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Dong J, Zhao J, Wu Z, Liu J, Wang B, Qi X. The Predictive Value of Neutrophil Extracellular Trap-Related Risk Score in Prognosis and Immune Microenvironment of Colorectal Cancer Patients. Mol Biotechnol 2025; 67:1509-1525. [PMID: 38580851 DOI: 10.1007/s12033-024-01135-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 02/23/2024] [Indexed: 04/07/2024]
Abstract
Colorectal cancer (CRC) has brought great healthy burden for patients. Neutrophil extracellular traps (NETs) have been explored in several tumors, while it remains largely unclear in CRC. CRC-related data were downloaded from Cancer Genome Atlas and Gene Expression Omnibus databases. Then, a NET risk score was built after univariate Cox and LASSO Cox regression analysis. Prognostic value was evaluated via survival analysis, stratification analysis, and ROC analysis. The functional enrichment analysis was conducted basing on bulk and scRNA-seq data. The immune landscape difference was analyzed using CIBERSORT, XCell, and MCPcounter portals. NET risk score was built for CRC patients, basing on G0S2, HIST1H2BC, CRISPLD2, and IL17A. In TCGA-CRC and validation datasets, regardless of age or gender, high-risk CRC patients had significantly worse prognosis, besides higher NET risk score was mainly found in samples with MSI-H and advanced T, N, and M stages. Employing multiple databases, we noticed that M0 and M2 Macrophages infiltrated the most in high-risk CRC patients, besides M2 Macrophages and neutrophils showed positive correlation with NET risk score. A novel reliable prognostic NET risk score was developed for CRC patients, and high-risk patients had unfavorable prognosis with advanced disease status.
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Affiliation(s)
- Jiuxing Dong
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Jia Zhao
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Zhenming Wu
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Jun Liu
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Baoxin Wang
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China
| | - Xiuheng Qi
- Department of Oncology, Hebei Petrochina Central Hospital, NO. 51 Xinkai Road, Langfang, 065000, Hebei, China.
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Xia T, Yu J, Du M, Chen X, Wang C, Li R. Vascular endothelial cell injury: causes, molecular mechanisms, and treatments. MedComm (Beijing) 2025; 6:e70057. [PMID: 39931738 PMCID: PMC11809559 DOI: 10.1002/mco2.70057] [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: 06/12/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 02/13/2025] Open
Abstract
Vascular endothelial cells form a single layer of flat cells that line the inner surface of blood vessels, extending from large vessels to the microvasculature of various organs. These cells are crucial metabolic and endocrine components of the body, playing vital roles in maintaining circulatory stability, regulating vascular tone, and preventing coagulation and thrombosis. Endothelial cell injury is regarded as a pivotal initiating factor in the pathogenesis of various diseases, triggered by multiple factors, including infection, inflammation, and hemodynamic changes, which significantly compromise vascular integrity and function. This review examines the causes, underlying molecular mechanisms, and potential therapeutic approaches for endothelial cell injury, focusing specifically on endothelial damage in cardiac ischemia/reperfusion (I/R) injury, sepsis, and diabetes. It delves into the intricate signaling pathways involved in endothelial cell injury, emphasizing the roles of oxidative stress, mitochondrial dysfunction, inflammatory mediators, and barrier damage. Current treatment strategies-ranging from pharmacological interventions to regenerative approaches and lifestyle modifications-face ongoing challenges and limitations. Overall, this review highlights the importance of understanding endothelial cell injury within the context of various diseases and the necessity for innovative therapeutic methods to improve patient outcomes.
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Affiliation(s)
- Tian Xia
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Jiachi Yu
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Meng Du
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Clinical LaboratoryHuaian Hospital of Huaian CityHuaianJiangsuChina
| | - Ximeng Chen
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Chengbin Wang
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
| | - Ruibing Li
- Department of Laboratory MedicineThe First Medical Center of Chinese PLA General HospitalBeijingChina
- Department of Laboratory MedicineMedical School of Chinese PLABeijingChina
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Bollar GE, Keith JD, Stanford DD, Oden AM, Raju SV, Poore TS, Birket SE. Chronic Coinfection with Pseudomonas aeruginosa and Normal Colony Staphylococcus aureus Causes Lung Structural Damage in the Cystic Fibrosis Rat. THE AMERICAN JOURNAL OF PATHOLOGY 2025; 195:174-187. [PMID: 39476957 PMCID: PMC11773620 DOI: 10.1016/j.ajpath.2024.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 09/16/2024] [Accepted: 09/19/2024] [Indexed: 11/13/2024]
Abstract
Cystic fibrosis (CF) respiratory outcomes are heavily influenced by complications of infection. Pseudomonas aeruginosa and Staphylococcus aureus are the most common colonizers of the cystic fibrosis lung, and frequently overlap to cause chronic and persistent coinfections associated with severe disease. However, the dynamics of P. aeruginosa and S. aureus coinfection and its impacts on the development of CF lung structural damage are poorly understood. Additionally, small colony variants (SCVs) of S. aureus have been associated with P. aeruginosa infections in people with CF, but their role in disease progression is largely unknown. In this work, the CF rat was used to model chronic lung coinfection with P. aeruginosa and S. aureus, using clinically and laboratory-derived normal colony and SCV strains of S. aureus to evaluate the impact of phenotype on clinical outcomes. Rats coinfected with clinically derived S. aureus of both phenotypes experienced increased inflammation in the lung. However, only the combination of P. aeruginosa and clinically normal colony S. aureus led to lung structural decline, including mucus obstruction and bronchiectasis. Regression analyses showed that the damage was associated with a higher burden of P. aeruginosa. These data indicate that chronic coinfection with normal colony S. aureus and P. aeruginosa may support the progression CF lung decline driven by P. aeruginosa, which might be avoided when coinfecting S. aureus exhibits the SCV phenotype.
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Affiliation(s)
- Gretchen E Bollar
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Johnathan D Keith
- Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Denise D Stanford
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ashley M Oden
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - S Vamsee Raju
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama
| | - T Spencer Poore
- Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama; Division of Pulmonology and Sleep Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Susan E Birket
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, Alabama.
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Yu F, Chen J, Zhang X, Ma Z, Wang J, Wu Q. Role of Neutrophil Extracellular Traps in Hypertension and Their Impact on Target Organs. J Clin Hypertens (Greenwich) 2025; 27:e14942. [PMID: 39686847 PMCID: PMC11771816 DOI: 10.1111/jch.14942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 10/27/2024] [Accepted: 10/29/2024] [Indexed: 12/18/2024]
Abstract
Hypertension is the predominant cause of cardiovascular diseases (CVDs) globally, and essential hypertension (EH) represents a significant public health challenge due to its multifactorial etiology involving complex interactions between genetic and environmental factors. However, the pathogenesis of EH is still unclear. Hypertension is a dysregulation in the renin-angiotensin-aldosterone system and sympathetic nervous system, both regulating saline homeostasis and cardiovascular function. However, current therapeutic interventions targeting these systems have limited efficacy in approximately 40% of cases, suggesting the involvement of alternative mechanisms. Inflammation is associated with the occurrence and progression of hypertension, but the underlying mechanism remains elusive, while chronic inflammation leads to tissue damage, fibrosis, and irreversible organ dysfunction. The development and maintenance of EH are caused by endothelial dysfunction, oxidative stress, and chronic inflammation. Neutrophils are involved in both acute and chronic inflammation since they represent the primary line of defense against inflammatory insults once recruited to the inflamed site where they remove harmful impurities. The process involving the formation of neutrophil extracellular traps (NETs) is called NETosis are involved in the pathogenesis and progression of CVDs, including coronary artery disease, acute myocardial infarction, peripheral arterial disease, heart failure, and atrial fibrillation. Recent investigations demonstrated that NETs facilitate the development of hypertension; however, the precise role of NETs in hypertension remains largely elusive. Therefore, this review aims to provide an overview of the current understanding regarding the involvement of NETosis in hypertension and explore the potential therapies targeting NETs for future interventions.
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Affiliation(s)
- Fei Yu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jianshu Chen
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Xiaowei Zhang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Zhengke Ma
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Jingtao Wang
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
| | - Qiang Wu
- Department of Cardiovascular MedicineLanzhou University Second HospitalLanzhouChina
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He Y, Guo T, Dai T, Zhou B, Xie H. Inflammatory proteins and vestibular neuronitis: A Mendelian randomization study. Medicine (Baltimore) 2024; 103:e41081. [PMID: 39705416 PMCID: PMC11666149 DOI: 10.1097/md.0000000000041081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 12/04/2024] [Accepted: 12/06/2024] [Indexed: 12/22/2024] Open
Abstract
Previous studies have highlighted the correlation between inflammatory responses and vestibular neuritis (VN). The aim of Mendelian randomization was to assess the causal associations between 91 inflammatory proteins and vestibular neuritis comprehensively. By leveraging publicly accessible genetic datasets, we probed whether 91 inflammatory proteins serve as upstream determinants of vestibular neuritis. We conducted a comprehensive sensitivity analysis to assess the robustness, heterogeneity, and polygenicity of our findings. Three inflammatory proteins were found to exert a significant causal effect on the VN: eotaxin levels are associated with a reduced risk of VN (inverse variance weighting [IVW]: odds ratio [OR] = 0.7113, 95% confidence intervals [CI] = 0.5199-0.9731, P = .0331). Similarly, the measurement of monocyte chemotactic protein-2 is linked to a decreased risk of VN (IVW: OR = 0.8535, 95% CI = 0.7328-0.9942, P = .0418). Conversely, an increase in the level of the T-cell surface glycoprotein CD5 is correlated with an increased risk of VN (IVW: OR = 1.3969, 95% CI = 1.0095-1.9331, P = .0437). This study suggested that eotaxin, monocyte chemotactic protein-2, and the T-cell surface glycoprotein CD5 may play crucial roles in the pathogenesis of VN. The potential use of these inflammatory proteins for diagnosing VN or as therapeutic targets has significant clinical implications.
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Affiliation(s)
- Yu He
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Hospital of Sichuan Province, Chengdu, Sichuan, China
| | - Tao Guo
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Hospital of Sichuan Province, Chengdu, Sichuan, China
| | - Tianrong Dai
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Hospital of Sichuan Province, Chengdu, Sichuan, China
| | - Bin Zhou
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Hospital of Sichuan Province, Chengdu, Sichuan, China
| | - Hui Xie
- Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
- Hospital of Chengdu University of Traditional Chinese Medicine, TCM Hospital of Sichuan Province, Chengdu, Sichuan, China
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Chen T, Zhou Z, Liu Y, Xu J, Zhu C, Sun R, Hu H, Liu Y, Dai L, Holmdahl R, Herrmann M, Zhang L, Muñoz LE, Meng L, Zhao Y. Neutrophils with low production of reactive oxygen species are activated during immune priming and promote development of arthritis. Redox Biol 2024; 78:103401. [PMID: 39471640 PMCID: PMC11550370 DOI: 10.1016/j.redox.2024.103401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/09/2024] [Accepted: 10/16/2024] [Indexed: 11/01/2024] Open
Abstract
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease mediated by immune cell dysfunction for which there is no universally effective prevention and treatment strategy. As primary effector cells, neutrophils are important in the inflammatory joint attack during the development of RA. Here, we used single-cell sequencing technology to thoroughly analyze the phenotypic characteristics of bone marrow-derived neutrophils in type II collagen (COL2)-induced arthritis (CIA) models, including mice primed and boosted with COL2. We identified a subpopulation of neutrophils with high expression of neutrophil cytoplasmic factor 1 (NCF1) in primed mice, accompanied by a characteristic reactive oxygen species (ROS) response, and a decrease in Ncf1 expression in boosted mice with the onset of arthritis. Furthermore, we found that after ROS reduction, arthritis occurred in primed mice but was attenuated in boosted mice. This bidirectional effect of ROS suggested a protective role of ROS during immune priming. Mechanistically, we combined functional assays and metabolomics identifying Ncf1-deficient neutrophils with enhanced migration, chemotactic receptor CXCR2 expression, inflammatory cytokine secretion, and Th1/Th17 differentiation. This alteration was mainly due to the metabolic reprogramming of Ncf1-deficient neutrophils from an energy supply pathway dominated by gluconeogenesis to an inflammatory immune pathway associated with the metabolism of histidine, glycine, serine, and threonine signaling, which in turn induced arthritis. In conclusion, we have systematically identified the functional and inflammatory phenotypic characteristics of neutrophils under ROS regulation, which provides a theoretical basis for understanding the pathogenesis of RA, to further improve prevention strategies and identify novel therapeutic targets.
