps in Cancer. Front Oncol 2021; 11:714357. [PMID: 34476216 PMCID: PMC8406742 DOI: 10.3389/fonc.2021.714357] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
Neutrophils are vital components of innate and adaptive immunity. It is widely acknowledged that in various pathological conditions, neutrophils are activated and release condensed DNA strands, triggering the formation of neutrophil extracellular traps (NETs). NETs have been shown to be effective in fighting against microbial infections and modulating the pathogenesis and progression of diseases, including malignant tumors. This review describes the current knowledge on the biological characteristics of NETs. Additionally, the mechanisms of NETs in cancer are discussed, including the involvement of signaling pathways and the crosstalk between other cancer-related mechanisms, including inflammasomes and autophagy. Finally, based on previous and current studies, the roles of NET formation and the potential therapeutic targets and strategies related to NETs in several well-studied types of cancers, including breast, lung, colorectal, pancreatic, blood, neurological, and cutaneous cancers, are separately reviewed and discussed.
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Affiliation(s)
| | | | | | - Ning-Li Chai
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - En-Qiang Linghu
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
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23
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Effects of Fluorine on Neutrophil Extracellular Trap Formation through Regulating AMPK/p38 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6693921. [PMID: 34394830 PMCID: PMC8355961 DOI: 10.1155/2021/6693921] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 06/29/2021] [Indexed: 01/02/2023]
Abstract
Fluorine is an important trace element that is widely dispersed, and studies showed that fluorine could cause severe toxicity to fish. The aim of this study was to investigate the effects of fluorine on neutrophil extracellular trap (NET) formation in common carp and clarify the possible mechanism. The neutrophils were isolated and exposed to 0.25, 0.5, or 1 mM sodium fluoride (NaF). The results showed that NaF could induce the formation of NETs which exhibited a DNA-based network structure modified with histones and myeloperoxidase (MPO). Furthermore, NaF led to the production of reactive oxygen species (ROS) in neutrophils. Western blot results showed that NaF significantly increased the phosphorylation of AMPK and p38. In addition, our results showed that NaF-induced NET formation could be inhibited by an AMPK or p38 inhibitor. In conclusion, our results showed that NaF induced NET formation in neutrophils through regulation of the AMPK/p38 signaling pathway.
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Dos Santos Ramos A, Viana GCS, de Macedo Brigido M, Almeida JF. Neutrophil extracellular traps in inflammatory bowel diseases: Implications in pathogenesis and therapeutic targets. Pharmacol Res 2021; 171:105779. [PMID: 34298111 DOI: 10.1016/j.phrs.2021.105779] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 07/04/2021] [Accepted: 07/19/2021] [Indexed: 02/07/2023]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the two main forms of inflammatory bowel disease (IBD). Among the various immune cells involved in IBD, neutrophils are the first to infiltrate and appear to contribute to the impairment of the epithelial barrier, destruction of tissues by oxidative and proteolytic damage, as well as to the perpetuation of inflammation by the release of cytokines and chemokines associated with pro-inflammatory effects. In addition to basic effector mechanisms, such as phagocytosis and chemotaxis, neutrophils can also form extracellular traps (NETs), which is made up of a mesh-like structure - which contains its chromatin (DNA + histones) together with granules and enzymes, such as myeloperoxidase (MPO) and neutrophilic elastase (NE) - and that acts as a trap that can result in the death of extracellular pathogens and/or can promote tissue damage. Recent evidence indicates that NETs also play an important and significant role in the pathogenesis of IBD. Previous studies have reported increased levels of NETs in tissue and serum samples from patients with IBD, as well as in experimental colitis. In this review, we discuss current knowledge about the formation of NETs and their role in the pathophysiology of IBD, pointing out potential mechanisms by which NETs promote tissue damage, as well as their involvement in complications associated with IBD. In addition, we propose potential targets for therapy to regulate the production of NETs, making it possible to expand the current spectrum of therapies for IBD.
