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Zhou Q, Zhu W, Cai X, Jing J, Wang M, Wang S, Jin A, Meng X, Wei T, Wang Y, Pan Y. Obesity and brain volumes: mediation by cardiometabolic and inflammatory measures. Stroke Vasc Neurol 2025; 10:e003045. [PMID: 39160093 DOI: 10.1136/svn-2023-003045] [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: 12/13/2023] [Accepted: 07/25/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND This study aimed to investigate the relationship between overall obesity, central obesity and brain volumes, as well as to determine the extent to which cardiometabolic and inflammatory measures act as mediators in the association between body mass index (BMI), waist-hip ratio (WHR) and brain volumes. METHODS In the context of counterfactual framework, mediation analysis was used to explore the potential mediation in which cardiometabolic and inflammatory measures may mediate the relationship between BMI, WHR, and brain volumes. RESULTS Among 2413 community-dwelling participants, those with high BMI or WHR levels experienced an approximately brain ageing of 4 years. Especially, individuals with high WHR or BMI under the age of 65 exhibited white matter hyperintensity volume (WMHV) differences equivalent to around 5 years of ageing. Conversely, in the high-level WHR population over the age of 65, premature brain ageing in gray matter volume (GMV) exceeded 4.5 years. For GMV, more than 45% of the observed effect of WHR was mediated by glycaemic metabolism indicators. This proportion increases to 78.70% when blood pressure, triglyceride, leucocyte count, and neutrophil count are jointly considered with glycaemic metabolism indicators. Regarding WHR and BMI's association with WMHV, cardiometabolic and inflammatory indicators, along with high-density lipoprotein cholesterol, mediated 35.50% and 20.20% of the respective effects. CONCLUSIONS Overall obesity and central obesity were associated with lower GMV and higher WMHV, a process that is partially mediated by the presence of cardiometabolic and inflammatory measures.
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Affiliation(s)
- Qi Zhou
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Wanlin Zhu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xueli Cai
- Department of Neurology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China
- Lishui Clinical Research Center for Neurological Diseases, Lishui, Zhejiang, China
| | - Jing Jing
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Mengxing Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Suying Wang
- Cerebrovascular Research Lab, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, China
| | - Aoming Jin
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Xia Meng
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Tiemin Wei
- Department of Cardiology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, Zhejiang, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
- Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, 2019RU018, Beijing, China
| | - Yuesong Pan
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
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Zhou X, Yang Y, Su Z, Luo Z. Dexmedetomidine Protects the Brain: Exploring the α2AR/FAK Pathway in Post-Stroke Intestinal Barrier Repair. FRONT BIOSCI-LANDMRK 2025; 30:27159. [PMID: 40018945 DOI: 10.31083/fbl27159] [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: 10/27/2024] [Revised: 12/19/2024] [Accepted: 01/09/2025] [Indexed: 03/01/2025]
Abstract
INTRODUCTION Globally, ischemic stroke is a major cause of mortality and disability, posing a significant challenge in clinical practice and public health. Recent studies have reported that stroke leads to the impairment of the intestinal barrier and the migration of intestinal bacteria to multiple organs. This process exacerbates neurological damage by further impairing intestinal barrier function and leading to bacterial translocation. Dexmedetomidine (Dex), an α2-adrenoceptor (α2AR) agonist, has proven anti-cerebral ischemic effects, yet its effects in post-stroke intestinal dysfunction remain unclear. This study aimed to determine whether Dex mitigates intestinal dysfunction and brain injury following cerebral ischemia-reperfusion. METHODS A C57BL/6J mouse model of middle cerebral artery occlusion (MCAO) was used for in vivo experiments, while lipopolysaccharide (LPS)-induced Caco-2 monolayers served as an in vitro model of intestinal barrier dysfunction. Neuronal apoptosis was evaluated using neuronal nuclei (NeuN) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) double labeling. Reverse transcription-quantitative PCR (RT-qPCR) was performed to measure pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Intestinal permeability was assessed using histological score, serum fluorescein isothiocyanate (FITC)-dextran fluorescence, and endotoxin levels. The expression levels of epithelial cadherin (E-cadherin), zonula occludens-1 (ZO-1), and occludin were analyzed by western blot and immunofluorescence. Statistical analyses included analysis of variance with Tukey's post-hoc test. RESULTS Dex treatment significantly reduced cerebral infarct volume (p < 0.001) and improved neurological scores compared to MCAO controls. Neuronal apoptosis was significantly inhibited (p < 0.01), as evidenced by reduced TUNEL-positive cells in Dex-treatment MCAO mice. TNF-α, IL-1β and IL-6 were markedly downregulated (p < 0.05). While MCAO increased intestinal permeability (elevated serum FITC-dextran and endotoxin levels, p < 0.01), Dex treatment restored barrier integrity. Dex upregulated E-cadherin expression significantly (p < 0.05) but did not restore the decreased levels of ZO-1 and occludin following MCAO. Dex promoted intestinal permeability repair and alleviated brain injury via the α2AR/focal adhesion kinase (FAK) pathway in MCAO mice. Similarly, Dex mitigated LPS-induced barrier dysfunction in Caco-2 monolayers by restoring FAK expression and improving intestinal barrier integrity. CONCLUSIONS Dex alleviates post-stroke intestinal barrier dysfunction and mitigates brain injury, possibly through activating the α2AR/FAK pathway. These findings underscore a potential therapeutic strategy for addressing secondary complications of ischemic stroke and improving patient outcomes.
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Affiliation(s)
- Xinting Zhou
- Department of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Yan Yang
- Department of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Zixuan Su
- Department of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
| | - Zhonghui Luo
- Department of Anaesthesiology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001 Hengyang, Hunan, China
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Dettori I, Bulli I, Venturini M, Magni G, Cherchi F, Rossi F, Lee H, Pedata F, Jacobson KA, Pugliese AM, Coppi E. MRS3997, a dual adenosine A 2A/A 2B receptor agonist, reduces brain ischemic damage and alleviates neuroinflammation in rats. Neuropharmacology 2025; 262:110214. [PMID: 39522676 PMCID: PMC11789432 DOI: 10.1016/j.neuropharm.2024.110214] [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: 05/28/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A1, A2A, A2B and A3 receptors (A1Rs, A2ARs, A2BRs and A3Rs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of A2ARs, as well as A2BRs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both A2ARs and A2BRs, would afford higher neuroprotection in post-ischemic damage. Chronic systemic treatment with MRS3997 reduced neurological deficit, body weight loss and infarct volume in the cortex and striatum measured 7 days after ischemia. The dual agonist counteracted neuronal loss, reduced myelin damage, and prevented morphological changes indicative of microglia and astrocyte activation. Finally, MRS3997 shifted plasma cytokine levels to an anti-inflammatory profile. These effects were preceded, at 2 days after the insult, by a reduced granulocyte infiltration in the ischemic cortex and, differently from what was observed with selective A2AR or A2BR agonism, also in striatum. In summary, we demonstrate here that MRS3997, systemically administered for 7 days after tMCAO, protects ischemic areas from neuronal and glial damage and inhibits neuroinflammation, therefore representing an attractive strategy to ameliorate post-stroke damage and neurological symptoms.
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Affiliation(s)
- Ilaria Dettori
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
| | - Irene Bulli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Martina Venturini
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Giada Magni
- Institute of Applied Physics "Nello Carrara", National Research Council (IFAC-CNR), Sesto Fiorentino, Florence, Italy
| | - Federica Cherchi
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Francesca Rossi
- Institute of Applied Physics "Nello Carrara", National Research Council (IFAC-CNR), Sesto Fiorentino, Florence, Italy
| | - Hobin Lee
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabe-tes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Felicita Pedata
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Kenneth A Jacobson
- Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabe-tes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Anna Maria Pugliese
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
| | - Elisabetta Coppi
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
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Harjunpää H, Tallberg R, Cui Y, Guenther C, Liew HK, Seelbach A, Saldo Rubio G, Airavaara M, Fagerholm SC. β2-Integrins Regulate Microglial Responses and the Functional Outcome of Hemorrhagic Stroke In Vivo. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:519-525. [PMID: 38921973 DOI: 10.4049/jimmunol.2300815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 06/10/2024] [Indexed: 06/27/2024]
Abstract
Stroke is one of the leading causes of death and long-term disabilities worldwide. In addition to interruption of blood flow, inflammation is widely recognized as an important factor mediating tissue destruction in stroke. Depending on their phenotype, microglia, the main leukocytes in the CNS, are capable of either causing further tissue damage or promoting brain restoration after stroke. β2-integrins are cell adhesion molecules that are constitutively expressed on microglia. The function of β2-integrins has been investigated extensively in animal models of ischemic stroke, but their role in hemorrhagic stroke is currently poorly understood. We show in this study that dysfunction of β2-integrins is associated with improved functional outcome and decreased inflammatory cytokine expression in the brain in a mouse model of hemorrhagic stroke. Furthermore, β2-integrins affect microglial phenotype and cytokine responses in vivo. Therefore, our findings suggest that targeting β2-integrins in hemorrhagic stroke may be beneficial.