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MESH Headings
- Animals
- Neutrophils/immunology
- Neutrophils/metabolism
- Reactive Oxygen Species/metabolism
- Mice
- Arthritis, Experimental/immunology
- Arthritis, Experimental/metabolism
- Arthritis, Experimental/pathology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/genetics
- Receptors, Interleukin-8B/metabolism
- Receptors, Interleukin-8B/genetics
- Male
- NADPH Oxidases/metabolism
- NADPH Oxidases/genetics
- Disease Models, Animal
- Collagen Type II/metabolism
- Collagen Type II/immunology
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Affiliation(s)
- Tao Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Zhen Zhou
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Jiayi Xu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Chenxi Zhu
- Frontiers Science Center for Disease-related Molecular Network, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Rui Sun
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Huifang Hu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Yan Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Lunzhi Dai
- Department of Rheumatology and Immunology, National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
| | - Rikard Holmdahl
- Medical Inflammation Research, Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Martin Herrmann
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany
| | - Lulu Zhang
- College of Foreign Languages and Cultures, Sichuan University, 610064, Chengdu, Sichuan, China
| | - Luis E Muñoz
- Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany.
| | - Liesu Meng
- Department of Rheumatology, and National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
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Tonyali NV, Sarsmaz K, Bayraktar B, Kahraman NC, Sucu ST, Aktemur G, Cakir BT, Seyhanli Z, Karabay G, Cakir A, Ustun Y. Delta neutrophil index (DNI) as a potential biomarker for fetal growth restriction: insights from maternal hematological changes and neonatal outcomes. BMC Pregnancy Childbirth 2024; 24:655. [PMID: 39375632 PMCID: PMC11460094 DOI: 10.1186/s12884-024-06853-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND This study investigates the role of Delta Neutrophil Index (DNI), an inflammation marker, in late-onset fetal growth restriction (LO-FGR) and its prediction of composite adverse neonatal outcomes. METHODS A retrospective study was conducted on 684 pregnant women (456 with normal fetal development and 228 with LO-FGR) who delivered at Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital between January 1, 2015, and June 30, 2018. Composite adverse neonatal outcomes were defined as at least one of the following: 5th minute APGAR score < 7, respiratory distress syndrome (RDS), or neonatal intensive care unit (NICU) admission. RESULTS The FGR group had significantly higher levels of neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), and DNI compared to controls (p < 0.05, for all). For FGR diagnosis, the DNI demonstrated the highest area under the curve (AUC = 0.677, 95% CI: 0.642-0.711) with a cut-off value of > -2.9, yielding a sensitivity of 78.41%, a specificity of 52.97%, a positive likelihood ratio (+ LR) of 1.68, and a negative likelihood ratio (-LR) of 0.37 (p < 0.001). For predicting composite adverse neonatal outcomes in the FGR group, DNI again demonstrated superior performance with an AUC of 0.635 (95% CI: 0.598-0.670), a cut-off value of > -2.2, a sensitivity of 69.90%, a specificity of 55.36%, a + LR of 1.56, and a -LR of 0.51 (p < 0.001). NLR, PLR, and MLR had AUCs below 0.55, indicating poor discriminative ability, with none reaching statistical significance. CONCLUSION This study highlights the potential role of DNI as a promising biomarker for detecting inflammatory processes associated with LO-FGR and its complications.
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Affiliation(s)
- Nazan Vanli Tonyali
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey.
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey.
| | - Kemal Sarsmaz
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Faculty of Medicine Celal, Bayar University, Manisa, Turkey
| | - Burak Bayraktar
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Neval Cayonu Kahraman
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
| | - Serap Topkara Sucu
- Department of Obstetrics and Gynecology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Gizem Aktemur
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Betul Tokgoz Cakir
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Zeynep Seyhanli
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Gulsan Karabay
- Department of Obstetrics and Gynecology, Division of Perinatology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Department of Obstetrics and Gynecology, Division of Perinatology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Ayberk Cakir
- Department of Obstetrics and Gynecology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
- Clinic of Obstetrics and Gynecology, Mus State Hospital, Mus, Turkey
| | - Yaprak Ustun
- Department of Obstetrics and Gynecology, Health Sciences University Etlik Zubeyde Hanim Women's Health Training and Research Hospital, Ankara, Turkey
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Yang HD, Yang YG, Tang ZS, Ma K, Xu HB. Identification of lignans as selective cyclooxygenase-2 inhibitors from the extract of Acanthopanacis cortex. PHYTOCHEMISTRY 2024; 226:114208. [PMID: 38972441 DOI: 10.1016/j.phytochem.2024.114208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 06/30/2024] [Accepted: 07/04/2024] [Indexed: 07/09/2024]
Abstract
Acanthopanacis cortex (the dried root bark of Acanthopanax gracilistylus W. W. Smith) has been used for the treatment of rheumatic diseases in China for over 2000 years. Four previously undescribed lignans (1-4) and 12 known lignans (5-16) were isolated from Acanthopanacis cortex. In this study, the inhibitory activities of compounds 1-16 against neutrophil elastase (NE), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) are reported. The results show that compounds 1-16 exhibit weak inhibitory activities against NE and COX-1. However, compounds 2, 6-8 and 13-16 demonstrate better COX-2 inhibitory effects with IC50 values from 0.75 to 8.17 μΜ. These findings provide useful information for the search for natural selective COX-2 inhibitors.
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Affiliation(s)
- Hao-Dong Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, 712083, Xianyang, PR China
| | - Yuan-Gui Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, 712083, Xianyang, PR China
| | - Zhi-Shu Tang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, 712083, Xianyang, PR China; China Academy of Chinese Medical Sciences, Beijing, 100700, PR China
| | - Kang Ma
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, 712083, Xianyang, PR China
| | - Hong-Bo Xu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, 712083, Xianyang, PR China.
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Yuan Q, Xiao LW, Zhang Y, Li L, Xia T, Xu Q, Xing SG, Wang LS. Inverted U-Shaped relationship Between Systemic Immune-Inflammation Index and Pulmonary Function: A Large Population-Based Study in US Adults. Int J Chron Obstruct Pulmon Dis 2024; 19:1971-1987. [PMID: 39247667 PMCID: PMC11379031 DOI: 10.2147/copd.s471068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 08/13/2024] [Indexed: 09/10/2024] Open
Abstract
Background Systemic immune-inflammation index (SII) is a novel comprehensive inflammatory marker. Inflammation is associated with impaired lung function. We aimed to explore the possible relationship between SII and lung function to examine the potential of SII in predicting lung function decline. Methods A cross-sectional survey was conducted using the data of the NHANES from 2007 to 2012. Multiple linear regression models were used to analyze the linear relationship between SII and pulmonary functions. Sensitivity analyses, subgroup analyses, and interaction tests were used to examine the robustness of this relationship across populations. Fitted smooth curves and threshold effect analysis were used to describe the nonlinear relationships. Results A total of 10,125 patients were included in this study. After adjusting for all covariates, multiple linear regression model analysis showed that high Log2-SII level was significantly associated with decreased FVC(β, -23.4061; 95% CI, -42.2805- -4.5317), FEV1(β, -46.7730; 95% CI, -63.3371- -30.2089), FEV1%(β, -0.7923; 95% CI, -1.1635- -0.4211), FEV1/FVC(β, -0.6366; 95% CI, -0.8328- -0.4404) and PEF(β, -121.4468; 95% CI,-164.1939- -78.6998). The negative correlation between Log2-SII and pulmonary function indexes remained stable in trend test and stratified analysis. Inverted U-shaped relationships between Log2-SII and FVC, FEV1, FEV1%, and PEF were observed, while a negative linear correlation existed between FEV1/FVC and Log2-SII. The cutoff values of the nonlinear relationship between Log2-SII and FVC, FEV1, FEV1%, PEF were 8.3736, 8.0688, 8.3745, and 8.5255, respectively. When SII exceeded the critical value, the lung function decreased significantly. Conclusion This study found a close correlation between SII and pulmonary function indicators. This study investigated the SII threshold when lung functions began to decline in the overall population. SII may become a promising serological indicator for predicting lung function decline. However, prospective studies were needed further to establish the causal relationship between these two factors.
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Affiliation(s)
- Qian Yuan
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Long-Wu Xiao
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Yao Zhang
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Long Li
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Teng Xia
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Qing Xu
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Shi-Gui Xing
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
| | - Liu-Shun Wang
- Department of Thoracic Surgery, Nan Jing Gaochun PEople's Hospital (The Gaochun Affiliated Hospital of Jiang Su University), Nanjing, Jiangsu, 210000, People's Republic of China
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10
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Luo S, Luo R, Deng G, Huang F, Lei Z. Programmed cell death, from liver Ischemia-Reperfusion injury perspective: An overview. Heliyon 2024; 10:e32480. [PMID: 39040334 PMCID: PMC11260932 DOI: 10.1016/j.heliyon.2024.e32480] [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: 01/22/2024] [Revised: 05/26/2024] [Accepted: 06/04/2024] [Indexed: 07/24/2024] Open
Abstract
Liver ischemia-reperfusion injury (LIRI) commonly occurs in liver resection, liver transplantation, shock, and other hemorrhagic conditions, resulting in profound local and systemic effects via associated inflammatory responses and hepatic cell death. Hepatocyte death is a significant component of LIRI and its mechanism was previously thought to be limited to apoptosis and necrosis. With the discovery of novel types of programmed cell death (PCD), necroptosis, ferroptosis, pyroptosis, autophagy, NETosis, and parthanatos have been shown to be involved in LIRI. Understanding the mechanisms underlying cell death following LIRI is indispensable to mitigating the widespread effects of LIRI. Here, we review the roles of different PCD and discuss potential therapy in LIRI.
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Affiliation(s)
- Shaobin Luo
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Rongkun Luo
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Gang Deng
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Feizhou Huang
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
| | - Zhao Lei
- Department of Hepatopancreatobiliary Surgery, The Third Xiangya Hospital, Central South University, Changsha , PR China
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11
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Yang HD, Hou BL, Yang YG, Tang ZS, Xu HB. Diterpenoids from Acanthopanacis Cortex and their anti-inflammatory activity studies. Fitoterapia 2024; 176:106021. [PMID: 38762074 DOI: 10.1016/j.fitote.2024.106021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/17/2024] [Accepted: 05/15/2024] [Indexed: 05/20/2024]
Abstract
Acanthopanacis Cortex (A.-C) with a long history of more than1000 years, has been used to treat rheumatism effectively. Nineteen diterpenoids have been isolated from A.-C, including six new compounds (1-6). Among them, compounds 7, 9-11, 13, and 17 were discovered from A.-C for the first time. The structures of 1-6 were determined by analyzing their NMR data and comparing their experimental and calculated electronic circular dichroism spectra. Moreover, the single-crystal X-ray diffraction data of 1, 2, 8, and 14 were provided. The anti-inflammatory activity of 1-5 and 7-18 on neutrophil elastase, cyclooxygenase-1 (COX-1), and cyclooxygenase-2 (COX-2) has been studied in vitro, and the results showed that 15 had almost no inhibitory effects on COX-1 at 200 μM but a significant activity against COX-2 with an IC50 of 0.73 ± 0.006 μΜ. It indicated that compound 15 can provide valuable information for the design of selective COX-2 inhibitors.