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Affiliation(s)
- Anderson Dos Santos Ramos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
| | | | | | - Juliana Franco Almeida
- Department of Cellular Biology, University of Brasilia, Brasilia, Brazil; Department of Cellular and Molecular Biology, Federal University of Paraíba, Paraíba, Brazil.
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25
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Khan U, Chowdhury S, Billah MM, Islam KMD, Thorlacius H, Rahman M. Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis. Int J Mol Sci 2021; 22:ijms22147260. [PMID: 34298878 PMCID: PMC8307027 DOI: 10.3390/ijms22147260] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/24/2022] Open
Abstract
Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.
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Affiliation(s)
- Umama Khan
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Sabrina Chowdhury
- Biochemistry and Biotechnology, North South University, Dhaka 1229, Bangladesh;
| | - Md Morsaline Billah
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Kazi Mohammed Didarul Islam
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Henrik Thorlacius
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 214 28 Malmö, Sweden;
| | - Milladur Rahman
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 214 28 Malmö, Sweden;
- Correspondence:
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26
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Chirivi RGS, van Rosmalen JWG, van der Linden M, Euler M, Schmets G, Bogatkevich G, Kambas K, Hahn J, Braster Q, Soehnlein O, Hoffmann MH, Es HHGV, Raats JMH. Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases. Cell Mol Immunol 2021; 18:1528-1544. [PMID: 32203195 PMCID: PMC8166830 DOI: 10.1038/s41423-020-0381-3] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 02/10/2020] [Indexed: 12/21/2022] Open
Abstract
Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.
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Affiliation(s)
- Renato G S Chirivi
- ModiQuest B.V., Oss, The Netherlands.
- Citryll B.V., Oss, The Netherlands.
| | | | | | - Maximilien Euler
- Department of Internal Medicine 3 - Rheumatology and Immunology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | | | - Galina Bogatkevich
- Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Konstantinos Kambas
- Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupoli, Greece
| | - Jonas Hahn
- Department of Internal Medicine 3 - Rheumatology and Immunology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
| | - Quinte Braster
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
| | - Oliver Soehnlein
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Markus H Hoffmann
- Department of Internal Medicine 3 - Rheumatology and Immunology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany
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27
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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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28
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Ding J, Hostallero DE, El Khili MR, Fonseca GJ, Milette S, Noorah N, Guay-Belzile M, Spicer J, Daneshtalab N, Sirois M, Tremblay K, Emad A, Rousseau S. A network-informed analysis of SARS-CoV-2 and hemophagocytic lymphohistiocytosis genes' interactions points to Neutrophil extracellular traps as mediators of thrombosis in COVID-19. PLoS Comput Biol 2021; 17:e1008810. [PMID: 33684134 PMCID: PMC7971900 DOI: 10.1371/journal.pcbi.1008810] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 03/18/2021] [Accepted: 02/17/2021] [Indexed: 01/10/2023] Open
Abstract
Abnormal coagulation and an increased risk of thrombosis are features of severe COVID-19, with parallels proposed with hemophagocytic lymphohistiocytosis (HLH), a life-threating condition associated with hyperinflammation. The presence of HLH was described in severely ill patients during the H1N1 influenza epidemic, presenting with pulmonary vascular thrombosis. We tested the hypothesis that genes causing primary HLH regulate pathways linking pulmonary thromboembolism to the presence of SARS-CoV-2 using novel network-informed computational algorithms. This approach led to the identification of Neutrophils Extracellular Traps (NETs) as plausible mediators of vascular thrombosis in severe COVID-19 in children and adults. Taken together, the network-informed analysis led us to propose the following model: the release of NETs in response to inflammatory signals acting in concert with SARS-CoV-2 damage the endothelium and direct platelet-activation promoting abnormal coagulation leading to serious complications of COVID-19. The underlying hypothesis is that genetic and/or environmental conditions that favor the release of NETs may predispose individuals to thrombotic complications of COVID-19 due to an increase risk of abnormal coagulation. This would be a common pathogenic mechanism in conditions including autoimmune/infectious diseases, hematologic and metabolic disorders.