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Affiliation(s)
- Heidi Harjunpää
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Robert Tallberg
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Yunhao Cui
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Carla Guenther
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Hock-Kean Liew
- Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Anna Seelbach
- Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Guillem Saldo Rubio
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
| | - Mikko Airavaara
- Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Susanna C Fagerholm
- Molecular and Integrative Biosciences Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland
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Denorme F, Ajanel A, Campbell RA. Immunothrombosis in neurovascular disease. Res Pract Thromb Haemost 2024; 8:102298. [PMID: 38292352 PMCID: PMC10825058 DOI: 10.1016/j.rpth.2023.102298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 02/01/2024] Open
Abstract
A State of the Art lecture titled "Immunothrombosis in Neurovascular Diseases" was presented at the International Society on Thrombosis and Haemostasis Congress in 2023. Despite significant clinical advancements in stroke therapy, stroke remains a prominent contributor to both mortality and disability worldwide. Brain injury resulting from an ischemic stroke is a dynamic process that unfolds over time. Initially, an infarct core forms due to the abrupt and substantial blockage of blood flow. In the subsequent hours to days, the surrounding tissue undergoes gradual deterioration, primarily driven by sustained hypoperfusion, programmed cell death, and inflammation. While anti-inflammatory strategies have proven highly effective in experimental models of stroke, their successful translation to clinical use has proven challenging. To overcome this translational hurdle, a better understanding of the distinct immune response driving ischemic stroke brain injury is needed. In this review article, we give an overview of current knowledge regarding the immune response in ischemic stroke and the contribution of immunothrombosis to this process. We discuss therapeutic approaches to overcome detrimental immunothrombosis in ischemic stroke and how these can be extrapolated to other neurovascular diseases, such as Alzheimer's disease and multiple sclerosis. Finally, we summarize relevant new data on this topic presented during the 2023 International Society on Thrombosis and Haemostasis Congress.
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Affiliation(s)
- Frederik Denorme
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Vascular Neurology, Department of Neurology, University of Utah, Salt Lake City, Utah, USA
| | - Abigail Ajanel
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Microbiology and Pathology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Robert A. Campbell
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, USA
- Division of Microbiology and Pathology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA
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Maisat W, Hou L, Sandhu S, Sin YC, Kim S, Pelt HV, Chen Y, Emani S, Kong SW, Emani S, Ibla J, Yuki K. Neutrophil extracellular traps formation is associated with postoperative complications in neonates and infants undergoing congenital cardiac surgery. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.21.572768. [PMID: 38187754 PMCID: PMC10769315 DOI: 10.1101/2023.12.21.572768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Pediatric patients with congenital heart diseases (CHD) often undergo surgical repair on cardiopulmonary bypass (CPB). Despite a significant medical and surgical improvement, the mortality of neonates and infants remains high. Damage-associated molecular patterns (DAMPs) are endogenous molecules released from injured/damaged tissues as danger signals. We examined 101 pediatric patients who underwent congenital cardiac surgery on CPB. The mortality rate was 4.0%, and the complication rate was 31.6%. We found that neonates/infants experienced multiple complications most, consistent with the previous knowledge. Neonates and infants in the complication group had received more transfusion intraoperatively than the non-complication arm with lower maximum amplitude (MA) on rewarming CPB thromboelastography (TEG). Despite TEG profiles were comparable at ICU admission between the two groups, the complication arm had higher postoperative chest tube output, requiring more blood transfusion. The complication group showed greater neutrophil extracellular traps (NETs) formation at the end of CPB and postoperatively. Plasma histones and high mobility group box 1 (HMGB1) levels were significantly higher in the complication arm. Both induced NETs in vitro and in vivo . As histones and HMGB1 target Toll-like receptor (TLR)2 and TLR4, their mRNA expression in neutrophils was upregulated in the complication arm. Taken together, NETs play a major role in postoperative complication in pediatric cardiac surgery and would be considered a target for intervention. Key points Neonates and infants showed highest postoperative complications with more upregulation of inflammatory transcriptomes of neutrophils.Neonates and infants with organ dysfunction had more NETs formation with higher plasma histones and HMGB1 levels.
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Han J, Yang L, Lou Z, Zhu Y. Association between Systemic Immune-Inflammation Index and Systemic Inflammation Response Index and Outcomes of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. Ann Indian Acad Neurol 2023; 26:655-662. [PMID: 38022472 PMCID: PMC10666886 DOI: 10.4103/aian.aian_85_23] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 04/28/2023] [Accepted: 05/17/2023] [Indexed: 12/01/2023] Open
Abstract
Systemic immune-inflammation index (SII) and systemic inflammation response index (SIRS) are being increasingly used to predict outcomes of various diseases. However, its utility for acute ischemic stroke (AIS) has not been established. Through this first systematic review and meta-analysis, we aimed to collate data on the prognostic ability of SII and SIRI for predicting functional outcomes and mortality after AIS. PubMed, CENTRAL, Scopus, Embase, and Web of Science were searched up to January 5, 2023, for studies reporting the association between SII or SIRI and outcomes of AIS. Adjusted data were pooled in a random-effects model. Meta-regression was conducted for variable cut-offs. Twelve studies were included. Pooled analysis of data showed that high SII was associated with poor functional outcomes after AIS (OR: 2.35 95% CI: 1.77, 3.10 I2 = 44% P < 0.00001). Meta-regression showed an increasing effect size with a higher cut-off of SII. Similarly, the meta-analysis demonstrated that AIS patients with high SIRI were at an increased risk of poor functional outcomes (OR: 1.69 95% CI: 1.08, 2.65 I2 = 78% P = 0.02). No association was noted with different cut-offs on meta-regression. Data on mortality were scarce but were suggestive of a higher risk of mortality with high SII and SIRI. SII and SIRI can be used to predict poor functional outcomes in AIS patients. Data on mortality are scarce to derive strong conclusions. Limited number of studies and variable cut-offs are important limitations that need to be overcome by future studies.
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Affiliation(s)
- Jian Han
- Department of Neurology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Liting Yang
- Department of Neurology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhuocong Lou
- Department of Neurology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Yubo Zhu
- Department of Neurology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
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Patel RB, Dhanesha N, Sutariya B, Ghatge M, Doddapattar P, Barbhuyan T, Kumskova M, Leira EC, Chauhan AK. Targeting Neutrophil α9 Improves Functional Outcomes After Stroke in Mice With Obesity-Induced Hyperglycemia. Stroke 2023; 54:2409-2419. [PMID: 37449422 PMCID: PMC10529694 DOI: 10.1161/strokeaha.123.042714] [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: 01/27/2023] [Accepted: 06/16/2023] [Indexed: 07/18/2023]
Abstract
BACKGROUND Obesity-induced hyperglycemia is a significant risk factor for stroke. Integrin α9β1 is expressed on neutrophils and stabilizes adhesion to the endothelium via ligands, including Fn-EDA (fibronectin containing extra domain A) and tenascin C. Although myeloid deletion of α9 reduces susceptibility to ischemic stroke, it is unclear whether this is mediated by neutrophil-derived α9. We determined the role of neutrophil-specific α9 in stroke outcomes in a mice model with obesity-induced hyperglycemia. METHODS α9Neu-KO (α9fl/flMRP8Cre+) and littermate control α9WT (α9fl/flMRP8Cre-) mice were fed on a 60% high-fat diet for 20 weeks to induce obesity-induced hyperglycemia. Functional outcomes were evaluated up to 28 days after stroke onset in mice of both sexes using a transient (30 minutes) middle cerebral artery ischemia. Infarct volume (magnetic resonance imaging) and postreperfusion thrombo-inflammation (thrombi, fibrin, neutrophil, phospho-nuclear factor kappa B [p-NFκB], TNF [tumor necrosis factor]-α, and IL [interleukin]-1β levels, markers of neutrophil extracellular traps) were measured post 6 or 48 hours of reperfusion. In addition, functional outcomes (modified Neurological Severity Score, rota-rod, corner, and wire-hanging test) were measured for up to 4 weeks. RESULTS Stroke upregulated neutrophil α9 expression more in obese mice (P<0.05 versus lean mice). Irrespective of sex, deletion of neutrophil α9 improved functional outcomes up to 4 weeks, concomitant with reduced infarct, improved cerebral blood flow, decreased postreperfusion thrombo-inflammation, and neutrophil extracellular traps formation (NETosis) (P<0.05 versus α9WT obese mice). Obese α9Neu-KO mice were less susceptible to thrombosis in FeCl3 injury-induced carotid thrombosis model. Mechanistically, we found that α9/cellular fibronectin axis contributes to NETosis via ERK (extracellular signal-regulated kinase) and PAD4 (peptidyl arginine deiminase 4), and neutrophil α9 worsens stroke outcomes via cellular fibronectin-EDA but not tenascin C. Obese wild-type mice infused with anti-integrin α9 exhibited improved functional outcomes up to 4 weeks (P<0.05 versus vehicle). CONCLUSIONS Genetic ablation of neutrophil-specific α9 or pharmacological inhibition improves long-term functional outcomes after stroke in mice with obesity-induced hyperglycemia, most likely by limiting thrombo-inflammation.