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Affiliation(s)
- Hao-Dong Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Bao-Long Hou
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Yuan-Gui Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Zhi-Shu Tang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China; China Academy of Chinese Medical Sciences, Beijing 100700, PR China
| | - Hong-Bo Xu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
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12
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Nickerson R, Thornton CS, Johnston B, Lee AHY, Cheng Z. Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response. Front Immunol 2024; 15:1405376. [PMID: 39015565 PMCID: PMC11250099 DOI: 10.3389/fimmu.2024.1405376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/14/2024] [Indexed: 07/18/2024] Open
Abstract
Pseudomonas aeruginosa is a highly adaptable opportunistic pathogen capable of exploiting barriers and immune defects to cause chronic lung infections in conditions such as cystic fibrosis. In these contexts, host immune responses are ineffective at clearing persistent bacterial infection, instead driving a cycle of inflammatory lung damage. This review outlines key components of the host immune response to chronic P. aeruginosa infection within the lung, beginning with initial pathogen recognition, followed by a robust yet maladaptive innate immune response, and an ineffective adaptive immune response that propagates lung damage while permitting bacterial persistence. Untangling the interplay between host immunity and chronic P. aeruginosa infection will allow for the development and refinement of strategies to modulate immune-associated lung damage and potentiate the immune system to combat chronic infection more effectively.
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Affiliation(s)
- Rhea Nickerson
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Christina S. Thornton
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Brent Johnston
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Amy H. Y. Lee
- Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, BC, Canada
| | - Zhenyu Cheng
- Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
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13
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Oh EH, Kim HS, Choi SY, Choi KD, Choi JH. Clinical Significance of Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Acute Unilateral Vestibulopathy. J Clin Neurol 2024; 20:315-320. [PMID: 38330419 PMCID: PMC11076183 DOI: 10.3988/jcn.2023.0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/06/2023] [Accepted: 09/19/2023] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND AND PURPOSE The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been identified as useful biomarkers for assessing the inflammatory response and for predicting the prognosis of various diseases. This study aimed to determine the clinical significance and effects on prognostic prediction of NLR and PLR in acute unilateral vestibulopathy (AUV). METHODS We retrospectively recruited 128 patients who were diagnosed with AUV from July 2016 to April 2021, and compared NLR and PLR values between these patients with AUV and age- and sex-matched healthy subjects. We also analyzed the correlations of various clinical parameters with NLR and PLR. RESULTS NLR and PLR in the AUV group were 3.41±2.80 (mean±standard deviation) and 128.86±67.06, respectively, with only NLR being significantly higher than that in the control group (1.55±0.60, p<0.001). The gain asymmetry of the horizontal vestibulo-ocular reflex (VOR) was slightly larger in patients with high NLR (n=52) than in those with normal NLR (n=76) (41.9%±20.2% vs. 33.6%±17.4%, p=0.048). However, the hospitalization period, preceding infection, canal paresis, and absolute horizontal VOR gain did not differ between patients with high and normal NLR and PLR values. The correlation analyses also revealed that none of the clinical parameters were significantly correlated with NLR or PLR. At 3-month follow-up examinations, NLR and PLR did not differ significantly between patients with and without function recovery of the horizontal VOR. CONCLUSIONS This study found a high NLR in AUV, suggesting an acute inflammatory status in the vestibular organ. However, the usefulness of NLR and PLR as prognostic markers remains unclear.
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Affiliation(s)
- Eun Hye Oh
- Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Korea
| | - Hyun Sung Kim
- Department of Neurology, Gyeongsan National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, Korea
| | - Seo Young Choi
- Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea
| | - Kwang-Dong Choi
- Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Biomedical Research Institute, Busan, Korea
| | - Jae-Hwan Choi
- Department of Neurology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Research Institute for Convergence of Biomedical Science and Technology, Yangsan, Korea.
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14
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Klak K, Maciuszek M, Pijanowski L, Marcinkowska M, Homa J, Verburg-van Kemenade BML, Rakus K, Chadzinska M. Evolutionarily conserved mechanisms regulating stress-induced neutrophil redistribution in fish. Front Immunol 2024; 15:1330995. [PMID: 38515741 PMCID: PMC10954836 DOI: 10.3389/fimmu.2024.1330995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 02/21/2024] [Indexed: 03/23/2024] Open
Abstract
Introduction Stress may pose a serious challenge to immune homeostasis. Stress however also may prepare the immune system for challenges such as wounding or infection, which are likely to happen during a fight or flight stress response. Methods In common carp (Cyprinus carpio L.) we studied the stress-induced redistribution of neutrophils into circulation, and the expression of genes encoding CXC chemokines known to be involved in the regulation of neutrophil retention (CXCL12) and redistribution (CXCL8), and their receptors (CXCR4 and CXCR1-2, respectively) in blood leukocytes and in the fish hematopoietic organ - the head kidney. The potential involvement of CXC receptors and stress hormone receptors in stress-induced neutrophil redistribution was determined by an in vivo study with selective CXCR inhibitors and antagonists of the receptors involved in stress regulation: glucocorticoid/mineralocorticoid receptors (GRs/MRs), adrenergic receptors (ADRs) and the melanocortin 2 receptor (MC2R). Results The stress-induced increase of blood neutrophils was accompanied by a neutrophil decrease in the hematopoietic organs. This increase was cortisol-induced and GR-dependent. Moreover, stress upregulated the expression of genes encoding CXCL12 and CXCL8 chemokines, their receptors, and the receptor for granulocytes colony-stimulation factor (GCSFR) and matrix metalloproteinase 9 (MMP9). Blocking of the CXCR4 and CXCR1 and 2 receptors with selective inhibitors inhibited the stress-induced neutrophil redistribution and affected the expression of genes encoding CXC chemokines and CXCRs as well as GCSFR and MMP9. Discussion Our data demonstrate that acute stress leads to the mobilization of the immune system, characterized by neutrophilia. CXC chemokines and CXC receptors are involved in this stress-induced redistribution of neutrophils from the hematopoietic tissue into the peripheral blood. This phenomenon is directly regulated by interactions between cortisol and the GR/MR. Considering the pivotal importance of neutrophilic granulocytes in the first line of defense, this knowledge is important for aquaculture, but will also contribute to the mechanisms involved in the stress-induced perturbation in neutrophil redistribution as often observed in clinical practice.
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Affiliation(s)
- Katarzyna Klak
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Magdalena Maciuszek
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | - Lukasz Pijanowski
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | - Magdalena Marcinkowska
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland
| | - Joanna Homa
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | | | - Krzysztof Rakus
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
| | - Magdalena Chadzinska
- Department of Evolutionary Immunology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, Poland
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15
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Rizo-Téllez SA, Filep JG. Beyond host defense and tissue injury: the emerging role of neutrophils in tissue repair. Am J Physiol Cell Physiol 2024; 326:C661-C683. [PMID: 38189129 PMCID: PMC11193466 DOI: 10.1152/ajpcell.00652.2023] [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: 11/29/2023] [Revised: 12/31/2023] [Accepted: 12/31/2023] [Indexed: 01/09/2024]
Abstract
Neutrophils, the most abundant immune cells in human blood, play a fundamental role in host defense against invading pathogens and tissue injury. Neutrophils carry potentially lethal weaponry to the affected site. Inadvertent and perpetual neutrophil activation could lead to nonresolving inflammation and tissue damage, a unifying mechanism of many common diseases. The prevailing view emphasizes the dichotomy of their function, host defense versus tissue damage. However, tissue injury may also persist during neutropenia, which is associated with disease severity and poor outcome. Numerous studies highlight neutrophil phenotypic heterogeneity and functional versatility, indicating that neutrophils play more complex roles than previously thought. Emerging evidence indicates that neutrophils actively orchestrate resolution of inflammation and tissue repair and facilitate return to homeostasis. Thus, neutrophils mobilize multiple mechanisms to limit the inflammatory reaction, assure debris removal, matrix remodeling, cytokine scavenging, macrophage reprogramming, and angiogenesis. In this review, we will summarize the homeostatic and tissue-reparative functions and mechanisms of neutrophils across organs. We will also discuss how the healing power of neutrophils might be harnessed to develop novel resolution and repair-promoting therapies while maintaining their defense functions.
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Affiliation(s)
- Salma A Rizo-Téllez
- Department of Pathology and Cell Biology, University of Montreal and Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
| | - János G Filep
- Department of Pathology and Cell Biology, University of Montreal and Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec, Canada
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16
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Geng H, Zhang H, Cheng L, Dong S. Sivelestat ameliorates sepsis-induced myocardial dysfunction by activating the PI3K/AKT/mTOR signaling pathway. Int Immunopharmacol 2024; 128:111466. [PMID: 38176345 DOI: 10.1016/j.intimp.2023.111466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 12/07/2023] [Accepted: 12/27/2023] [Indexed: 01/06/2024]
Abstract
The cardioprotective role of sivelestat, a neutrophil elastase inhibitor, has already been demonstrated, but the underlying molecular mechanism remains unclear. This study aimed to explore the mechanism underlying the role of sivelestat in sepsis-induced myocardial dysfunction (SIMD). We found that sivelestat treatment remarkably improved the viability and suppressed the apoptosis of lipopolysaccharide (LPS)-stimulated H9c2 cells. In vivo, sivelestat treatment was associated with an improved survival rate; reduced serum cTnT, TNF-α, IL-1β levels and myocardial TNF-α and IL-1β levels; ameliorated cardiac function and structure; and reduced cardiomyocyte apoptosis. Moreover, sivelestat treatment substantially increased Bcl-2 expression and suppressed caspase-3 and Bax expression in LPS-induced H9c2 cells and in the heart tissues of septic rats. Furthermore, the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) signaling pathway was activated both in vitro and in vivo. The protective effect of sivelestat against SIMD was reversed by the PI3K inhibitor LY294002. In summary, sivelestat can protect against SIMD by activating the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Hongyu Geng
- Department of Intensive Care Unit, Baoding First Central Hospital, Baoding, China
| | - Hongbo Zhang
- Department of General Surgery, Baoding First Central Hospital, Baoding, China
| | - Lianfang Cheng
- Department of Intensive Care Unit, Baoding First Central Hospital, Baoding, China
| | - Shimin Dong
- Department of Emergency, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
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Xiao Y, Cheng Y, Liu WJ, Liu K, Wang Y, Xu F, Wang DM, Yang Y. Effects of neutrophil fate on inflammation. Inflamm Res 2023; 72:2237-2248. [PMID: 37925664 DOI: 10.1007/s00011-023-01811-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 09/18/2023] [Accepted: 10/24/2023] [Indexed: 11/07/2023] Open
Abstract
INTRODUCTION Neutrophils are important participants in the innate immune response. They rapidly and efficiently identify and clear infectious agents by expressing large numbers of membrane receptors. Upon tissue injury or pathogen invasion, neutrophils are the first immune cells to reach the site of injury and participate in the inflammatory response. MATERIALS AND METHODS A thorough search on PubMed related to neutrophil death or clearance pathways was performed. CONCLUSION Inflammatory response and tissue damage can be aggravated when neutrophils are not removed rapidly from the site of injury. Recent studies have shown that neutrophils can be cleared through a variety of pathways, including non-inflammatory and inflammatory death, as well as reverse migration. Non-inflammatory death pathways include apoptosis and autophagy. Inflammatory death pathways include necroptosis, pyroptosis and NETosis. This review highlights the basic properties of neutrophils and the impact of their clearance pathways on the inflammatory response.
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Affiliation(s)
- Yuan Xiao
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Yang Cheng
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Wen-Jie Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Kun Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Yan Wang
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Feng Xu
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - De-Ming Wang
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
| | - Yi Yang
- Department of Anesthesiology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, China.