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Affiliation(s)
- Jun Ding
- Computational Biology Department, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America
- The Meakins-Christie Laboratories at the Research Institute of the McGill University Heath Centre Research Institute, Montréal, Canada
| | - David Earl Hostallero
- Department of Electrical and Computer Engineering, McGill University, Montréal, Canada
| | - Mohamed Reda El Khili
- Department of Electrical and Computer Engineering, McGill University, Montréal, Canada
| | - Gregory Joseph Fonseca
- The Meakins-Christie Laboratories at the Research Institute of the McGill University Heath Centre Research Institute, Montréal, Canada
| | - Simon Milette
- Goodman Cancer Research Centre, McGill University, Montréal, Canada
| | - Nuzha Noorah
- The Meakins-Christie Laboratories at the Research Institute of the McGill University Heath Centre Research Institute, Montréal, Canada
| | - Myriam Guay-Belzile
- The Meakins-Christie Laboratories at the Research Institute of the McGill University Heath Centre Research Institute, Montréal, Canada
| | - Jonathan Spicer
- Division of Thoracic and Upper Gastrointestinal Surgery, McGill University Health Centre Research Institute, Montréal, Canada
| | - Noriko Daneshtalab
- School of Pharmacy, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada
| | - Martin Sirois
- Montreal Heart Institute and Department of pharmacology and physiology, Faculty of medicine, Université de Montréal, Montréal, Canada
| | - Karine Tremblay
- Pharmacology-physiology Department, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Centre intégré universitaire de santé et de services sociaux du Saguenay-Lac-Saint-Jean (Chicoutimi University Hospital) Research Center, Saguenay, Canada
| | - Amin Emad
- Department of Electrical and Computer Engineering, McGill University, Montréal, Canada
| | - Simon Rousseau
- The Meakins-Christie Laboratories at the Research Institute of the McGill University Heath Centre Research Institute, Montréal, Canada
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29
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Dragoni G, De Hertogh G, Vermeire S. The Role of Citrullination in Inflammatory Bowel Disease: A Neglected Player in Triggering Inflammation and Fibrosis? Inflamm Bowel Dis 2021; 27:134-144. [PMID: 32426830 DOI: 10.1093/ibd/izaa095] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Indexed: 02/07/2023]
Abstract
Citrullination is a posttranslational modification of proteins mediated by a specific family of enzymes called peptidylarginine deiminases (PAD). Dysregulation of these enzymes is involved in the etiology of various diseases, from cancer to autoimmune disorders. In inflammatory bowel disease (IBD), data for a role of citrullination in the disease process are starting to accumulate at different experimental levels including gene expression analyses, RNA, and protein quantifications. Most data have been generated in ulcerative colitis, but data in Crohn disease are lacking so far. In addition, the citrullination of histones is the fundamental process promoting inflammation through the formation of neutrophil extracellular traps (NETs). Interestingly, NETs have also been shown to activate fibroblasts into myofibroblasts in fibrotic interstitial lung disease. Therefore, citrullination merits more thorough study in the bowel to determine its role in driving disease complications such as fibrosis. In this review we describe the process of citrullination and the different players in this pathway, the role of citrullination in autoimmunity with a special focus on IBD, the emerging role for citrullination and NETs in triggering fibrosis, and, finally, how this process could be therapeutically targeted.