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Affiliation(s)
- Rakesh B. Patel
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Nirav Dhanesha
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Brijesh Sutariya
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Madankumar Ghatge
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Prakash Doddapattar
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Tarun Barbhuyan
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Mariia Kumskova
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Enrique C. Leira
- Departments of Neurology, Neurosurgery and Epidemiology, University of Iowa, Iowa City, Iowa, USA
| | - Anil K. Chauhan
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
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Truong SHT, Bonnici B, Rupasinghe S, Kemp-Harper BK, Samuel CS, Broughton BRS. Post-stroke administration of H2 relaxin reduces functional deficits, neuronal apoptosis and immune cell infiltration into the mouse brain. Pharmacol Res 2023; 187:106611. [PMID: 36526079 DOI: 10.1016/j.phrs.2022.106611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 12/11/2022] [Accepted: 12/11/2022] [Indexed: 12/15/2022]
Abstract
Brain inflammation and apoptosis contribute to neuronal damage and loss following ischaemic stroke, leading to cognitive and functional disability. It is well-documented that the human gene-2 (H2)-relaxin hormone exhibits pleiotropic properties via its cognate receptor, Relaxin Family Peptide Receptor 1 (RXFP1), including anti-inflammatory and anti-apoptotic effects, thus making it a potential therapeutic for stroke. Hence, the current study investigated whether post-stroke H2-relaxin administration could improve functional and histological outcomes. 8-12-week-old male C57BL/6 mice were subjected to sham operation or photothrombotic stroke and intravenously-administered with either saline (vehicle) or 0.02, 0.2 or 2 mg/kg doses of recombinant H2-relaxin at 6, 24 and 48 h post-stroke. Motor function was assessed using the hanging wire and cylinder test pre-surgery, and at 24 and 72 h post-stroke. Brains were removed after 72 h and infarct volume was assessed via thionin staining, and RXFP1 expression, leukocyte infiltration and apoptosis were determined by immunofluorescence. RXFP1 was identified on neurons, astrocytes and macrophages, and increased post-stroke. Whilst H2-relaxin did not alter infarct volume, it did cause a dose-dependent improvement in motor function at 24 and 72 h post-stroke. Moreover, 2 mg/kg H2-relaxin significantly decreased the number of apoptotic cells as well as macrophages and neutrophils within the ischaemic hemisphere, but did not alter T or B cells numbers. The anti-inflammatory and anti-apoptotic effects of H2-relaxin when administered at 6 h post-cerebral ischaemia may provide a novel therapeutic option for patients following ischaemic stroke.
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Affiliation(s)
- Shirley H T Truong
- Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Benjamin Bonnici
- Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Samoda Rupasinghe
- Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Barbara K Kemp-Harper
- Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Chrishan S Samuel
- Fibrosis Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia; Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Brad R S Broughton
- Cardiovascular & Pulmonary Pharmacology Group, Department of Pharmacology and Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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Caimi G, Lo Presti R, Carollo C, Montana M, Carlisi M. Polymorphonuclear phenotypical expression of CD18, at baseline and after in vitro activation, in several clinical disorders: Revision of our case series. Clin Hemorheol Microcirc 2023; 85:41-58. [PMID: 37482987 DOI: 10.3233/ch-231771] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
BACKGROUND In relation to the different and important roles of the beta2 integrins, we have revisited the expression of polymorphonuclear leukocyte CD18 in several clinical disorders, at baseline and after in vitro activation. SUBJECTS we have examined subjects with type 1 diabetes mellitus, vascular atherosclerotic disease, type 2 diabetes mellitus without and with macrovascular complications, chronic renal failure on conservative treatment, essential hypertension, deep venous thrombosis, acute ischemic stroke and subjects with venous leg ulcers. METHODS unfractioned leukocyte suspension was prepared according to the Mikita's method, while the leukocyte were separated into mononuclear and polymorphonuclear cells with a Ficoll-Hypaque medium. Using specific monoclonal antibody, the CD18 expression was evaluated with cytofluorimetric analysis, using FACScan (Becton Dickinson) be Cellquest software; the activation in vitro with PMA was effected according to modified Yasui and Masuda methods. RESULTS in type 1 diabetes mellitus, at baseline CD18 is under expressed in comparison with normal control, and not changes after PMA activation were observed; in subjects with vascular atherosclerotic disease, in type 2 diabetes mellitus CD18 is over expressed at baseline but does not vary after activation; in subjects with chronic renal failure, essential hypertension and in subjects with acute ischemic stroke the CD18 up-regulate at baseline compared to normal control, and it increases further after activation; in subjects with deep venous thrombosis the CD18 expression is not different from control group at baseline, but it increases after activation; finally, in subjects with venous leg ulcers the CD18 is normally expressed at baseline, and it does not change after PMA activation. CONCLUSIONS in the different clinical disorders, the trend of this integrin subunit provides some specific information, useful to select the best therapeutic strategy in clinical practice.
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Affiliation(s)
- Gregorio Caimi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Rosalia Lo Presti
- Department of Psychology, Educational Science and Human Movement, University of Palermo, Palermo, Italy
| | - Caterina Carollo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maria Montana
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Melania Carlisi
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
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11
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Hidalgo A, Libby P, Soehnlein O, Aramburu IV, Papayannopoulos V, Silvestre-Roig C. Neutrophil extracellular traps: from physiology to pathology. Cardiovasc Res 2022; 118:2737-2753. [PMID: 34648022 PMCID: PMC9586562 DOI: 10.1093/cvr/cvab329] [Citation(s) in RCA: 170] [Impact Index Per Article: 56.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/21/2021] [Accepted: 10/12/2021] [Indexed: 12/13/2022] Open
Abstract
At the frontline of the host defence response, neutrophil antimicrobial functions have adapted to combat infections and injuries of different origins and magnitude. The release of web-like DNA structures named neutrophil extracellular traps (NETs) constitutes an important mechanism by which neutrophils prevent pathogen dissemination or deal with microorganisms of a bigger size. At the same time, nuclear and granule proteins with microbicidal activity bind to these DNA structures promoting the elimination of entrapped pathogens. However, these toxic properties may produce unwanted effects in the host, when neutrophils uncontrollably release NETs upon persistent inflammation. As a consequence, NET accumulation can produce vessel occlusion, tissue damage, and prolonged inflammation associated with the progression and exacerbation of multiple pathologic conditions. This review outlines recent advances in understanding the mechanisms of NET release and functions in sterile disease. We also discuss mechanisms of physiological regulation and the importance of neutrophil heterogeneity in NET formation and composition.