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18
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Yang HD, Tang ZS, Xue TT, Zhu YY, Su ZH, Xu HB. Acyl-quinic acids from the root bark of Acanthopanax gracilistylus and their inhibitory effects on neutrophil elastase and cyclooxygenase-2 in vitro. Bioorg Chem 2023; 140:106798. [PMID: 37634270 DOI: 10.1016/j.bioorg.2023.106798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Revised: 08/09/2023] [Accepted: 08/19/2023] [Indexed: 08/29/2023]
Abstract
Eleven new acyl-quinic acids (AQAs) 1a-9, and 18 known AQAs 10-27 were isolated from the root bark of Acanthopanax gracilistylus W. W. Smith (Acanthopanacis Cortex). The planar structures of 1a-9 were determined based on their HR-ESIMS, IR, and NMR data. The absolute configurations of 1a-6 were identified by comparing the experimental and the calculated electronic circular dichroism (ECD) spectra. This is the first report of the isolation of AQAs from Acanthopanacis Cortex. Notably, 1a-6 were determined as unusual oxyneolignan-(-)-quinic acids heterodimers, representing a new class of natural products. The inhibitory activities of 1a-27 on neutrophil elastase (NE) and cyclooxygenase-2 (COX-2) were studied in vitro, and the results indicated they possessed significant inhibitory activities on COX-2. Among them, the IC50 values of 1a-9 were 0.63±0.014, 0.75±0.028, 0.15±0.023, 0.63±0.016, 0.30±0.013, 35.63±4.600, 8.70±1.241, 16.51±0.480, 0.69±0.049, 0.39±0.017, and 0.26±0.080 μM, respectively. This study represents the inaugural disclosure of the anti-COX-2 constituents found in Acanthopanacis Cortex, thereby furnishing valuable insights into the exploration of novel COX-2 inhibitors derived from natural reservoirs.
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Affiliation(s)
- Hao-Dong Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Zhi-Shu Tang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China; China Academy of Chinese Medical Sciences, Beijing 100700, PR China
| | - Tao-Tao Xue
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Ya-Ya Zhu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Zeng-Hu Su
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China
| | - Hong-Bo Xu
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, PR China.
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Chen Y, Han P, Gao Y, Jiang R, Tao M, Li X. The value of the neutrophil to lymphocyte ratio and PLT count for the diagnosis and prediction of COVID-19 severity. PLoS One 2023; 18:e0293432. [PMID: 37903087 PMCID: PMC10615267 DOI: 10.1371/journal.pone.0293432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/12/2023] [Indexed: 11/01/2023] Open
Abstract
BACKGROUND COVID-19 and influenza A can cause severe respiratory illness. Differentiating between the two diseases and identifying critically ill patients in times of epidemics become a challenge for frontline medical staff. We sought to investigate whether both diseases and their severity could be recognized by routine blood parameters. METHODS Our retrospective study analysed the clinical data and first-time routine blood parameters of 80 influenza A patients and 123 COVID-19 patients. COVID-19 patients were divided into three groups according to treatment modalities and outcomes: outpatient group, inpatient without invasive mechanical ventilation (IMV) group, and inpatient with IMV group. We used the Mann-Whitney and Kruskal-Wallis tests to analyze the differences in routine blood parameters between the two or three groups. Receiver operating characteristic (ROC) curve analysis and area under the curve (AUC) were used to assess the diagnostic accuracy. RESULTS Compared with outpatient influenza A patients, outpatient COVID-19 patients had a higher neutrophil to lymphocyte ratio (NLR) (6.63 vs 3.55). ROC analysis showed that the NLR had a high diagnostic value for differentiating COVID-19 from influenza A (AUC = 0.739). The best cut-off point of the NLR was 6.48, the diagnostic sensitivity was 0.523, and the specificity was 0.925. The median platelet (PLT) count in the different COVID-19 groups was as follows: outpatient group (189×109/L), inpatient without IMV group (161×109/L), and inpatient with IMV group (94×109/L). Multivariate logistic regression analysis found a significant association between PLT and treatment modality and outcome in COVID-19 patients (p<0.001). CONCLUSIONS NLR can be used as a potential biological indicator to distinguish COVID-19 and influenza A. Decreased PLT predicts the critical condition of COVID-19 patients and helps stratify the treatment of COVID-19 patients.
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Affiliation(s)
- Yingji Chen
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Pingyang Han
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yunjie Gao
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Ruifeng Jiang
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Mei Tao
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Ximin Li
- Department of Nephrology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
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20
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Soliman AM, Barreda DR. The acute inflammatory response of teleost fish. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2023; 146:104731. [PMID: 37196851 DOI: 10.1016/j.dci.2023.104731] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 05/19/2023]
Abstract
Acute inflammation is crucial to the immune responses of fish. The process protects the host from infection and is central to induction of subsequent tissue repair programs. Activation of proinflammatory signals reshapes the microenvironment within an injury/infection site, initiates leukocyte recruitment, promotes antimicrobial mechanisms and contributes to the resolution of inflammation. Inflammatory cytokines and lipid mediators are primary contributors to these processes. Uncontrolled or persistent induction results in delayed tissue healing. The kinetics by which inducers and regulators of acute inflammation exert their actions is essential for understanding the pathogenesis of fish diseases and identifying potential treatments. Although, a number of these are well-conserved across, others are not, reflecting the unique physiologies and life histories of members of this unique animal group.
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Affiliation(s)
- Amro M Soliman
- Department of Biological Sciences, University of Alberta, Canada
| | - Daniel R Barreda
- Department of Biological Sciences, University of Alberta, Canada; Department of Agricultural, Food and Nutritional Science, University of Alberta, Canada.
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21
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Malicki S, Książek M, Sochaj Gregorczyk A, Kamińska M, Golda A, Chruścicka B, Mizgalska D, Potempa J, Marti HP, Kozieł J, Wieczorek M, Pieczykolan J, Mydel P, Dubin G. Identification and characterization of aptameric inhibitors of human neutrophil elastase. J Biol Chem 2023; 299:104889. [PMID: 37286041 PMCID: PMC10359491 DOI: 10.1016/j.jbc.2023.104889] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 05/17/2023] [Accepted: 06/01/2023] [Indexed: 06/09/2023] Open
Abstract
Human neutrophil elastase (HNE) plays a pivotal role in innate immunity, inflammation, and tissue remodeling. Aberrant proteolytic activity of HNE contributes to organ destruction in various chronic inflammatory diseases including emphysema, asthma, and cystic fibrosis. Therefore, elastase inhibitors could alleviate the progression of these disorders. Here, we used the systematic evolution of ligands by exponential enrichment to develop ssDNA aptamers that specifically target HNE. We determined the specificity of the designed inhibitors and their inhibitory efficacy against HNE using biochemical and in vitro methods, including an assay of neutrophil activity. Our aptamers inhibit the elastinolytic activity of HNE with nanomolar potency and are highly specific for HNE and do not target other tested human proteases. As such, this study provides lead compounds suitable for the evaluation of their tissue-protective potential in animal models.
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Affiliation(s)
- Stanisław Malicki
- Laboratory of Proteolysis and Post-translational Modification of Proteins, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
| | - Mirosław Książek
- Laboratory of Proteolysis and Post-translational Modification of Proteins, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Alicja Sochaj Gregorczyk
- Laboratory of Proteolysis and Post-translational Modification of Proteins, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Marta Kamińska
- Broegelmann Research Laboratory, University of Bergen, Bergen, Norway
| | - Anna Golda
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Barbara Chruścicka
- Laboratory of Proteolysis and Post-translational Modification of Proteins, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland; Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Danuta Mizgalska
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Jan Potempa
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, Louisville, Kentucky, USA
| | - Hans-Peter Marti
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Joanna Kozieł
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Maciej Wieczorek
- Innovative Drugs R&D Department, Celon Pharma Inc, Lomianki, Poland
| | | | - Piotr Mydel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Broegelmann Research Laboratory, University of Bergen, Bergen, Norway
| | - Grzegorz Dubin
- Protein Crystallography Research, Group Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland
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22
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Khan AH, Chowers I, Lotery AJ. Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment. Cells 2023; 12:1708. [PMID: 37443742 PMCID: PMC10340338 DOI: 10.3390/cells12131708] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Revised: 06/22/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Landmark genetic studies have revealed the effect of complement biology and its regulation on the pathogenesis of age-related macular degeneration (AMD). Limited phase 3 clinical trial data showing a benefit of complement inhibition in AMD raises the prospect of more complex mediators at play. Substantial evidence supports the role of para-inflammation in maintaining homeostasis in the retina and choroid. With increasing age, a decline in immune system regulation, known as immunosenescence, has been shown to alter the equilibrium maintained by para-inflammation. The altered equilibrium results in chronic, sterile inflammation with aging, termed 'inflammaging', including in the retina and choroid. The chronic inflammatory state in AMD is complex, with contributions from cells of the innate and adaptive branches of the immune system, sometimes with overlapping features, and the interaction of their secretory products with retinal cells such as microglia and retinal pigment epithelium (RPE), extracellular matrix and choroidal vascular endothelial cells. In this review, the chronic inflammatory state in AMD will be explored by immune cell type, with a discussion of factors that will need to be overcome in the development of curative therapies.
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Affiliation(s)
- Adnan H. Khan
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
- Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Itay Chowers
- Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91121, Israel
| | - Andrew J. Lotery
- Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK
- Southampton Eye Unit, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
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23
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Singh V, Singh N, Pradhan A, Kumar Y, Bhatnagar S. Structure-activity relationships of dihydropyrimidone inhibitors against native and auto-processed human neutrophil elastase. Comput Biol Med 2023; 161:107004. [PMID: 37230015 DOI: 10.1016/j.compbiomed.2023.107004] [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: 12/18/2022] [Revised: 04/22/2023] [Accepted: 05/02/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Human neutrophil elastase (HNE) is a key driver of systemic and cardiopulmonary inflammation. Recent studies have established the existence of a pathologically active auto-processed form of HNE with reduced binding affinity against small molecule inhibitors. METHOD AutoDock Vina v1.2.0 and Cresset Forge v10 software were used to develop a 3D-QSAR model for a series of 47 DHPI inhibitors. Molecular Dynamics (MD) simulations were carried out using AMBER v18 to study the structure and dynamics of sc (single-chain HNE) and tcHNE (two-chain HNE). MMPBSA binding free energies of the previously reported clinical candidate BAY 85-8501 and the highly active BAY-8040 were calculated with sc and tcHNE. RESULTS The DHPI inhibitors occupy the S1 and S2 subsites of scHNE. The robust 3D-QSAR model showed acceptable predictive and descriptive capability with regression coefficient of r2 = 0.995 and cross-validation regression coefficient q2 = 0.579 for the training set. The key descriptors of shape, hydrophobics and electrostatics were mapped to the inhibitory activity. In auto-processed tcHNE, the S1 subsite undergoes widening and disruption. All the DHPI inhibitors docked with the broadened S1'-S2' subsites of tcHNE with lower AutoDock binding affinities. The MMPBSA binding free energy of BAY-8040 with tcHNE reduced in comparison with scHNE while the clinical candidate BAY 85-8501 dissociated during MD. Thus, BAY-8040 may have lower inhibitory activity against tcHNE whereas the clinical candidate BAY 85-8501 is likely to be inactive. CONCLUSION SAR insights gained from this study will aid the future development of inhibitors active against both forms of HNE.
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Affiliation(s)
- Vasundhara Singh
- Computational and Structural Biology Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India
| | - Nirupma Singh
- Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology, Dwarka, New Delhi, 110078, India
| | - Amartya Pradhan
- Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology, Dwarka, New Delhi, 110078, India
| | - Yatender Kumar
- Mammalian Cell Culture Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India
| | - Sonika Bhatnagar
- Computational and Structural Biology Laboratory, Department of Biological Sciences and Engineering, Netaji Subhas University of Technology, Dwarka, New Delhi, 110078, India; Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology, Dwarka, New Delhi, 110078, India.