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Affiliation(s)
- Gabriele Dragoni
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium.,Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences Mario Serio, University of Florence, Florence, Italy.,Department of Medical Biotechnologies, University of Siena, Italy
| | - Gert De Hertogh
- KU Leuven, Department of Imaging and Pathology, Translational Cell & Tissue Research, Leuven, Belgium
| | - Séverine Vermeire
- KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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30
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Qiu D, Zhang L, Zhan J, Yang Q, Xiong H, Hu W, Ji Q, Huang J. Hyperglycemia Decreases Epithelial Cell Proliferation and Attenuates Neutrophil Activity by Reducing ICAM-1 and LFA-1 Expression Levels. Front Genet 2020; 11:616988. [PMID: 33414814 PMCID: PMC7785031 DOI: 10.3389/fgene.2020.616988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 11/23/2020] [Indexed: 11/17/2022] Open
Abstract
Delayed repair is a serious public health concern for diabetic populations. Intercellular adhesion molecule 1 (ICAM-1) and Lymphocyte function-associated antigen 1 (LFA-1) play important roles in orchestrating the repair process. However, little is known about their effects on endothelial cell (EC) proliferation and neutrophil activity in subjects with hyperglycemia (HG). We cultured ECs and performed a scratch-closure assay to determine the relationship between ICAM-1 and EC proliferation. Specific internally labeled bacteria were used to clarify the effects of ICAM-1 and LFA-1 on neutrophil phagocytosis. Transwell assay and fluorescence-activated cell sorting analysis evaluated the roles of ICAM-1 and LFA-1 in neutrophil recruitment. ICAM-1+/+ and ICAM-1-/- mice were used to confirm the findings in vivo. The results demonstrated that HG decreased the expression of ICAM-1, which lead to the low proliferation of ECs. HG also attenuated neutrophil recruitment and phagocytosis by reducing the expression of ICAM-1 and LFA-1, which were strongly associated with the delayed repair.
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Affiliation(s)
- Dongxu Qiu
- Xiangya Hospital, Central South University, Changsha, China
| | - Lei Zhang
- Xiangya Hospital, Central South University, Changsha, China
| | - Junkun Zhan
- Department of Geriatrics, The Second Hospital of Xiangya, Hunan, China
| | - Qiong Yang
- Department of Geriatrics, The Second Hospital of Xiangya, Hunan, China
| | - Hongliang Xiong
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weitong Hu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Qiao Ji
- The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiabing Huang
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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31
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Boettcher M, Esser M, Trah J, Klohs S, Mokhaberi N, Wenskus J, Trochimiuk M, Appl B, Reinshagen K, Raluy LP, Klinke M. Markers of neutrophil activation and extracellular traps formation are predictive of appendicitis in mice and humans: a pilot study. Sci Rep 2020; 10:18240. [PMID: 33106536 PMCID: PMC7588418 DOI: 10.1038/s41598-020-74370-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 09/25/2020] [Indexed: 12/29/2022] Open
Abstract
Appendicitis is one of the most frequent emergencies in pediatric surgery, yet current biomarkers for diagnosis are unspecific and have low predictive values. As neutrophils and extracellular traps (ETs) are an essential component of the immune defense against bacterial infections, and appendicitis is considered an inflammation reaction of the appendix, we hypothesized that neutrophil activation and NET formation play an essential role in appendicitis development and maintenance. Therefore, this pilot study aimed to establish a murine model of appendicitis and to evaluate ETs markers to diagnose appendicitis in mice and humans. The study used 20 (12 appendicitis- and 8 controls) 6-week old mice which underwent advanced appendicitis induction using a modified caecal ligation puncture procedure. During the study, cell-free DNA, neutrophil elastase (NE), myeloperoxidase (MPO), and citrullinated Histone H3 (H3cit) were assessed. Additionally, samples of 5 children with histologically confirmed appendicitis and 5 matched controls with catarrhal appendicitis, were examined for the same biomarkers. Moreover, NE, MPO, and H3cit were assessed histologically via immunofluorescence in mice and humans. All mice in the appendicitis group developed an advanced form of appendicitis with focal peritonitis. In mice and humans with appendicitis, markers of neutrophil activation and ETs formation (especially cfDNA, NE and H3cit) were significantly elevated in blood and tissue compared to controls. Ultimately, biomarkers correlated extremely well with tissue expression and thus disease severity. It appears that neutrophil activation and possibly NETs contribute to appendicitis development and biomarkers of neutrophil activation and ET formation reflect disease severity and thus could be used as biomarkers for appendicitis. However, large prospective clinical studies are needed to confirm our findings.