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Affiliation(s)
- Andres Hidalgo
- Area of Cell and Developmental Biology, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Melchor Fernández Almagro 3, 28029, Madrid, Spain
| | - Peter Libby
- Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - Oliver Soehnlein
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Von-Esmarch-Straße 56, 48149, Münster, Germany
- Department of Physiology and Pharmacology (FyFa), Karolinska Institute, Solnavägen 1, 171 77, Stockholm, Sweden
| | - Iker Valle Aramburu
- Laboratory of Antimicrobial Defence, The Francis Crick Institute, London NW1 1AT, UK
| | | | - Carlos Silvestre-Roig
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation (ZMBE), University of Münster, Von-Esmarch-Straße 56, 48149, Münster, Germany
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12
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The Association between Systemic Immune-Inflammation Index and All-Cause Mortality in Acute Ischemic Stroke Patients: Analysis from the MIMIC-IV Database. Emerg Med Int 2022; 2022:4156489. [PMID: 35959219 PMCID: PMC9363175 DOI: 10.1155/2022/4156489] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 06/16/2022] [Accepted: 07/07/2022] [Indexed: 12/31/2022] Open
Abstract
Purpose. Acute ischemic stroke (AIS) is a devastating disease and remains the leading cause of death and disability. This retrospective study aims to investigate associations between systemic immune-inflammation index (SII) and all-cause mortality in patients with AIS. Patients and Methods. We used the data from Medical Information Mart for Intensive Care IV. A total of 1,181 patients with acute ischemic stroke (AIS) were included. Systemic immune-inflammation index (SII) was calculated as platelet count (/L) × neutrophil count (/L)/lymphocyte count (/L). The main outcomes were 30-day all-cause mortality. The association between SII with mortality was evaluated using the Cox proportional hazards regression model. Results. After adjusting for potential covariates, the highest quartiles of SII versus the lowest quartiles of SII, the HR was 2.74 (CI 1.79–4.19,
). Log-transformed SII was significantly associated with 30-day all-cause mortality (HR 2.44; CI 1.72–3.46,
). Furthermore, we found that there is a nearly linear relationship (
) between logarithmic transformed SII with all-cause mortality. Conclusion. Elevated SII of patients with acute ischemic stroke increased the risk of 30-day all-cause mortality. SII may serve as a useful marker to elucidate the role of thrombocytosis, inflammation, and immunity interaction in the development of AIS.
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13
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Barkaway A, Attwell D, Korte N. Immune-vascular mural cell interactions: consequences for immune cell trafficking, cerebral blood flow, and the blood-brain barrier. NEUROPHOTONICS 2022; 9:031914. [PMID: 35581998 PMCID: PMC9107322 DOI: 10.1117/1.nph.9.3.031914] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/13/2022] [Indexed: 06/15/2023]
Abstract
Brain barriers are crucial sites for cerebral energy supply, waste removal, immune cell migration, and solute exchange, all of which maintain an appropriate environment for neuronal activity. At the capillary level, where the largest area of brain-vascular interface occurs, pericytes adjust cerebral blood flow (CBF) by regulating capillary diameter and maintain the blood-brain barrier (BBB) by suppressing endothelial cell (EC) transcytosis and inducing tight junction expression between ECs. Pericytes also limit the infiltration of circulating leukocytes into the brain where resident microglia confine brain injury and provide the first line of defence against invading pathogens. Brain "waste" is cleared across the BBB into the blood, phagocytosed by microglia and astrocytes, or removed by the flow of cerebrospinal fluid (CSF) through perivascular routes-a process driven by respiratory motion and the pulsation of the heart, arteriolar smooth muscle, and possibly pericytes. "Dirty" CSF exits the brain and is probably drained around olfactory nerve rootlets and via the dural meningeal lymphatic vessels and possibly the skull bone marrow. The brain is widely regarded as an immune-privileged organ because it is accessible to few antigen-primed leukocytes. Leukocytes enter the brain via the meninges, the BBB, and the blood-CSF barrier. Advances in genetic and imaging tools have revealed that neurological diseases significantly alter immune-brain barrier interactions in at least three ways: (1) the brain's immune-privileged status is compromised when pericytes are lost or lymphatic vessels are dysregulated; (2) immune cells release vasoactive molecules to regulate CBF, modulate arteriole stiffness, and can plug and eliminate capillaries which impairs CBF and possibly waste clearance; and (3) immune-vascular interactions can make the BBB leaky via multiple mechanisms, thus aggravating the influx of undesirable substances and cells. Here, we review developments in these three areas and briefly discuss potential therapeutic avenues for restoring brain barrier functions.
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Affiliation(s)
- Anna Barkaway
- University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom
| | - David Attwell
- University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom
| | - Nils Korte
- University College London, Department of Neuroscience, Physiology and Pharmacology, London, United Kingdom
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14
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Barow E, Quandt F, Cheng B, Gelderblom M, Jensen M, Königsberg A, Boutitie F, Nighoghossian N, Ebinger M, Endres M, Fiebach JB, Thijs V, Lemmens R, Muir KW, Pedraza S, Simonsen CZ, Gerloff C, Thomalla G. Association of White Blood Cell Count With Clinical Outcome Independent of Treatment With Alteplase in Acute Ischemic Stroke. Front Neurol 2022; 13:877367. [PMID: 35769368 PMCID: PMC9235538 DOI: 10.3389/fneur.2022.877367] [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: 02/16/2022] [Accepted: 04/29/2022] [Indexed: 12/03/2022] Open
Abstract
Introduction Higher white blood cell (WBC) count is associated with poor functional outcome in acute ischemic stroke (AIS). However, little is known about whether the association is modified by treatment with intravenous alteplase. Methods WAKE-UP was a randomized controlled trial of the efficacy and safety of magnetic resonance imaging [MRI]-based thrombolysis in unknown onset stroke. WBC count was measured on admission and again at 22–36 h after randomization to treatment (follow-up). Favorable outcome was defined by a score of 0 or 1 on the modified Rankin scale (mRS) 90 days after stroke. Further outcome were stroke volume and any hemorrhagic transformation (HT) that were assessed on follow-up CT or MRI. Multiple logistic regression analysis was used to assess the association between outcome and WBC count and treatment group. Results Of 503 randomized patients, WBC count and baseline parameters were available in 437 patients (μ = 64.7 years, 35.2% women) on admission and 355 patients (μ = 65.1 years, 34.1% women) on follow-up. Median WBC count on admission was 7.6 × 109/L (interquartile range, IQR, 6.1–9.4 × 109/L) and 8.2 × 109/L (IQR, 6.7–9.7 × 109/L) on follow-up. Higher WBC count both on admission and follow-up was associated with lower odds of favorable outcome, adjusted for age, National Institutes of Health (NIH) Stroke Scale Score, temperature, and treatment (alteplase vs. placebo, adjusted odds ratio, aOR 0.85, 95% confidence interval [CI] 0.78–0.94 and aOR 0.88, 95% CI 0.79–0.97). No interaction between WBC count and treatment group was observed (p = 0.11). Furthermore, WBC count on admission and follow-up was significantly associated with HT (aOR 1.14, 95% CI 1.05–1.24 and aOR 1.13, 95% CI 1.00–1.26). Finally, WBC count on follow-up was associated with larger stroke volume (aOR 2.57, 95% CI 1.08–6.07). Conclusion Higher WBC count is associated with unfavorable outcome, an increased risk of HT, and larger stroke volume, independent of treatment with alteplase. Whether immunomodulatory manipulation of WBC count improves stroke outcome needs to be tested. Trial Registration ClinicalTrials.gov Identifier: NCT01525290.