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24
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Aguinagalde Salazar L, den Boer MA, Castenmiller SM, Zwarthoff SA, de Haas C, Aerts PC, Beurskens FJ, Schuurman J, Heck AJR, van Kessel K, Rooijakkers SHM. Promoting Fc-Fc interactions between anti-capsular antibodies provides strong immune protection against Streptococcus pneumoniae. eLife 2023; 12:e80669. [PMID: 36947116 PMCID: PMC10032657 DOI: 10.7554/elife.80669] [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: 05/30/2022] [Accepted: 03/09/2023] [Indexed: 03/23/2023] Open
Abstract
Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and an important cause of childhood mortality. Despite the introduction of successful vaccines, the global spread of both non-vaccine serotypes and antibiotic-resistant strains reinforces the development of alternative therapies against this pathogen. One possible route is the development of monoclonal antibodies (mAbs) that induce killing of bacteria via the immune system. Here, we investigate whether mAbs can be used to induce killing of pneumococcal serotypes for which the current vaccines show unsuccessful protection. Our study demonstrates that when human mAbs against pneumococcal capsule polysaccharides (CPS) have a poor capacity to induce complement activation, a critical process for immune protection against pneumococci, their activity can be strongly improved by hexamerization-enhancing mutations. Our data indicate that anti-capsular antibodies may have a low capacity to form higher-order oligomers (IgG hexamers) that are needed to recruit complement component C1. Indeed, specific point mutations in the IgG-Fc domain that strengthen hexamerization strongly enhance C1 recruitment and downstream complement activation on encapsulated pneumococci. Specifically, hexamerization-enhancing mutations E430G or E345K in CPS6-IgG strongly potentiate complement activation on S. pneumoniae strains that express capsular serotype 6 (CPS6), and the highly invasive serotype 19A strain. Furthermore, these mutations improve complement activation via mAbs recognizing CPS3 and CPS8 strains. Importantly, hexamer-enhancing mutations enable mAbs to induce strong opsonophagocytic killing by human neutrophils. Finally, passive immunization with CPS6-IgG1-E345K protected mice from developing severe pneumonia. Altogether, this work provides an important proof of concept for future optimization of antibody therapies against encapsulated bacteria.
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Affiliation(s)
| | - Maurits A den Boer
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht UniversityUtrechtNetherlands
- Netherlands Proteomics CenterUtrechtNetherlands
| | - Suzanne M Castenmiller
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
| | - Seline A Zwarthoff
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
| | - Carla de Haas
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
| | - Piet C Aerts
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
| | | | | | - Albert JR Heck
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht UniversityUtrechtNetherlands
- Netherlands Proteomics CenterUtrechtNetherlands
| | - Kok van Kessel
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
| | - Suzan HM Rooijakkers
- Medical Microbiology, University Medical Center Utrecht, Utrecht UniversityUtrechtNetherlands
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25
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Abstract
Mucosal tissues are constantly exposed to the outside environment. They receive signals from the commensal microbiome and tissue-specific triggers including alimentary and airborne elements and are tasked to maintain balance in the absence of inflammation and infection. Here, we present neutrophils as sentinel cells in mucosal immunity. We discuss the roles of neutrophils in mucosal homeostasis and overview clinical susceptibilities in patients with neutrophil defects. Finally, we present concepts related to specification of neutrophil responses within specific mucosal tissue microenvironments.
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Affiliation(s)
- Lakmali M. Silva
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
- Proteases and Tissue Remodeling Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Tae Sung Kim
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
| | - Niki M. Moutsopoulos
- Oral Immunity and Infection Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892
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26
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Uriarte SM, Hajishengallis G. Neutrophils in the periodontium: Interactions with pathogens and roles in tissue homeostasis and inflammation. Immunol Rev 2023; 314:93-110. [PMID: 36271881 PMCID: PMC10049968 DOI: 10.1111/imr.13152] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Neutrophils are of key importance in periodontal health and disease. In their absence or when they are functionally defective, as occurs in certain congenital disorders, affected individuals develop severe forms of periodontitis in early age. These observations imply that the presence of immune-competent neutrophils is essential to homeostasis. However, the presence of supernumerary or hyper-responsive neutrophils, either because of systemic priming or innate immune training, leads to imbalanced host-microbe interactions in the periodontium that culminate in dysbiosis and inflammatory tissue breakdown. These disease-provoking imbalanced interactions are further exacerbated by periodontal pathogens capable of subverting neutrophil responses to their microbial community's benefit and the host's detriment. This review attempts a synthesis of these findings for an integrated view of the neutrophils' ambivalent role in periodontal disease and, moreover, discusses how some of these concepts underpin the development of novel therapeutic approaches to treat periodontal disease.
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Affiliation(s)
- Silvia M. Uriarte
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, KY, USA
| | - George Hajishengallis
- Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, USA
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27
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Bauer A, Pachl E, Hellmuth JC, Kneidinger N, Heydarian M, Frankenberger M, Stubbe HC, Ryffel B, Petrera A, Hauck SM, Behr J, Kaiser R, Scherer C, Deng L, Teupser D, Ahmidi N, Muenchhoff M, Schubert B, Hilgendorff A. Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166592. [PMID: 36328146 PMCID: PMC9622026 DOI: 10.1016/j.bbadis.2022.166592] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 10/27/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development.
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Affiliation(s)
- Alina Bauer
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany
| | - Elisabeth Pachl
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Fraunhofer IKS, Fraunhofer Institute for Cognitive Systems IKS, 80686 Munich, Germany
| | - Johannes C. Hellmuth
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany,German Cancer Consortium (DKTK), Munich, Germany,COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany
| | - Nikolaus Kneidinger
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany,Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
| | | | - Marion Frankenberger
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany
| | - Hans C. Stubbe
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Bernhard Ryffel
- Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355 CNRS-University of Orleans and Artimmune, Orléans, France
| | - Agnese Petrera
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, Munich, Germany
| | - Stefanie M. Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, Munich, Germany
| | - Jürgen Behr
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany,Department of Medicine V, University Hospital, LMU Munich, Member of the German Center for Lung Research (DZL), Munich, Germany
| | - Rainer Kaiser
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Clemens Scherer
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Medizinische Klinik und Poliklinik I, University Hospital, LMU Munich, Munich, Germany,DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Li Deng
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Institute of Virology, Technical University of Munich, 81675 Munich, Germany
| | - Daniel Teupser
- Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany
| | - Narges Ahmidi
- Fraunhofer IKS, Fraunhofer Institute for Cognitive Systems IKS, 80686 Munich, Germany
| | - Maximilian Muenchhoff
- COVID-19 Registry of the LMU Munich (CORKUM), University Hospital, LMU Munich, Munich, Germany,Max von Pettenkofer Institute and Gene Center, Virology, National Reference Center for Retroviruses, LMU München, Munich, Germany,German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany
| | - Benjamin Schubert
- Helmholtz Zentrum München, Computational Health Department, Member of the German Center for Lung Research (DZL), 85764 Munich, Germany,Department of Mathematics, Technical University of Munich, 85748 Garching bei München, Germany
| | - Anne Hilgendorff
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC-M bioArchive, Helmholtz Zentrum Muenchen, Member of the German Center for Lung Research (DZL), Munich, Germany; Center for Comprehensive Developmental Care (CDeC(LMU)) at the Interdisciplinary Social Pediatric Center (iSPZ), LMU Hospital, Munich, Germany.
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28
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Shakya S, Pyles KD, Albert CJ, Patel RP, McCommis KS, Ford DA. Myeloperoxidase-derived hypochlorous acid targets human airway epithelial plasmalogens liberating protein modifying electrophilic 2-chlorofatty aldehydes. Redox Biol 2023; 59:102557. [PMID: 36508858 PMCID: PMC9763693 DOI: 10.1016/j.redox.2022.102557] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Neutrophil and airway epithelial cell interactions are critical in the inflammatory response to viral infections including respiratory syncytial virus, Sendai virus, and SARS-CoV-2. Airway epithelial cell dysfunction during viral infections is likely mediated by the interaction of virus and recruited neutrophils at the airway epithelial barrier. Neutrophils are key early responders to viral infection. Neutrophil myeloperoxidase catalyzes the conversion of hydrogen peroxide to hypochlorous acid (HOCl). Previous studies have shown HOCl targets host neutrophil and endothelial cell plasmalogen lipids, resulting in the production of the chlorinated lipid, 2-chlorofatty aldehyde (2-ClFALD). We have previously shown that the oxidation product of 2-ClFALD, 2-chlorofatty acid (2-ClFA) is present in bronchoalveolar lavage fluid of Sendai virus-infected mice, which likely results from the attack of the epithelial plasmalogen by neutrophil-derived HOCl. Herein, we demonstrate small airway epithelial cells contain plasmalogens enriched with oleic acid at the sn-2 position unlike endothelial cells which contain arachidonic acid enrichment at the sn-2 position of plasmalogen. We also show neutrophil-derived HOCl targets epithelial cell plasmalogens to produce 2-ClFALD. Further, proteomics and over-representation analysis using the ω-alkyne analog of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDyA) showed cell adhesion molecule binding and cell-cell junction enriched categories similar to that observed previously in endothelial cells. However, in contrast to endothelial cells, proteins in distinct metabolic pathways were enriched with 2-ClFALD modification, particularly pyruvate metabolism was enriched in epithelial cells and mitochondrial pyruvate respiration was reduced. Collectively, these studies demonstrate, for the first time, a novel plasmalogen molecular species distribution in airway epithelial cells that are targeted by myeloperoxidase-derived hypochlorous acid resulting in electrophilic 2-ClFALD, which potentially modifies epithelial physiology by modifying proteins.
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Affiliation(s)
- Shubha Shakya
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Kelly D Pyles
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Carolyn J Albert
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - Rakesh P Patel
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA; Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Kyle S McCommis
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA
| | - David A Ford
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
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Enzyme Inhibitors from Gorgonians and Soft Corals. Mar Drugs 2023; 21:md21020104. [PMID: 36827145 PMCID: PMC9963996 DOI: 10.3390/md21020104] [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: 12/23/2022] [Revised: 01/28/2023] [Accepted: 01/28/2023] [Indexed: 02/04/2023] Open
Abstract
For decades, gorgonians and soft corals have been considered promising sources of bioactive compounds, attracting the interest of scientists from different fields. As the most abundant bioactive compounds within these organisms, terpenoids, steroids, and alkaloids have received the highest coverage in the scientific literature. However, enzyme inhibitors, a functional class of bioactive compounds with high potential for industry and biomedicine, have received much less notoriety. Thus, we revised scientific literature (1974-2022) on the field of marine natural products searching for enzyme inhibitors isolated from these taxonomic groups. In this review, we present representative enzyme inhibitors from an enzymological perspective, highlighting, when available, data on specific targets, structures, potencies, mechanisms of inhibition, and physiological roles for these molecules. As most of the characterization studies for the new inhibitors remain incomplete, we also included a methodological section presenting a general strategy to face this goal by accomplishing STRENDA (Standards for Reporting Enzymology Data) project guidelines.
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Zhang Y, Xu X, Cheng H, Zhou F. AIM2 and Psoriasis. Front Immunol 2023; 14:1085448. [PMID: 36742336 PMCID: PMC9889639 DOI: 10.3389/fimmu.2023.1085448] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 01/04/2023] [Indexed: 01/20/2023] Open
Abstract
Psoriasis is a chronic inflammatory skin disease occurring worldwide, with multiple systemic complications, which seriously affect the quality of life and physical and mental health of patients. The pathogenesis of psoriasis is related to the environment, genetics, epigenetics, and dysregulation of immune cells such as T cells, dendritic cells (DCs), and nonimmune cells such as keratinocytes. Absent in melanoma 2 (AIM2), a susceptibility gene locus for psoriasis, has been strongly linked to the genetic and epigenetic aspects of psoriasis and increased in expression in psoriatic keratinocytes. AIM2 was found to be activated in an inflammasome-dependent way to release IL-1β and IL-18 to mediate inflammation, and to participate in immune regulation in psoriasis, or in an inflammasome-independent way by regulating the function of regulatory T(Treg) cells or programming cell death in keratinocytes as well as controlling the proliferative state of different cells. AIM2 may also play a role in the recurrence of psoriasis by trained immunity. In this review, we will elaborate on the characteristics of AIM2 and how AIM2 mediates the development of psoriasis.