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Affiliation(s)
- Michael Boettcher
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany.
| | - Melina Esser
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Julian Trah
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Stefan Klohs
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Nariman Mokhaberi
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Julia Wenskus
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Madgalena Trochimiuk
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Birgit Appl
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Konrad Reinshagen
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Laia Pagerols Raluy
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
| | - Michaela Klinke
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, UKE Medical School, Martinistrasse 52, 20246, Hamburg, Germany
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32
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Li T, Jiang H, Liu H, Cooper DKC, Wang Y. Extracellular histones and xenotransplantation. Xenotransplantation 2020; 27:e12618. [PMID: 32940936 DOI: 10.1111/xen.12618] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/24/2020] [Accepted: 05/15/2020] [Indexed: 12/14/2022]
Affiliation(s)
- Tao Li
- Department of Organ Transplantation The Second Affiliated Hospital of Hainan Medical University Haikou Hainan China
- The Transplantation Insititute of Hainan Medical University Haikou Hainan China
| | - Hongtao Jiang
- Department of Organ Transplantation The Second Affiliated Hospital of Hainan Medical University Haikou Hainan China
- The Transplantation Insititute of Hainan Medical University Haikou Hainan China
| | - Houqin Liu
- Department of Organ Transplantation The Second Affiliated Hospital of Hainan Medical University Haikou Hainan China
- The Transplantation Insititute of Hainan Medical University Haikou Hainan China
| | - David K. C. Cooper
- Xenotransplantation Program Department of Surgery University of Alabama at Birmingham Birmingham AL USA
| | - Yi Wang
- Department of Organ Transplantation The Second Affiliated Hospital of Hainan Medical University Haikou Hainan China
- The Transplantation Insititute of Hainan Medical University Haikou Hainan China
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33
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Lin EYH, Lai HJ, Cheng YK, Leong KQ, Cheng LC, Chou YC, Peng YC, Hsu YH, Chiang HS. Neutrophil Extracellular Traps Impair Intestinal Barrier Function during Experimental Colitis. Biomedicines 2020; 8:biomedicines8080275. [PMID: 32764411 PMCID: PMC7459452 DOI: 10.3390/biomedicines8080275] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/21/2020] [Accepted: 07/30/2020] [Indexed: 12/19/2022] Open
Abstract
Aberrant neutrophil extracellular trap (NET) formation and the loss of barrier integrity in inflamed intestinal tissues have long been associated with inflammatory bowel disease (IBD). However, whether NETs alter intestinal epithelium permeability during colitis remains elusive. Here, we demonstrated that NETs promote the breakdown in intestinal barrier function for the pathogenesis of intestinal inflammation in mouse models of colitis. NETs were abundant in the colon of mice with colitis experimentally induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Analysis of the intestinal barrier integrity revealed that NETs impaired gut permeability, enabling the initiation of luminal bacterial translocation and inflammation. Furthermore, NETs induced the apoptosis of epithelial cells and disrupted the integrity of tight junctions and adherens junctions. Intravenous administration of DNase I, an enzyme that dissolves the web-like DNA filaments of NETs, during colitis restored the mucosal barrier integrity which reduced the dissemination of luminal bacteria and attenuated intestinal inflammation in both DSS and TNBS models. We conclude that NETs serve a detrimental factor in the gut epithelial barrier function leading to the pathogenesis of mucosal inflammation during acute colitis.