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Affiliation(s)
- Ewgenia Barow
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- *Correspondence: Ewgenia Barow
| | - Fanny Quandt
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bastian Cheng
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mathias Gelderblom
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Märit Jensen
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alina Königsberg
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florent Boutitie
- Hospices Civils de Lyon, Service de Biostatistique, Lyon, France
- Université Lyon 1, Villeurbanne, France
- Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
| | - Norbert Nighoghossian
- Department of Stroke Medicine, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Martin Ebinger
- Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
- Medical Park Berlin Humboldtmühle, Klinik für Neurologie, Berlin, Germany
| | - Matthias Endres
- Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
- Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
- German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen), Berlin, Germany
- German Center for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung), Berlin, Germany
| | - Jochen B. Fiebach
- Centrum für Schlaganfallforschung Berlin (CSB), Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Vincent Thijs
- Stroke Division, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Heidelberg, VIC, Australia
- Department of Neurology, Austin Health, Heidelberg, VIC, Australia
| | - Robin Lemmens
- Department of Neurology, University Hospitals Leuven, Leuven, Belgium
- Department of Neurosciences, Experimental Neurology, University of Leuven, Leuven, Belgium
- Laboratory of Neurobiology, Center for Brain & Disease Research, Leuven, Belgium
| | - Keith W. Muir
- Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom
| | - Salvador Pedraza
- Department of Radiology, Institut de Diagnostic per la Image (IDI), Girona, Spain
| | - Claus Z. Simonsen
- Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
| | - Christian Gerloff
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Götz Thomalla
- Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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15
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Zhou YX, Li WC, Xia SH, Xiang T, Tang C, Luo JL, Lin MJ, Xia XW, Wang WB. Predictive Value of the Systemic Immune Inflammation Index for Adverse Outcomes in Patients With Acute Ischemic Stroke. Front Neurol 2022; 13:836595. [PMID: 35370926 PMCID: PMC8971364 DOI: 10.3389/fneur.2022.836595] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/16/2022] [Indexed: 12/11/2022] Open
Abstract
Background and Purpose The systemic immune-inflammation index, a new index based on platelets, neutrophils and lymphocytes, has been shown to be associated with outcomes of patients with venous sinus thrombosis and cancer. However, its application in acute ischemic stroke has rarely been reported. Therefore, we examined the relationship between systemic immune-inflammation index levels at hospital admission and the outcomes of patients 3 months after onset, and plotted a nomogram to predict the probability of adverse outcomes in patients with acute ischemic stroke. Methods We retrospectively analyzed a total of 208 patients with acute ischemic stroke who were admitted between January 2020 and December 2020, and recorded the modified Rankin score 3 months later. A modified Rankin score ≥ 3 was defined as an adverse outcome. Age, sex, NIHSS score, SII, hypertension and coronary heart disease were included in the binary logistic regression, and the nomogram was plotted with a regression equation. Results Receiver operating characteristic (ROC) curve analysis indicated that the best cutoff value of the systemic immune-inflammation index was 802.8, with a sensitivity of 70.9% and specificity of 58.2% (area under the curve: 0.657, 95% confidence interval: 0.572–0.742). The nomogram had a C index of 0.802. The average error of the calibration curves of the training set and the validation set was 0.021 and 0.034, respectively. Conclusion The systemic immune-inflammation index is associated with short-term adverse outcomes in patients with acute ischemic stroke, and the nomograms can predict the risk of adverse outcomes in patients with acute ischemic stroke.
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Affiliation(s)
- Yun-Xiang Zhou
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Wen-Cai Li
- Department of Neurosurgery, Huizhou Municipal Central Hospital, Huizhou, China
| | - Shao-Huai Xia
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Ting Xiang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Can Tang
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jia-Li Luo
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Ming-Jian Lin
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Xue-Wei Xia
- Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Wen-Bo Wang
- Department of Neurosurgery, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
- *Correspondence: Wen-Bo Wang
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16
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Mollet I, Martins C, Ângelo-Dias M, Carvalho AS, Aloria K, Matthiesen R, Baptista MV, Borrego LM, Vieira HL. Pilot study in human healthy volunteers on the mechanisms underlying remote ischemic conditioning (RIC) – Targeting circulating immune cells and immune-related proteins. J Neuroimmunol 2022; 367:577847. [DOI: 10.1016/j.jneuroim.2022.577847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/03/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022]
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17
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Dong W, Liu X, Liu W, Wang C, Zhao S, Wen S, Gong T, Chen W, Chen Q, Ye W, Li Z, Wang Y. Dual antiplatelet therapy improves functional recovery and inhibits inflammation after cerebral ischemia/reperfusion injury. ANNALS OF TRANSLATIONAL MEDICINE 2022; 10:283. [PMID: 35433995 PMCID: PMC9011245 DOI: 10.21037/atm-22-735] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 03/04/2022] [Indexed: 01/21/2023]
Abstract
Background Dual antiplatelet therapy with aspirin and clopidogrel (ASA + CPG) during the first 21 days has been shown to reduce the risk of major ischemic events in patients with transient ischemic attack (TIA) or minor stroke. However, the mechanisms underlying combination treatment with ASA + CPG in experimental ischemic stroke has not been fully elucidated. Methods Minor cerebral ischemia was induced in mice by transient distal middle cerebral artery occlusion (tdMCAO). Two doses of ASA + CPG (12 and 24 mg/kg/day) or vehicle were administered by gavage daily. Neurological behaviors were assessed using the modified Garcia scores, Rotarod test, Y maze, and open field test. Platelet function was assessed in vitro by flow cytometry and in vivo by bleeding and clotting time. The neutrophil ratio and the levels of inflammatory cytokines were measured by flow cytometry and the Meso Scale Discovery (MSD) electrochemilunimescence, respectively. Results Sensorimotor function was partially recovered with ASA + CPG treatment after ischemia. Anxiety levels and cognitive functions showed improvement in the ASA + CPG group at 12 mg/kg/day after 21 days. Both tail bleeding time and flow cytometry showed significantly decreased platelet function after ASA + CPG treatment. Notably, ASA + CPG at 12 mg/kg/day prolonged clotting time at 28 days after injury. Furthermore, the ratio of neutrophils, an indicator of inflammation, was reduced with 12 mg/kg/day ASA + CPG treatment in the bone marrow (BM) at 21 days and in the peripheral blood (PB) at 21 and 28 days after tdMCAO. Both doses of ASA + CPG decreased pro-inflammatory cytokine interleukin (IL)-6 expression 21 days after stroke. Taken together, these results demonstrated that combination treatment with ASA + CPG improved long-term neurological function after stroke and may inhibit platelet-neutrophil interaction by decreasing the concentration of pro-inflammatory cytokine, IL-6. Conclusions These findings indicate a neuroprotective effect of combination treatment with ASA + CPG for a duration of 21 days in an experimental acute minor stroke model. These findings provide further evidence that dual antiplatelet therapy may be a viable neuroprotective treatment to decrease the recurrence of stroke.
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Affiliation(s)
- Wen Dong
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xiangrong Liu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wenqian Liu
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chunjuan Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shunying Zhao
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shaohong Wen
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ting Gong
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Wentao Chen
- China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qingfang Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Weizhen Ye
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Zixiao Li
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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18
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Could the systemic immune-inflammation index be a predictor to estimate cerebrovascular events in hypertensive patients? Blood Press Monit 2022; 27:33-38. [PMID: 34992205 DOI: 10.1097/mbp.0000000000000560] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVES Hypertension is one of the most important risk factors for cardiovascular and cerebrovascular events. Inflammatory processes occupy an important place in the pathogenesis of hypertension. Many studies have studied inflammatory markers responsible for the onset of hypertension and organ damage. In this study, we investigated whether the systemic immune-inflammation index (SII) (platelet × neutrophil/lymphocyte), - one of the new inflammatory markers - can be used to predict cerebrovascular events in hypertensive patients. METHODS Ambulatory blood pressure monitoring results between January 2019 and June 2020 of approximately 379 patients followed up with hypertension were retrospectively analyzed. These patients were divided into two groups as with or without a previous cerebrovascular event in the analyzed database. In all patients, complete blood count and biochemistry test results just before the cerebrovascular event were found from the database. SII, atherogenic index, neutrophil-lymphocyte ratio were calculated from the complete blood count. Forty-nine patients with stroke (group 1: 12.9%; mean age: 64.3 ± 14.6) and 330 patients without stroke (group 2: 87.1%; mean age: 50.8 ± 14.4). RESULTS Ambulatory blood pressure measurements were lower in group 1. Lipid parameters were also lower in this group. Receiver operating characteristic curve analysis showed that SII had a sensitivity of 85.7% and specificity of 84.8 % for stroke in individuals who participated in the study when the cutoff value of SII was 633.26 × 103 (P = 0.0001) area under curve (95%); 0.898 (0.856-0.941). In multivariate logistic regression analysis, age and SII were significantly associated with a higher risk of stroke. Age, (hazard ratio:1.067; 95% CI, 1.021-1.115), SII (hazard ratio:1.009; 95% CI, 1.000-1.009), respectively. CONCLUSIONS In conclusion, SII is a simple, useful new inflammatory parameter for predicting stroke from hypertension. We found that the high SII levels increase the risk of stroke in hypertensive patients.
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19
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Sienel RI, Kataoka H, Kim SW, Seker FB, Plesnila N. Adhesion of Leukocytes to Cerebral Venules Precedes Neuronal Cell Death and Is Sufficient to Trigger Tissue Damage After Cerebral Ischemia. Front Neurol 2022; 12:807658. [PMID: 35140676 PMCID: PMC8818753 DOI: 10.3389/fneur.2021.807658] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 12/20/2021] [Indexed: 12/18/2022] Open
Abstract
Background Leukocytes contribute to tissue damage after cerebral ischemia; however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury. Methods Male wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII−/−)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology. Results In wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%; p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01); the number of intraparenchymal leukocytes was not affected. Conclusions Our findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage.