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Affiliation(s)
- Yuxi Zhang
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.,Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xiaoqing Xu
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.,Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Hui Cheng
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.,Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Fusheng Zhou
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.,Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei, Anhui, China.,Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
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31
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Geerdink RJ, Pascoal Ramos MI, van den Hoogen LL, Radstake TRDJ, Shibayama S, Shibuya A, Bont L, Meyaard L. Differential isoform expression of Allergin-1 during acute and chronic inflammation. Immun Inflamm Dis 2022; 10:e739. [PMID: 36444625 PMCID: PMC9695092 DOI: 10.1002/iid3.739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/08/2022] [Accepted: 10/28/2022] [Indexed: 11/27/2022] Open
Abstract
INTRODUCTION Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation elicits immune pathology. Currently, no effective treatment exists to curb neutrophil activation. However, neutrophils express a variety of inhibitory receptors which may represent potential therapeutic targets to limit neutrophilic inflammation. Indeed, we previously showed that the inhibitory collagen receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) regulates neutrophilic airway inflammation and inhibits neutrophil extracellular trap formation. The inhibitory receptor Allergin-1 is expressed by myeloid cells and B cells. Allergin-1 suppresses mast cell and basophil activation, but a potential regulatory role on neutrophils remains unexplored. We aimed to demonstrate the regulation of neutrophils by Allergin-1. METHODS We examine Allergin-1 isoform expression on human neutrophils during homeostatic (healthy donors) and chronic inflammatory (systemic lupus erythematosus patients) conditions in comparison to other circulating leukocytes by flow cytometry. To reveal a potential role for Allergin-1 in regulating neutrophilic inflammation, we experimentally infect wild-type (WT) and Allergin-1-deficient mice with a respiratory syncytial virus (RSV) and monitor disease severity and examine cellular airway infiltrate. Flow cytometry was used to confirm Allergin-1 expression by airway-infiltrated neutrophils in RSV infection-induced bronchiolitis patients. RESULTS Only the short 1 (S1) isoform, but not the long (L) or S2 isoform could be detected on blood leukocytes, with the exception of nonclassical monocytes, which exclusively express the S2 isoform. Allergin-1 expression levels did not vary significantly between healthy individuals and patients with the systemic inflammatory disease on any interrogated cell type. Airway-infiltrated neutrophils of pediatric RSV bronchiolitis patients were found to express Allergin-1S1. However, Allergin-1-deficient mice experimentally infected with RSV did not show exacerbated disease or increased neutrophil airway infiltration compared to WT littermates. CONCLUSION Allergin-1 isoform expression is unaffected by chronic inflammatory conditions. In stark contrast to fellow inhibitory receptor LAIR-1, Allergin-1 does not regulate neutrophilic inflammation in a mouse model of RSV bronchiolitis.
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Affiliation(s)
- Ruben J. Geerdink
- Center for Translational Immunology, University Medical Centre UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Maria Inês Pascoal Ramos
- Center for Translational Immunology, University Medical Centre UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Luuk L. van den Hoogen
- Department of Rheumatology and Clinical ImmunologyUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Timothy R. D. J. Radstake
- Center for Translational Immunology, University Medical Centre UtrechtUtrecht UniversityUtrechtThe Netherlands
| | - Shiro Shibayama
- Research Centre of Immunology, Tsukuba InstituteONO Pharmaceutical Co., Ltd.TsukubaIbarakiJapan
| | - Akira Shibuya
- Department of Immunology, Faculty of MedicineUniversity of TsukubaTsukubaIbarakiJapan
| | - Louis Bont
- Center for Translational Immunology, University Medical Centre UtrechtUtrecht UniversityUtrechtThe Netherlands
- Department of Paediatrics, Wilhelmina Children's HospitalUniversity Medical Centre UtrechtUtrechtThe Netherlands
| | - Linde Meyaard
- Center for Translational Immunology, University Medical Centre UtrechtUtrecht UniversityUtrechtThe Netherlands
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Sconocchia G, Lanzilli G, Cesarini V, Silvestris DA, Rezvani K, Arriga R, Caratelli S, Chen K, Dou J, Cenciarelli C, Toietta G, Baldari S, Sconocchia T, De Paolis F, Aureli A, Iezzi G, Irno Consalvo M, Buccisano F, Del Principe MI, Maurillo L, Venditti A, Ottaviani A, Spagnoli GC. Direct CD32 T-cell cytotoxicity: implications for breast cancer prognosis and treatment. Life Sci Alliance 2022; 5:e202201590. [PMID: 36241426 PMCID: PMC9586128 DOI: 10.26508/lsa.202201590] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 09/07/2022] [Accepted: 09/07/2022] [Indexed: 11/24/2022] Open
Abstract
The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice from subcutaneous growth of MDA-MB-468 BC cells. RNAseq analysis identified a 42 gene fingerprint predicting BC cell sensitivity and favorable outcomes in advanced BC. ICAM1 was a major regulator of CD32-CR T cell-mediated cytotoxicity. CD32-CR T cells may help identify cell surface CD32 ligand(s) and novel prognostically relevant transcriptomic signatures and develop innovative BC treatments.
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Affiliation(s)
- Giuseppe Sconocchia
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Giulia Lanzilli
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Valeriana Cesarini
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | | | - Katayoun Rezvani
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Roberto Arriga
- Department of Systems Medicine, the University of Rome "Tor Vergata", Rome, Italy
| | - Sara Caratelli
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Ken Chen
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Jinzhuang Dou
- Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Carlo Cenciarelli
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Gabriele Toietta
- Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Silvia Baldari
- Tumor Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Tommaso Sconocchia
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
| | - Francesca De Paolis
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Anna Aureli
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Giandomenica Iezzi
- Department of Surgery, Università Svizzera Italiana, Lugano, Switzerland
| | - Maria Irno Consalvo
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Francesco Buccisano
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Maria I Del Principe
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Luca Maurillo
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Adriano Venditti
- Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy
| | - Alessio Ottaviani
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
| | - Giulio C Spagnoli
- Department of Biomedicine Institute of Translational Pharmacology (IFT), National Research Council (CNR), Rome, Italy
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Rizo-Téllez SA, Sekheri M, Filep JG. Myeloperoxidase: Regulation of Neutrophil Function and Target for Therapy. Antioxidants (Basel) 2022; 11:antiox11112302. [PMID: 36421487 PMCID: PMC9687284 DOI: 10.3390/antiox11112302] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/04/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Neutrophils, the most abundant white blood cells in humans, are critical for host defense against invading pathogens. Equipped with an array of antimicrobial molecules, neutrophils can eradicate bacteria and clear debris. Among the microbicide proteins is the heme protein myeloperoxidase (MPO), stored in the azurophilic granules, and catalyzes the formation of the chlorinating oxidant HOCl and other oxidants (HOSCN and HOBr). MPO is generally associated with killing trapped bacteria and inflicting collateral tissue damage to the host. However, the characterization of non-enzymatic functions of MPO suggests additional roles for this protein. Indeed, evolving evidence indicates that MPO can directly modulate the function and fate of neutrophils, thereby shaping immunity. These actions include MPO orchestration of neutrophil trafficking, activation, phagocytosis, lifespan, formation of extracellular traps, and MPO-triggered autoimmunity. This review scrutinizes the multifaceted roles of MPO in immunity, focusing on neutrophil-mediated host defense, tissue damage, repair, and autoimmunity. We also discuss novel therapeutic approaches to target MPO activity, expression, or MPO signaling for the treatment of inflammatory and autoimmune diseases.
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Affiliation(s)
- Salma A. Rizo-Téllez
- Department of Pathology and Cell Biology, University of Montreal, Montreal, QC H3T 1J4, Canada
- Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada
| | - Meriem Sekheri
- Department of Pathology and Cell Biology, University of Montreal, Montreal, QC H3T 1J4, Canada
- Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada
| | - János G. Filep
- Department of Pathology and Cell Biology, University of Montreal, Montreal, QC H3T 1J4, Canada
- Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada
- Correspondence: ; Tel.: +1-514-252-3400 (ext. 4662)
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Braun SA, Bauer AT, Németh C, Rózsa A, Rusch L, Erpenbeck L, Schloer S, Silling S, Metze D, Gerber PA, Schneider SW, Gyulai R, Homey B. Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts. Int J Mol Sci 2022; 23:ijms232113377. [PMID: 36362165 PMCID: PMC9656782 DOI: 10.3390/ijms232113377] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/20/2022] [Accepted: 10/30/2022] [Indexed: 11/06/2022] Open
Abstract
Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.
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Affiliation(s)
- Stephan A. Braun
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
- Correspondence: ; Tel.: +49-2351-83-58637
| | - Alexander T. Bauer
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Csongor Németh
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Annamária Rózsa
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Louisa Rusch
- Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Luise Erpenbeck
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
| | - Sebastian Schloer
- Center for Molecular Biology of Inflammation, Institute of Medical Biochemistry, University of Muenster, 48149 Muenster, Germany
- Leibniz Institute of Virology, 20251 Hamburg, Germany
| | - Steffi Silling
- Institute of Virology, National Reference Center for Papilloma- and Polyomaviruses, Faculty of Medicine and University Hospital Cologne, 50935 Cologne, Germany
| | - Dieter Metze
- Department of Dermatology, University Hospital Muenster, 48149 Muenster, Germany
| | - Peter A. Gerber
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
| | - Stefan W. Schneider
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Rolland Gyulai
- Department of Dermatology, Venereology and Oncodermatology, University of Pécs, Medical Center, 7632 Pécs, Hungary
| | - Bernhard Homey
- Department of Dermatology, Medical Faculty, Heinrich-Heine University, 40225 Duesseldorf, Germany
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Takemura Y, Tanifuji T, Okazaki S, Shinko Y, Otsuka I, Horai T, Shirai T, Aso K, Yamamoto N, Hishimoto A. Epigenetic clock analysis in methamphetamine dependence. Psychiatry Res 2022; 317:114901. [PMID: 36244160 DOI: 10.1016/j.psychres.2022.114901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/24/2022] [Accepted: 10/08/2022] [Indexed: 01/05/2023]
Abstract
Methamphetamine (MA) is used worldwide and causes serious public health and social problems. MA affects the central nervous, cardiac, and immune systems, which causes neuropsychiatric and cardiovascular diseases and infection. Epigenetic changes, including DNA methylation (DNAm), are associated with various clinical phenotypes of MA abuse. DNAm is related to biological aging and health risks; hence, we aimed to assess the changes in biological aging in MA dependence using the DNAm age and DNA methylation-based telomere length (DNAmTL). We used five measures of DNAm age (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, and GrimAge), DNAmTL, and DNAm-based age-predictive factors (plasma proteins and blood cell composition). We compared patients with MA dependence and healthy controls (n = 24 each) using the DNAm profiles obtained from whole-blood samples. Patients with MA dependence showed significant acceleration in PhenoAge and GrimAge, as well as a trend for significant acceleration in DNAmTL. Following adjustment for confounding factors, MA dependence was significantly associated with accelerations in PhenoAge, GrimAge, and DNAmTL, as well as alterations in DNAm-based age-predictive factors (beta-2-microglobulin, granulocytes, and naive cluster of differentiation 4+ T cells). Our results suggested an acceleration of biological aging and specific changes in the DNAm of age- predictive factors in MA dependence.
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Affiliation(s)
- Yukihiro Takemura
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Psychiatry, Fukko-kai Tarumi Hospital, Kobe, Japan
| | - Takaki Tanifuji
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Satoshi Okazaki
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
| | - Yutaka Shinko
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Ikuo Otsuka
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Tadasu Horai
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Toshiyuki Shirai
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
| | - Katsuro Aso
- Department of Psychiatry, Fukko-kai Tarumi Hospital, Kobe, Japan
| | - Noriya Yamamoto
- Department of Psychiatry, Fukko-kai Tarumi Hospital, Kobe, Japan
| | - Akitoyo Hishimoto
- Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Department of Psychiatry, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Sun Y, Zou Y, Wang H, Cui G, Yu Z, Ren Z. Immune response induced by novel coronavirus infection. Front Cell Infect Microbiol 2022; 12:988604. [PMID: 36389144 PMCID: PMC9641212 DOI: 10.3389/fcimb.2022.988604] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has been prominent around the world since it was first discovered, affecting more than 100 million people. Although the symptoms of most infected patients are not serious, there is still a considerable proportion of patients who need hospitalization and even develop fatal symptoms such as cytokine storms, acute respiratory distress syndrome and so on. Cytokine storm is usually described as a collection of clinical manifestations caused by overactivation of the immune system, which plays an important role in tissue injury and multiorgan failure. The immune system of healthy individuals is composed of two interrelated parts, the innate immune system and the adaptive immune system. Innate immunity is the body's first line of defense against viruses; it can quickly perceive viruses through pattern recognition receptors and activate related inflammatory pathways to clear pathogens. The adaptive immune system is activated by specific antigens and is mainly composed of CD4+ T cells, CD8+ T cells and B cells, which play different roles in viral infection. Here, we discuss the immune response after SARS-CoV-2 infection. In-depth study of the recognition of and response of innate immunity and adaptive immunity to SARS-CoV-2 will help to prevent the development of critical cases and aid the exploration of more targeted treatments.