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Affiliation(s)
- Elliot Yi-Hsin Lin
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Hsuan-Ju Lai
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Yuan-Kai Cheng
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Kai-Quan Leong
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Li-Chieh Cheng
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Yi-Chun Chou
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10617, Taiwan;
| | - Yu-Chun Peng
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Yi-Hsuan Hsu
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
| | - Hao-Sen Chiang
- Department of Life Science, National Taiwan University, Taipei 10617, Taiwan; (E.Y.-H.L.); (H.-J.L.); (Y.-K.C.); (K.-Q.L.); (L.-C.C.); (Y.-C.P.); (Y.-H.H.)
- Genome and Systems Biology Degree Program, National Taiwan University, Taipei 10617, Taiwan;
- Correspondence: ; Tel.: +886-2-3366-2454
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Widbom L, Schneede J, Midttun Ø, Ueland PM, Karling P, Hultdin J. Elevated plasma cotinine is associated with an increased risk of developing IBD, especially among users of combusted tobacco. PLoS One 2020; 15:e0235536. [PMID: 32614903 PMCID: PMC7332008 DOI: 10.1371/journal.pone.0235536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 06/17/2020] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life. DESIGN We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn's disease (CD)) and in sex and age-matched controls (n = 191). RESULTS Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01-1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09-1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users. CONCLUSIONS Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers.
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Affiliation(s)
- Lovisa Widbom
- Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden
- * E-mail:
| | - Jörn Schneede
- Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology, Umeå University, Umeå, Sweden
| | | | - Per Magne Ueland
- Medicine and Pathology, Haukeland University Hospital, Bergen, Norway
| | - Pontus Karling
- Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden
| | - Johan Hultdin
- Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden
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Curciarello R, Sobande T, Jones S, Giuffrida P, Di Sabatino A, Docena GH, MacDonald TT, Kok K. Human Neutrophil Elastase Proteolytic Activity in Ulcerative Colitis Favors the Loss of Function of Therapeutic Monoclonal Antibodies. J Inflamm Res 2020; 13:233-243. [PMID: 32547155 PMCID: PMC7251227 DOI: 10.2147/jir.s234710] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 01/15/2020] [Indexed: 12/14/2022] Open
Abstract
Purpose Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients. Patients and Methods Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNF-neutralizing activity was assessed with a reporter cell line. Results We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin. Conclusion Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.
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Affiliation(s)
- Renata Curciarello
- Instituto de Estudios Inmunológicos y Fisiopatológicos IIFP-CONICET, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina.,Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK
| | - Toni Sobande
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK
| | - Samantha Jones
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK
| | - Paolo Giuffrida
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK.,First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Guillermo H Docena
- Instituto de Estudios Inmunológicos y Fisiopatológicos IIFP-CONICET, Universidad Nacional de La Plata, La Plata, Buenos Aires, Argentina
| | - Thomas T MacDonald
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK
| | - Klaartje Kok
- Centre for Immunobiology, The Blizard Institute, Queen Mary University of London, London, UK.,Barts Health NHS Trust, Royal London Hospital, London, UK
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Cell-Free Nucleic Acids and their Emerging Role in the Pathogenesis and Clinical Management of Inflammatory Bowel Disease. Int J Mol Sci 2019; 20:ijms20153662. [PMID: 31357438 PMCID: PMC6696129 DOI: 10.3390/ijms20153662] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/24/2019] [Accepted: 07/24/2019] [Indexed: 12/12/2022] Open
Abstract
Cell-free nucleic acids (cfNAs) are defined as any nucleic acids that are present outside the cell. They represent valuable biomarkers in various diagnostic protocols such as prenatal diagnostics, the detection of cancer, and cardiovascular or autoimmune diseases. However, in the current literature, little is known about their implication in inflammatory bowel disease (IBD). IBD is a group of multifactorial, autoimmune, and debilitating diseases with increasing incidence worldwide. Despite extensive research, their etiology and exact pathogenesis is still unclear. Since cfNAs were observed in other autoimmune diseases and appear to be relevant in inflammatory processes, their role in the pathogenesis of IBD has also been suggested. This review provides a summary of knowledge from the available literature about cfDNA and cfRNA and the structures involving them such as exosomes and neutrophil extracellular traps and their association with IBD. Current studies showed the promise of cfNAs in the management of IBD not only as biomarkers distinguishing patients from healthy people and differentiating active from inactive disease state, but also as a potential therapeutic target. However, the detailed biological characteristics of cfNAs need to be fully elucidated in future experimental and clinical studies.