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Affiliation(s)
- Rebecca Isabella Sienel
- Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center, Munich, Germany
- Munich Cluster of Systems Neurology (Synergy), Munich, Germany
| | - Hiroharu Kataoka
- Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seong-Woong Kim
- Department of Neurosurgery, University of Giessen, Giessen, Germany
| | - Fatma Burcu Seker
- Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center, Munich, Germany
- Munich Cluster of Systems Neurology (Synergy), Munich, Germany
| | - Nikolaus Plesnila
- Laboratory of Experimental Stroke Research, Institute for Stroke and Dementia Research (ISD), University of Munich Medical Center, Munich, Germany
- Munich Cluster of Systems Neurology (Synergy), Munich, Germany
- *Correspondence: Nikolaus Plesnila
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Stuckey SM, Ong LK, Collins-Praino LE, Turner RJ. Neuroinflammation as a Key Driver of Secondary Neurodegeneration Following Stroke? Int J Mol Sci 2021; 22:ijms222313101. [PMID: 34884906 PMCID: PMC8658328 DOI: 10.3390/ijms222313101] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 11/25/2021] [Accepted: 12/01/2021] [Indexed: 01/13/2023] Open
Abstract
Ischaemic stroke involves the rapid onset of focal neurological dysfunction, most commonly due to an arterial blockage in a specific region of the brain. Stroke is a leading cause of death and common cause of disability, with over 17 million people worldwide suffering from a stroke each year. It is now well-documented that neuroinflammation and immune mediators play a key role in acute and long-term neuronal tissue damage and healing, not only in the infarct core but also in distal regions. Importantly, in these distal regions, termed sites of secondary neurodegeneration (SND), spikes in neuroinflammation may be seen sometime after the initial stroke onset, but prior to the presence of the neuronal tissue damage within these regions. However, it is key to acknowledge that, despite the mounting information describing neuroinflammation following ischaemic stroke, the exact mechanisms whereby inflammatory cells and their mediators drive stroke-induced neuroinflammation are still not fully understood. As a result, current anti-inflammatory treatments have failed to show efficacy in clinical trials. In this review we discuss the complexities of post-stroke neuroinflammation, specifically how it affects neuronal tissue and post-stroke outcome acutely, chronically, and in sites of SND. We then discuss current and previously assessed anti-inflammatory therapies, with a particular focus on how failed anti-inflammatories may be repurposed to target SND-associated neuroinflammation.
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Affiliation(s)
- Shannon M. Stuckey
- Discipline of Anatomy and Pathology, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide 5005, Australia; (S.M.S.); (L.E.C.-P.)
| | - Lin Kooi Ong
- School of Pharmacy, Monash University Malaysia, Subang Jaya 47500, Malaysia;
- School of Biomedical Sciences and Pharmacy and the Priority Research Centre for Stroke and Brain Injury, The University of Newcastle, Callaghan 2308, Australia
| | - Lyndsey E. Collins-Praino
- Discipline of Anatomy and Pathology, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide 5005, Australia; (S.M.S.); (L.E.C.-P.)
| | - Renée J. Turner
- Discipline of Anatomy and Pathology, School of Biomedicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide 5005, Australia; (S.M.S.); (L.E.C.-P.)
- Correspondence: ; Tel.: +61-8-8313-3114
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21
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Rayasam A, Jullienne A, Chumak T, Faustino J, Szu J, Hamer M, Ek CJ, Mallard C, Obenaus A, Vexler ZS. Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis. J Cereb Blood Flow Metab 2021; 41:3171-3186. [PMID: 34293939 PMCID: PMC8669290 DOI: 10.1177/0271678x211032737] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy-by administration of viral mimetic TLR3-agonist Polyinosinic:polycytidylic acid (Poly-IC) in juvenile mice-we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (∼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.
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Affiliation(s)
- Aditya Rayasam
- Department of Neurology, University California San Francisco, San Francisco, CA, USA
| | - Amandine Jullienne
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - Tetyana Chumak
- Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Joel Faustino
- Department of Neurology, University California San Francisco, San Francisco, CA, USA
| | - Jenny Szu
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - Mary Hamer
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - C Joakim Ek
- Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Carina Mallard
- Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Andre Obenaus
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
| | - Zinaida S Vexler
- Department of Neurology, University California San Francisco, San Francisco, CA, USA
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22
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Abstract
PURPOSE OF REVIEW In this review, we will describe how the combined ability of platelets and neutrophils to interact with each other drives ischemic stroke brain injury. RECENT FINDINGS Neutrophils are one of the first cells to respond during ischemic stroke. Although animals stroke models have indicated targeting neutrophils improves outcomes, clinical trials have failed to yield successful strategies. Platelets play a critical role in recruiting neutrophils to sites of injury by acting as a bridge to the injured endothelium. After initial platelet adhesion, neutrophils can rapidly bind platelets through P-selectin and glycoprotein Ibα. In addition, recent data implicated platelet phosphatidylserine as a novel key regulator of platelet-neutrophil interactions in the setting of ischemic stroke. Inhibition of procoagulant platelets decreases circulating platelet-neutrophil aggregates and thereby reduces infarct size. Platelet binding alters neutrophil function, which contributes to the injury associated with ischemic stroke. This includes inducing the release of neutrophil extracellular traps, which are neurotoxic and pro-thrombotic, leading to impaired stroke outcomes. SUMMARY Platelet-neutrophil interactions significantly contribute to the pathophysiology of ischemic stroke brain injury. Better understanding the mechanisms behind their formation and the downstream consequences of their interactions will lead to improved therapies for stroke patients.
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Affiliation(s)
- Frederik Denorme
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, 84112
| | - John L Rustad
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, 84112
| | - Robert A. Campbell
- University of Utah Molecular Medicine Program, Salt Lake City, Utah, 84112
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah, 84132
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23
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Liu Q, Sorooshyari SK. Quantitative and Correlational Analysis of Brain and Spleen Immune Cellular Responses Following Cerebral Ischemia. Front Immunol 2021; 12:617032. [PMID: 34194419 PMCID: PMC8238006 DOI: 10.3389/fimmu.2021.617032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 04/15/2021] [Indexed: 11/18/2022] Open
Abstract
Stroke is a multiphasic process, and the initial ischemic phase of neuronal damage is followed by secondary innate and adaptive responses that unfold over days after stroke, offer a longer time frame of intervention, and represent a novel therapeutic target. Therefore, revealing the distinct functions of immune cells in both brain and periphery is important for identification of immunotherapeutic targets for stroke to extend the treatment time window. In this paper an examination of the cellular dynamics of the immune response in the central nervous system (CNS) and periphery provoked by cerebral ischemia is provided. New data is presented for the number of immune cells in brain and spleen of mice during the 7 days following middle cerebral artery occlusion (MCAO). A novel analysis of the correlation among various cell types in the brain and spleen following stroke is presented. It is found that the infiltrated macrophages in the ischemic hemisphere positively correlate with neutrophils which implies their synergic effect in migrating into the brain after stroke onset. It is noted that during infiltration of adaptive immune cells, the number of neutrophils correlate positively with T cells, which suggests neutrophils contribute to T cell infiltration in the stroked brain. Furthermore, the correlation among neurological deficit and various immune cells suggests that microglia and splenic adaptive immune cells (T and B cells) are protective while infiltrating peripheral myeloid cells (macrophage and neutrophils) worsen stroke outcome. Comprehension of such immune responses post cerebral ischemia is crucial for differentiating the drivers of outcomes and also predicting the stroke outcome.
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Affiliation(s)
- Qingkun Liu
- Department of Neurology, School of Medicine, Stanford, CA, United States
- Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Siamak K. Sorooshyari
- Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States
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Ören O, Haki C, Kaya H, Yüksel M. Predictive value of admission neutrophil/lymphocyte ratio in symptomatic intracranial hemorrhage after stroke thrombolysis. Neurol Sci 2021; 43:435-440. [PMID: 34018076 DOI: 10.1007/s10072-021-05326-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/15/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Stroke is one of the most common causes of morbidity and mortality. The need for additional objective parameters as well as the existing criteria continues for eligible patients. The objective of this study is to determine whether the baseline neutrophil/lymphocyte ratio (NLR) predicts symptomatic intracranial hemorrhage (SICH) due to intravenous thrombolytic therapy. MATERIAL AND METHODS One hundred thirty-three consecutive patients aged 18 years and over who were admitted to the emergency department of a training and research hospital for acute ischemic stroke and underwent intravenous thrombolytic therapy were retrospectively analyzed. For the definition of SICH, European Cooperative Acute Stroke Study III (ECASS III) classification was accepted. RESULTS When the groups with and without intracranial hemorrhage were compared, there was a significant difference in terms of the initial National Institutes of Health Stroke Scale (NIHSS) score (p < 0.006), glucose level (p < 0.018), and systolic blood pressure (SBP) (p < 0.050). The NLR value of the patients ranged from 0.47 to 13.74. In the group with SICH, NLR was found to be higher but not statistically significant. (p = 0.125). CONCLUSION For predicting SICH, NLR did not provide strong specificity and sensitivity. A precise cut-off value could not be found to predict the hemorrhagic transformation.