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Affiliation(s)
- Ying Sun
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yawen Zou
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Haiyu Wang
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Alakesh A, Jothiprakasam T, Raghavan JV, Jhunjhunwala S. Sterile inflammation alters neutrophil kinetics in mice. J Leukoc Biol 2022; 112:395-409. [PMID: 35172385 PMCID: PMC7616002 DOI: 10.1002/jlb.1a0321-132rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Neutrophils play a crucial role in establishing inflammation in response to an infection or injury, but their production rates, as well as blood and tissue residence times, remain poorly characterized under these conditions. Herein, using a biomaterial implant model to establish inflammation followed by in vivo tracking of newly formed neutrophils, we determine neutrophil kinetics under inflammatory conditions. To obtain quantifiable information from our experimental observations, we develop an ordinary differential equation-based mathematical model to extract kinetic parameters. Our data show that in the presence of inflammation resulting in emergency granulopoiesis-like conditions, neutrophil maturation time in the bone marrow reduces by around 60% and reduced half-life in the blood, compared with noninflammatory conditions. Additionally, neutrophil residence time at the inflammatory site increases by 2-fold. Together, these data improve our understanding of neutrophil kinetics under inflammatory conditions, which could pave the way for therapies that focus on modulating in vivo neutrophil dynamics.
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Affiliation(s)
- Alakesh Alakesh
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India – 560012
| | | | - Jayashree V. Raghavan
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India – 560012
| | - Siddharth Jhunjhunwala
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India – 560012
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Ventura-Santana E, Ninan JR, Snyder CM, Okeke EB. Neutrophil Extracellular Traps, Sepsis and COVID-19 - A Tripod Stand. Front Immunol 2022; 13:902206. [PMID: 35757734 PMCID: PMC9226304 DOI: 10.3389/fimmu.2022.902206] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/11/2022] [Indexed: 12/12/2022] Open
Abstract
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic. Majority of COVID-19 patients have mild disease but about 20% of COVID-19 patients progress to severe disease. These patients end up in the intensive care unit (ICU) with clinical manifestations of acute respiratory distress syndrome (ARDS) and sepsis. The formation of neutrophil extracellular traps (NETs) has also been associated with severe COVID-19. Understanding of the immunopathology of COVID-19 is critical for the development of effective therapeutics. In this article, we discuss evidence indicating that severe COVID-19 has clinical presentations consistent with the definitions of viral sepsis. We highlight the role of neutrophils and NETs formation in the pathogenesis of severe COVID-19. Finally, we highlight the potential of therapies inhibiting NETs formation for the treatment of COVID-19.
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Affiliation(s)
- Esmeiry Ventura-Santana
- Department of Biology, State University of New York at Fredonia, Fredonia, NY, United States
| | - Joshua R Ninan
- Department of Biology, State University of New York at Fredonia, Fredonia, NY, United States
| | - Caitlin M Snyder
- Department of Biology, State University of New York at Fredonia, Fredonia, NY, United States
| | - Emeka B Okeke
- Department of Biology, State University of New York at Fredonia, Fredonia, NY, United States
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Endothelial Cell Protein Targeting by Myeloperoxidase-Derived 2-Chlorofatty Aldehyde. Antioxidants (Basel) 2022; 11:antiox11050940. [PMID: 35624804 PMCID: PMC9138145 DOI: 10.3390/antiox11050940] [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: 04/07/2022] [Revised: 05/04/2022] [Accepted: 05/04/2022] [Indexed: 11/17/2022] Open
Abstract
Neutrophils are important cellular mediators of injury and repair in diseases including ischemic heart disease, atherosclerosis, and sepsis. Myeloperoxidase-derived (MPO)-oxidants released from neutrophils are potential mediators of endothelial injury in disease. MPO-derived HOCl attacks plasmalogen phospholipid to liberate 2-chlorofatty aldehyde (2-ClFALD). Both 2-ClFALD and its oxidation product, 2-chlorofatty acid (2-ClFA), are electrophilic lipids, and both probably react with proteins through several mechanisms. In the present study, we investigate protein modification specifically by 2-ClFALD under non-reducing conditions (e.g., without stabilizing Schiff base bonds), which likely reflects nucleophilic targeting of the electrophilic chlorinated carbon. Protein modification by the ω-alkyne analog of 2-chlorohexadecanal (2-ClHDA), 2-ClHDyA, was compared to that with the ω-alkyne analog of 2-chlorohexadecanoic acid (2-ClHA), 2-ClHyA, in multiple cell lines, which demonstrated 2-ClFALD preferentially modifies proteins compared to 2-ClFA. The 2-ClHDyA modified proteins from EA.hy926 cells and human lung microvascular endothelial cells analyzed by shotgun proteomics and over-representation analysis included adherens junction, cell adhesion molecule binding, and cell substrate junction enrichment categories. It is possible that proteins in these groups may have roles in previously described 2-ClFALD-elicited endothelial barrier dysfunction.
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Barman TK, Singh AK, Bonin JL, Nafiz TN, Salmon SL, Metzger DW. Lethal synergy between SARS-CoV-2 and Streptococcus pneumoniae in hACE2 mice and protective efficacy of vaccination. JCI Insight 2022; 7:159422. [PMID: 35482422 DOI: 10.1172/jci.insight.159422] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 04/26/2022] [Indexed: 11/17/2022] Open
Abstract
Secondary infections are frequent complications of viral respiratory infections but the potential consequence of SARS-CoV-2 co-infection with common pulmonary pathogens is poorly understood. We report that co-infection of human ACE2 transgenic mice with sublethal doses of SARS-CoV-2 and Streptococcus pneumoniae results in synergistic lung inflammation and lethality. Mortality was observed regardless of whether SARS-CoV-2 challenge occurred before or after establishment of sublethal pneumococcal infection. Increased bacterial levels following co-infection were associated with alveolar macrophage depletion and treatment with murine GM-CSF reduced lung bacteria numbers and pathology, and partially protected from death. However, therapeutic targeting of interferons, an approach that is effective against influenza co-infections, failed to increase survival. Combined vaccination against both SARS-CoV-2 and pneumococci resulted in 100% protection against subsequent co-infection. The results indicate that when seasonal respiratory infections return to pre-pandemic levels, they could lead to an increased incidence of lethal COVID-19 superinfections, especially among the unvaccinated population. .
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Affiliation(s)
- Tarani Kanta Barman
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
| | - Amit K Singh
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
| | - Jesse L Bonin
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
| | - Tanvir N Nafiz
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
| | - Sharon L Salmon
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
| | - Dennis W Metzger
- Department of Immunology and Microbial Disease, Albany Medical College, Albany, United States of America
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Filep JG. Targeting Neutrophils for Promoting the Resolution of Inflammation. Front Immunol 2022; 13:866747. [PMID: 35371088 PMCID: PMC8966391 DOI: 10.3389/fimmu.2022.866747] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 02/21/2022] [Indexed: 12/15/2022] Open
Abstract
Acute inflammation is a localized and self-limited innate host-defense mechanism against invading pathogens and tissue injury. Neutrophils, the most abundant immune cells in humans, play pivotal roles in host defense by eradicating invading pathogens and debris. Ideally, elimination of the offending insult prompts repair and return to homeostasis. However, the neutrophils` powerful weaponry to combat microbes can also cause tissue damage and neutrophil-driven inflammation is a unifying mechanism for many diseases. For timely resolution of inflammation, in addition to stopping neutrophil recruitment, emigrated neutrophils need to be disarmed and removed from the affected site. Accumulating evidence documents the phenotypic and functional versatility of neutrophils far beyond their antimicrobial functions. Hence, understanding the receptors that integrate opposing cues and checkpoints that determine the fate of neutrophils in inflamed tissues provides insight into the mechanisms that distinguish protective and dysregulated, excessive inflammation and govern resolution. This review aims to provide a brief overview and update with key points from recent advances on neutrophil heterogeneity, functional versatility and signaling, and discusses challenges and emerging therapeutic approaches that target neutrophils to enhance the resolution of inflammation.
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Affiliation(s)
- János G Filep
- Department of Pathology and Cell Biology, University of Montreal, Montreal, QC, Canada.,Research Center, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
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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: 34] [Impact Index Per Article: 11.3] [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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NETosis and SARS-COV-2 infection related thrombosis: a narrative review. Thromb J 2022; 20:13. [PMID: 35354492 PMCID: PMC8965217 DOI: 10.1186/s12959-022-00375-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 03/23/2022] [Indexed: 12/23/2022] Open
Abstract
Background Coronavirus disease 2019 (COVID-19) infection is related to immune hyperactivity, the release of inflammatory cytokines, and immunothrombosis. Among the underlying mechanisms in COVID-19 thrombosis, neutrophil extracellular traps (NETs) formation, NETosis, may have a significant role. COVID-19 thrombi obtained from extracorporeal membrane oxygenation contained an accumulation of neutrophils and in a higher amount of NETs when compared with non-COVID-19 thrombi specimens. Main body During sepsis and inflammatory status, NETs released from neutrophils and histones and nucleosomes extruded into the extracellular space and take part in the host innate immunity defense, inflammation, and thrombosis. Excessive NETosis is related to clinical progression and respiratory failure in infections and sepsis. NETosis act as a scaffold for thrombus formation, and new associative data support the relation between deregulated immune responses with thrombus formation and organ failure. NETosis is reported in COVID-19 patients. In COVID-19 infection, overproduction of tissue factor (TF) by neutrophils has a role in immunothrombosis. Additionally, NETs can trap TF pathway inhibitor (TFPI) as the only endogenous protein that effectively inhibits the activity of the significant proteases– complexes, TF–FVIIa and prothrombinase. Conclusion Because of NETosis can induce intrinsic and extrinsic coagulation cascade activation through the production of TF, activation of FXII, and inhibition of TFPI and fibrinolysis and induce immunothrombosis, targeting NETosis may diminish thrombus formation related to NETs in COVID-19 patients.
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Wang X, Sanborn MA, Dai Y, Rehman J. Temporal transcriptomic analysis using TrendCatcher identifies early and persistent neutrophil activation in severe COVID-19. JCI Insight 2022; 7:157255. [PMID: 35175937 PMCID: PMC9057597 DOI: 10.1172/jci.insight.157255] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Studying temporal gene expression shifts during disease progression provides important insights into the biological mechanisms that distinguish adaptive and maladaptive responses. Existing tools for the analysis of time course transcriptomic data are not designed to optimally identify distinct temporal patterns when analyzing dynamic differentially expressed genes (DDEGs). Moreover, there are not enough methods to assess and visualize the temporal progression of biological pathways mapped from time course transcriptomic data sets. In this study, we developed an open-source R package TrendCatcher (https://github.com/jaleesr/TrendCatcher), which applies the smoothing spline ANOVA model and break point searching strategy, to identify and visualize distinct dynamic transcriptional gene signatures and biological processes from longitudinal data sets. We used TrendCatcher to perform a systematic temporal analysis of COVID-19 peripheral blood transcriptomes, including bulk and single-cell RNA-Seq time course data. TrendCatcher uncovered the early and persistent activation of neutrophils and coagulation pathways, as well as impaired type I IFN (IFN-I) signaling in circulating cells as a hallmark of patients who progressed to severe COVID-19, whereas no such patterns were identified in individuals receiving SARS-CoV-2 vaccinations or patients with mild COVID-19. These results underscore the importance of systematic temporal analysis to identify early biomarkers and possible pathogenic therapeutic targets.