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Loktionov A. Eosinophils in the gastrointestinal tract and their role in the pathogenesis of major colorectal disorders. World J Gastroenterol 2019; 25:3503-3526. [PMID: 31367153 PMCID: PMC6658389 DOI: 10.3748/wjg.v25.i27.3503] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 05/22/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023] Open
Abstract
Eosinophils are currently regarded as versatile mobile cells controlling and regulating multiple biological pathways and responses in health and disease. These cells store in their specific granules numerous biologically active substances (cytotoxic cationic proteins, cytokines, growth factors, chemokines, enzymes) ready for rapid release. The human gut is the main destination of eosinophils that are produced and matured in the bone marrow and then transferred to target tissues through the circulation. In health the most important functions of gut-residing eosinophils comprise their participation in the maintenance of the protective mucosal barrier and interactions with other immune cells in providing immunity to microbiota of the gut lumen. Eosinophils are closely involved in the development of inflammatory bowel disease (IBD), when their cytotoxic granule proteins cause damage to host tissues. However, their roles in Crohn's disease and ulcerative colitis appear to follow different immune response patterns. Eosinophils in IBD are especially important in altering the structure and protective functions of the mucosal barrier and modulating massive neutrophil influx to the lamina propria followed by transepithelial migration to colorectal mucus. IBD-associated inflammatory process involving eosinophils then appears to expand to the mucus overlaying the internal gut surface. The author hypothesises that immune responses within colorectal mucus as well as ETosis exerted by both neutrophils and eosinophils on the both sides of the colonic epithelial barrier act as additional pathogenetic factors in IBD. Literature analysis also shows an association between elevated eosinophil levels and better colorectal cancer (CRC) prognosis, but mechanisms behind this effect remain to be elucidated. In conclusion, the author emphasises the importance of investigating colorectal mucus in IBD and CRC patients as a previously unexplored milieu of disease-related inflammatory responses.
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Effect of a Milk-Based Fruit Beverage Enriched with Plant Sterols and/or Galactooligosaccharides in a Murine Chronic Colitis Model. Foods 2019; 8:foods8040114. [PMID: 30987294 PMCID: PMC6517912 DOI: 10.3390/foods8040114] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 03/29/2019] [Accepted: 04/01/2019] [Indexed: 12/12/2022] Open
Abstract
The potential anti-inflammatory effect of plant sterols (PS) enriched milk-based fruit beverages (PS, 1 g/100 mL) (MfB) with/without galactooligosaccharides (GOS, 2 g/100 mL) (MfB-G) in an experimental mice model of chronic ulcerative colitis was evaluated. Beverages were orally administered to mice every day by gavage to achieve PS and GOS doses of 35 and 90 mg/kg, respectively, and experimental colitis was induced by giving mice drinking water ad libitum containing 2% (w/v) dextran sulphate sodium (DSS) for 7 days, alternating with periods without DSS up to the end of the study (56 days). MfB beverage showed significant reduction of symptoms associated to ulcerative colitis and improved the colon shortening and mucosal colonic damage, but it was not able to reduce the increase of myeloperoxidase levels produced by DSS. MfB-G showed higher incidence of bloody feces and loss of stool consistency than MfB, as well as high levels of immune cells infiltration in colon tissue and myeloperoxidase. Therefore, PS-enriched milk-based fruit beverage could be an interesting healthy food to extend the remission periods of the diseases and the need to evaluate, in a pre-clinical model, the anti-inflammatory effect of the combination of bioactive compounds in the context of a whole food matrix.
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