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Affiliation(s)
- Oğuz Ören
- Department of Emergency Medicine,University of Health Sciences, Yüksek İhtisas Training and Research Hospital, Bursa, Turkey.
| | - Cemile Haki
- Department of Neurology, University of Health Sciences, Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Halil Kaya
- Department of Emergency Medicine,University of Health Sciences, Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Melih Yüksel
- Department of Emergency Medicine,University of Health Sciences, Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
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25
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Osuka K, Watanabe Y, Suzuki C, Iwami K, Miyachi S. Sequential expression of neutrophil chemoattractants in cerebrospinal fluid after subarachnoid hemorrhage. J Neuroimmunol 2021; 357:577610. [PMID: 34030107 DOI: 10.1016/j.jneuroim.2021.577610] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/04/2021] [Accepted: 05/11/2021] [Indexed: 10/21/2022]
Abstract
OBJECTIVE Neutrophils induce inflammation through the exocytosis of cytotoxic granule proteins. Recently, neutrophils have been reported to be an independent parameter associated with unfavorable outcomes after subarachnoid hemorrhage (SAH). However, the mechanism by which neutrophils accumulate within the CSF after SAH remains undetermined. METHODS Concentrations of C5a, epithelial neutrophil activating peptide 78 (ENA-78), interleukin-8 (IL-8), growth-regulated oncogene-α (GRO-α), neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO) were measured serially until day 14 in the CSF of 10 patients with SAH. CSF samples obtained from patients suffering from unruptured aneurysms were used as controls. RESULTS The concentrations of C5a and ENA-78 were significantly increased on day 1, while those of IL-8 and GRO-α significantly increased during days 3-7 compared with those of the control samples. The levels of NGAL and MPO, components of neutrophil granules, significantly increased during days 1-5 and days 1-3, respectively, after SAH and gradually decreased thereafter. The correlations between ENA-78 and C5a on day 1, IL-8 and GRO-α on days 3-7, and NGAL and MPO on days 1-3 were significant. CONCLUSION These neutrophil chemoattractants might be serially involved in the infiltration of neutrophils into the CSF after SAH. Migrated neutrophils play an important role in inflammatory reactions in the central nervous system after SAH.
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Affiliation(s)
- Koji Osuka
- Department of Neurological Surgery, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan.
| | - Yasuo Watanabe
- High Technology Research Center, Pharmacology, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan
| | - Chiharu Suzuki
- Department of Neurological Surgery, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Kenichiro Iwami
- Department of Neurological Surgery, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
| | - Shigeru Miyachi
- Department of Neurological Surgery, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi 480-1195, Japan
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26
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Platelet endothelial cell adhesion molecule-1 is a gatekeeper of neutrophil transendothelial migration in ischemic stroke. Brain Behav Immun 2021; 93:277-287. [PMID: 33388423 DOI: 10.1016/j.bbi.2020.12.026] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/24/2020] [Accepted: 12/22/2020] [Indexed: 11/21/2022] Open
Abstract
RATIONALE Adhesion molecules are key elements in stroke-induced brain injury by regulating the migration of effector immune cells from the circulation to the lesion site. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an adhesion molecule highly expressed on endothelial cells and leukocytes, which controls the final steps of trans-endothelial migration. A functional role for PECAM-1 in post-ischemic brain injury has not yet been demonstrated. OBJECTIVE Using genetic Pecam-1 depletion and PECAM-1 blockade using a neutralizing anti-PECAM-1 antibody, we evaluated the role of PECAM-1 mediated trans-endothelial immune cell migration for ischemic injury, delayed brain atrophy, and brain immune cell infiltrates. Trans-endothelial immune cell migration was furthermore evaluated in cultured human cerebral microvascular endothelial cells. METHODS AND RESULTS Transient middle cerebral artery occlusion (tMCAO) was induced in 10-12-week-old male Pecam-1-/- and Pecam-1+/+ wildtype mice. PECAM-1 levels increased in the ischemic brain tissue due to the infiltration of PECAM-1+ leukocytes. Using magnetic resonance imaging, we observed smaller infarct volume, less edema formation, and less brain atrophy in Pecam-1-/- compared with Pecam-1+/+ wildtype mice. The transmigration of leukocytes, specifical neutrophils, was selectively reduced by Pecam-1-/-, as shown by immune fluorescence and flow cytometry in vivo and transmigration assays in vitro. Importantly, inhibition with an anti-PECAM-1 antibody in wildtype mice decreased neutrophil brain influx and infarct. CONCLUSION PECAM-1 controls the trans-endothelial migration of neutrophils in a mouse model of ischemic stroke. Antibody blockade of PECAM-1 after stroke onset ameliorates stroke severity in mice, making PECAM-1 an interesting target to dampen post-stroke neuroinflammation, reduce ischemic brain injury, and enhance post-ischemic brain remodeling.
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27
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Han Z, He X, Peng S. Neutrophil count to albumin ratio as a prognostic indicator for HBV-associated decompensated cirrhosis. J Clin Lab Anal 2021; 35:e23730. [PMID: 33609049 PMCID: PMC8059716 DOI: 10.1002/jcla.23730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND To explore the value of neutrophil count to albumin ratio (NAR) in predicting the outcomes of patients with HBV-associated decompensated cirrhosis (HBV-DeCi). METHODS One hundred and fifty-four HBV-DeCi patients were enrolled. The 30-day mortality was determined. Multivariate analysis was applied to identify risk factors for poor outcomes. Receiver operating characteristic curve analyses was performed to evaluate prognostic accuracy. RESULTS The 30-day mortality was 10.4%. NAR was significantly higher in non-survivors than in survivors and was an independent predictor for unfavorable prognosis. CONCLUSIONS The present results indicate that increased NAR is associated with poor survival in HBV-DeCi patients and has potential for clinical application.
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Affiliation(s)
- Zhong Han
- Department of Clinical Laboratory, Shengzhou People's Hospital, Shengzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China
| | - Xia He
- Department of Clinical Laboratory, Shengzhou People's Hospital, Shengzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China
| | - SongQing Peng
- Department of Clinical Laboratory, Shengzhou People's Hospital, Shengzhou Branch of the First Affiliated Hospital of Zhejiang University, Shengzhou, China
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28
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Dettori I, Gaviano L, Ugolini F, Lana D, Bulli I, Magni G, Rossi F, Giovannini MG, Pedata F. Protective Effect of Adenosine A 2B Receptor Agonist, BAY60-6583, Against Transient Focal Brain Ischemia in Rat. Front Pharmacol 2021; 11:588757. [PMID: 33643036 PMCID: PMC7905306 DOI: 10.3389/fphar.2020.588757] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 09/21/2020] [Indexed: 01/03/2023] Open
Abstract
Cerebral ischemia is a multifactorial pathology characterized first by an acute injury, due to excitotoxicity, followed by a secondary brain injury that develops hours to days after ischemia. During ischemia, adenosine acts as an endogenous neuroprotectant. Few studies have investigated the role of A2B receptor in brain ischemia because of the low potency of adenosine for it and the few selective ligands developed so far. A2B receptors are scarcely but widely distributed in the brain on neurons, glial and endothelial cells and on hematopoietic cells, lymphocytes and neutrophils, where they exert mainly anti-inflammatory effects, inhibiting vascular adhesion and inflammatory cells migration. Aim of this work was to verify whether chronic administration of the A2B agonist, BAY60-6583 (0.1 mg/kg i.p., twice/day), starting 4 h after focal ischemia induced by transient (1 h) Middle Cerebral Artery occlusion (tMCAo) in the rat, was protective after the ischemic insult. BAY60-6583 improved the neurological deficit up to 7 days after tMCAo. Seven days after ischemia BAY60-6583 reduced significantly the ischemic brain damage in cortex and striatum, counteracted ischemia-induced neuronal death, reduced microglia activation and astrocytes alteration. Moreover, it decreased the expression of TNF-α and increased that of IL-10 in peripheral plasma. Two days after ischemia BAY60-6583 reduced blood cell infiltration in the ischemic cortex. The present study indicates that A2B receptors stimulation can attenuate the neuroinflammation that develops after ischemia, suggesting that A2B receptors may represent a new interesting pharmacological target to protect from degeneration after brain ischemia.