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Affiliation(s)
- Xinge Wang
- Department of Biomedical Engineering, University of Illinois Colleges of Engineering and Medicine, Chicago, United States of America
| | - Mark A Sanborn
- Department of Pharmacology and Regenerative Medicine, University of Illinois Colleges of Engineering and Medicine, Chicago, United States of America
| | - Yang Dai
- Department of Biomedical Engineering, University of Illinois Colleges of Engineering and Medicine, Chicago, United States of America
| | - Jalees Rehman
- Department of Pharmacology and Regenerative Medicine, University of Illinois Colleges of Engineering and Medicine, Chicago, United States of America
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Kraus RF, Gruber MA. Neutrophils-From Bone Marrow to First-Line Defense of the Innate Immune System. Front Immunol 2022; 12:767175. [PMID: 35003081 PMCID: PMC8732951 DOI: 10.3389/fimmu.2021.767175] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022] Open
Abstract
Neutrophils (polymorphonuclear cells; PMNs) form a first line of defense against pathogens and are therefore an important component of the innate immune response. As a result of poorly controlled activation, however, PMNs can also mediate tissue damage in numerous diseases, often by increasing tissue inflammation and injury. According to current knowledge, PMNs are not only part of the pathogenesis of infectious and autoimmune diseases but also of conditions with disturbed tissue homeostasis such as trauma and shock. Scientific advances in the past two decades have changed the role of neutrophils from that of solely immune defense cells to cells that are responsible for the general integrity of the body, even in the absence of pathogens. To better understand PMN function in the human organism, our review outlines the role of PMNs within the innate immune system. This review provides an overview of the migration of PMNs from the vascular compartment to the target tissue as well as their chemotactic processes and illuminates crucial neutrophil immune properties at the site of the lesion. The review is focused on the formation of chemotactic gradients in interaction with the extracellular matrix (ECM) and the influence of the ECM on PMN function. In addition, our review summarizes current knowledge about the phenomenon of bidirectional and reverse PMN migration, neutrophil microtubules, and the microtubule organizing center in PMN migration. As a conclusive feature, we review and discuss new findings about neutrophil behavior in cancer environment and tumor tissue.
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Affiliation(s)
- Richard Felix Kraus
- Department of Anesthesiology, University Medical Center Regensburg, Regensburg, Germany
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Poto R, Cristinziano L, Modestino L, de Paulis A, Marone G, Loffredo S, Galdiero MR, Varricchi G. Neutrophil Extracellular Traps, Angiogenesis and Cancer. Biomedicines 2022; 10:biomedicines10020431. [PMID: 35203640 PMCID: PMC8962440 DOI: 10.3390/biomedicines10020431] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 12/07/2022] Open
Abstract
Human neutrophils, the most abundant circulating leukocytes, are fundamental components of the host response against different pathogens. Until a few years ago, neutrophils received limited attention in cancer immunology. Recently, it was discovered that both circulating, and tumor-associated, neutrophils possess functional plasticity when exposed to various inflammatory stimuli and in the tumor microenvironment. Neutrophils and their mediators can exert several pro-tumor activities in cancer and promote metastasis through different mechanisms. Angiogenesis plays a pivotal role in inflammation and tumor growth. Activated human neutrophils release several angiogenic factors [vascular endothelial growth factor-A (VEGF-A), angiopoietin-1 (ANGPT1), CXCL8, hepatocyte growth factor (HGF), and metalloproteinase 9 (MMP-9)] and form neutrophil extracellular traps (NETs). NETs promote tumor growth and metastasis formation through several mechanisms: they can awake dormant cancer cells, capture circulating tumor cells, coat and shield cancer cells, thus preventing CD8+- and natural killer (NK) cell-mediated cytotoxicity. ANGPTs released by endothelial and periendothelial mural cells induce platelet-activating factor (PAF) synthesis and neutrophil adhesion to endothelial cells. NETs can directly exert several proangiogenic activities in human endothelial cells and NETs induced by ANGPTs and PAF increase several aspects of angiogenesis in vitro and in vivo. A better understanding of the pathophysiological functions of NETs in cancer and angiogenesis could be of importance in the early diagnosis, prevention and treatment of tumors.
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Affiliation(s)
- Remo Poto
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
| | - Leonardo Cristinziano
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
| | - Luca Modestino
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
| | - Amato de Paulis
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131 Naples, Italy
| | - Stefania Loffredo
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131 Naples, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131 Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy; (R.P.); (L.C.); (L.M.); (A.d.P.); (G.M.); (S.L.); (M.R.G.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80131 Naples, Italy
- World Allergy Organization (WAO) Center of Excellence, 80131 Naples, Italy
- Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council, 80131 Naples, Italy
- Correspondence:
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DI Stefano A, Gnemmi I, Dossena F, Ricciardolo FL, Maniscalco M, Lo Bello F, Balbi B. Pathogenesis of COPD at the cellular and molecular level. Minerva Med 2022; 113:405-423. [PMID: 35138077 DOI: 10.23736/s0026-4806.22.07927-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chronic inflammatory responses in the lung of patients with stable mild-to severe forms of COPD play a central role in the definition, comprehension and monitoring of the disease state. A better understanding of the COPD pathogenesis can't avoid a detailed knowledge of these inflammatory changes altering the functional health of the lung during the disease progression. We here summarize and discuss the role and principal functions of the inflammatory cells populating the large, small airways and lung parenchyma of patients with COPD of increasing severity in comparison with healthy control subjects: T and B lymphocytes, NK and Innate Lymphoid cells, macrophages, and neutrophils. The differential inflammatory distribution in large and small airways of patients is also discussed. Furthermore, relevant cellular mechanisms controlling the homeostasis and the "normal" balance of these inflammatory cells and of structural cells in the lung, such as autophagy, apoptosis, necroptosis and pyroptosis are as well presented and discussed in the context of the COPD severity.
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Affiliation(s)
- Antonino DI Stefano
- Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri, SpA, Società Benefit, IRCCS, Veruno, Novara, Italy -
| | - Isabella Gnemmi
- Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri, SpA, Società Benefit, IRCCS, Veruno, Novara, Italy
| | - Francesca Dossena
- Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri, SpA, Società Benefit, IRCCS, Veruno, Novara, Italy
| | - Fabio L Ricciardolo
- Rare Lung Disease Unit and Severe Asthma Centre, Department of Clinical and Biological Sciences, San Luigi Gonzaga University Hospital Orbassano, University of Turin, Turin, Italy
| | - Mauro Maniscalco
- Divisione di Pneumologia, Istituti Clinici Scientifici Maugeri, SpA, Società Benefit, IRCCS, Telese, Benevento, Italy
| | - Federica Lo Bello
- Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy
| | - Bruno Balbi
- Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri, SpA, Società Benefit, IRCCS, Veruno, Novara, Italy
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Antonelou M, Evans RDR, Henderson SR, Salama AD. Neutrophils are key mediators in crescentic glomerulonephritis and targets for new therapeutic approaches. Nephrol Dial Transplant 2022; 37:230-238. [PMID: 33057680 DOI: 10.1093/ndt/gfaa206] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Indexed: 12/26/2022] Open
Abstract
Crescentic glomerulonephritis (CGN) results from a diverse set of diseases associated with immune dysregulation and the breakdown of self-tolerance to a wide range of autoantigens, some known and some that remain unknown. Experimental data demonstrate that neutrophils have an important role in the pathogenesis of CGN. Upon activation, neutrophils generate reactive oxygen species, release serine proteases and form neutrophil extracellular traps (NETs), all of which can induce direct tissue damage. In addition, serine proteases such as myeloperoxidase and proteinase 3, presented on NETs, can be processed and recognized as autoantigens, leading to the generation and maintenance of autoimmune responses in susceptible individuals. The basis of the specificity of autoimmune responses in different patients to NET proteins is unclear, but relates at least in part to differences in human leucocyte antigen expression. Conditions associated with CGN are often characterized by aberrant neutrophil activation and NETosis and, in some, impaired NET degradation. Targeting neutrophil degranulation and NETosis is now possible using a variety of novel compounds and may provide a promising therapeutic alternative to glucocorticoid use, which has been a mainstay of management in CGN for decades and is associated with significant adverse effects. In this review, we discuss the evidence supporting the role of neutrophils in the development of CGN and the pathways identified in neutrophil degranulation and NETosis that may translate to novel therapeutic applications.
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Affiliation(s)
- Marilina Antonelou
- University College London, Department of Renal Medicine, Royal Free Hospital, London, UK
| | - Rhys D R Evans
- University College London, Department of Renal Medicine, Royal Free Hospital, London, UK
| | - Scott R Henderson
- University College London, Department of Renal Medicine, Royal Free Hospital, London, UK
| | - Alan D Salama
- University College London, Department of Renal Medicine, Royal Free Hospital, London, UK
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Heinkel F, Verstraete MM, Cao S, Li J, Farber P, Stangle E, Silva-Moreno B, Peng F, Dixit S, Boulanger MJ, Spreter Von Kreudenstein T, Escobar-Cabrera E. Engineering a pure and stable heterodimeric IgA for the development of multispecific therapeutics. MAbs 2022; 14:2141637. [PMID: 36343329 PMCID: PMC9645255 DOI: 10.1080/19420862.2022.2141637] [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] [Indexed: 11/09/2022] Open
Abstract
ABBREVIATIONS CE-SDS: capillary electrophoresis sodium dodecyl sulfate; DSC: differential scanning calorimetry; FACS: fluorescence-activated cell sorting; FSA: full-sized antibody; Her2: human epidermal growth factor receptor 2; MFI: mean fluorescent intensity; OAA: one-armed antibody; PBS: phosphate-buffered saline; PDB: Protein Data Bank; SEC: size-exclusion chromatography; prepSEC (preparative SEC); RMSD: root-mean-square deviation; RU: resonance units; SPR: surface plasmon resonance; TAA: tumor-associated antigen; WT: wild-type.
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Affiliation(s)
| | - Meghan M. Verstraete
- Zymeworks Inc., Vancouver, BC, Canada,CONTACT Meghan M. Verstraete Zymeworks Inc, 114 East 4th Avenue, Suite 800, Vancouver, BCV5T 1G4, Canada
| | - Siran Cao
- Zymeworks Inc., Vancouver, BC, Canada
| | | | | | | | | | - Fangni Peng
- Department of Biochemistry and Microbiology; University of Victoria, Victoria, BC, Canada
| | | | - Martin J. Boulanger
- Department of Biochemistry and Microbiology; University of Victoria, Victoria, BC, Canada
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Lopes-Pires ME, Frade-Guanaes JO, Quinlan GJ. Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention. Antioxidants (Basel) 2021; 11:88. [PMID: 35052592 PMCID: PMC8773140 DOI: 10.3390/antiox11010088] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 11/17/2022] Open
Abstract
Sepsis is regarded as one of the main causes of death among the critically ill. Pathogen infection results in a host-mediated pro-inflammatory response to fight infection; as part of this response, significant endogenous reactive oxygen (ROS) and nitrogen species (RNS) production occurs, instigated by a variety of sources, including activated inflammatory cells, such as neutrophils, platelets, and cells from the vascular endothelium. Inflammation can become an inappropriate self-sustaining and expansive process, resulting in sepsis. Patients with sepsis often exhibit loss of aspects of normal vascular homeostatic control, resulting in abnormal coagulation events and the development of disseminated intravascular coagulation. Diagnosis and treatment of sepsis remain a significant challenge for healthcare providers globally. Targeting the drivers of excessive oxidative/nitrosative stress using antioxidant treatments might be a therapeutic option. This review focuses on the association between excessive oxidative/nitrosative stress, a common feature in sepsis, and loss of homeostatic control at the level of the vasculature. The literature relating to potential antioxidants is also described.
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Affiliation(s)
- Maria Elisa Lopes-Pires
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London W12 0NN, UK;
| | | | - Gregory J. Quinlan
- National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London W12 0NN, UK;
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