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Affiliation(s)
- Ilaria Dettori
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Lisa Gaviano
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Filippo Ugolini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Daniele Lana
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Irene Bulli
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
| | - Giada Magni
- Institute of Applied Physics "Nello Carrara", National Research Council (IFAC-CNR), Florence, Italy
| | - Francesca Rossi
- Institute of Applied Physics "Nello Carrara", National Research Council (IFAC-CNR), Florence, Italy
| | - Maria Grazia Giovannini
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Felicita Pedata
- Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy
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29
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Hou D, Wang C, Ye X, Zhong P, Wu D. Persistent inflammation worsens short-term outcomes in massive stroke patients. BMC Neurol 2021; 21:62. [PMID: 33568099 PMCID: PMC7874622 DOI: 10.1186/s12883-021-02097-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/31/2021] [Indexed: 11/10/2022] Open
Abstract
Background Persistent inflammation is an important driver of disease progression and affects prognosis. Some indicators of inflammation predict short-term outcomes. The relationship between prognosis, especially mortality, and persistent inflammation in massive stroke has not been studied, and this has been the subject of our research. Methods From April 1, 2017 to February 1, 2020, consecutive patients were prospectively enrolled. Clinical data, laboratory data, imaging data and follow-up infections morbidity were compared between 2 groups according to modified Rankin scale (mRS) scores (mRS < 3 and ≥ 3) at 1 month. The binomial logistic analysis was used to determine independent factors of 1-month prognosis. Short-term functional outcome, mortality and infection rates in massive stroke with and without persistent inflammation were compared. Results One hundred thirty-nine patients with massive stroke were included from 800 patients. We found that admission blood glucose levels (p = 0.005), proportions of cerebral hemispheric (p = 0.001), posterior circulatory (p = 0.035), and lacunar (p = 0.022) ischemia were higher in poor outcome patients; neutrophil-to-lymphocyte ratio (odd ratio = 1.87, 95%CI 1.14–3.07, p = 0.013) and blood glucose concentrations (odd ratio = 1.34, 95%CI 1.01–1.79, p = 0.043) can independently predict the short-term prognosis in massive stroke patients. We also found that the incidence of pulmonary infection (p = 0.009), one-month mortality (p = 0.003) and adverse outcomes (p = 0.0005) were higher in patients with persistent inflammation. Conclusions This study suggested that persistent inflammation is associated with poor prognosis, 1-month mortality and the occurrence of in-hospital pulmonary infection and that higher baseline inflammation level predicts short-term poor outcomes in massive stroke. Supplementary Information The online version contains supplementary material available at 10.1186/s12883-021-02097-9.
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Affiliation(s)
- Duanlu Hou
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Shanghai, 200240, China
| | - Chunjie Wang
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Shanghai, 200240, China.,Jiangchuan Community Health Service Center of Minhang District, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Ping Zhong
- Department of Neurology, Shidong Hospital of Yangpu District, Shanghai, No.999, Shiguang Road, Shanghai, 200438, China.
| | - Danhong Wu
- Department of Neurology, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Shanghai, 200240, China.
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30
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Blood substitution therapy rescues the brain of mice from ischemic damage. Nat Commun 2020; 11:4078. [PMID: 32843630 PMCID: PMC7447645 DOI: 10.1038/s41467-020-17930-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 07/22/2020] [Indexed: 12/15/2022] Open
Abstract
Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage. Acute stroke causes complex, pathological, and systemic responses which remain challenging to treat. Here, the authors show that substituting the blood of stroke model mice with whole-blood from naive healthy donor mice reduces infarct volume and improves neurological deficits.
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31
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Hou D, Wang C, Luo Y, Ye X, Han X, Feng Y, Zhong P, Wu D. Systemic immune-inflammation index (SII) but not platelet-albumin-bilirubin (PALBI) grade is associated with severity of acute ischemic stroke (AIS). Int J Neurosci 2020; 131:1203-1208. [PMID: 32546038 DOI: 10.1080/00207454.2020.1784166] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Introduction: Inflammation plays an important role in stroke. Many inflammatory markers in peripheral blood are proved to be associated with stroke severity or prognosis. But few comprehensive models or scales to evaluate the severity of stroke have been reported. Systemic immune-inflammation index (SII) and platelet-albumin-bilirubin (PALBI) grade as new markers of inflammation have shown their positive association with liver cancer. The relation between SII, or PALBI and stroke remains uncertain.Objective: To investigate the relationship between SII, PALBI grade and stroke severity.Methods: Patients with ischemic stroke with hospital admission <24 h after symptom onset were prospectively included in a stroke registry. Demographic, clinical, and laboratory data were collected immediately after admission in all patients. The National Institutes of Health Stroke Scale (NIHSS) was used to assess stroke severity upon admission. Minor stroke was defined as NIHSS score < =5, moderate-to-severe stroke as NIHSS score >5. SII, calculated as platelet × neutrophil/lymphocyte was divided into four groups according to interquartile range: lowest SII (SII < 353.9 × 109/L), low SII (353.9-532.8 × 109/L), high SII (532.8-783.9 × 109/L), and highest SII (>783.9 × 109/L) group.Results: A total of 362 patients with ischemic stroke were included, and between minor and moderate-to-severe stroke significant difference was found in SII (p < 0.0001), NLR (p < 0.0001), and PLR (p = 0.001), respectively. After multivariate regression analyses, SII groups (Odd ratio = 1.351, 95% confidence interval 1.084-1.684, p = 0.007) not PALBI was an independent risk factor for stroke severity.Conclusion: We found that SII but not PALBI, which both are markers of inflammation, was independently associated with stroke severity.
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Affiliation(s)
- Duanlu Hou
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Chunjie Wang
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.,Jiangchuan Community Health Service Center of Minhang District, Shanghai, China
| | - Yufan Luo
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Second Military Medical University, Shanghai, China
| | - Xiang Han
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China
| | - Yanhua Feng
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.,Department of Neurology, Shangri-La People's Hospital, Shangri-La, Yunnan, China
| | - Ping Zhong
- Department of Neurology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Chinese Medicine, Shanghai, China
| | - Danhong Wu
- Department of Neurology, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China
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Dhanesha N, Jain M, Tripathi AK, Doddapattar P, Chorawala M, Bathla G, Nayak MK, Ghatge M, Lentz SR, Kon S, Chauhan AK. Targeting Myeloid-Specific Integrin α9β1 Improves Short- and Long-Term Stroke Outcomes in Murine Models With Preexisting Comorbidities by Limiting Thrombosis and Inflammation. Circ Res 2020; 126:1779-1794. [PMID: 32195632 PMCID: PMC7274887 DOI: 10.1161/circresaha.120.316659] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
RATIONALE Currently, there is no effective intervention available that can reduce brain damage following reperfusion. Clinical studies suggest a positive correlation between the increased influx of neutrophils and severity of brain injury following reperfusion. Integrin α9β1 is highly expressed on activated neutrophils and contributes to stable adhesion, but its role in stroke outcome has not been demonstrated to date. OBJECTIVE We sought to determine the mechanistic role of myeloid-specific α9β1 in the progression of ischemic stroke in murine models with preexisting comorbidities. METHODS AND RESULTS We generated novel myeloid-specific α9-deficient (α9-/-) wild type (α9fl/flLysMCre+/-), hyperlipidemic (α9fl/flLysMCre+/-Apoe-/-), and aged (bone marrow chimeric) mice to evaluate stroke outcome. Susceptibility to ischemia/reperfusion injury was evaluated at 1, 7, and 28 days following reperfusion in 2 models of experimental stroke: filament and embolic. We found that peripheral neutrophils displayed elevated α9 expression following stroke. Irrespective of sex, genetic deletion of α9 in myeloid cells improved short- and long-term stroke outcomes in the wild type, hyperlipidemic, and aged mice. Improved stroke outcome and enhanced survival in myeloid-specific α9-/- mice was because of marked decrease in cerebral thromboinflammatory response as evidenced by reduced fibrin, platelet thrombi, neutrophil, NETosis, and decreased phospho-NF-κB (nuclear factor-κB), TNF (tumor necrosis factor)-α, and IL (interleukin)-1β levels. α9-/- mice were less susceptible to FeCl3 injury-induced carotid artery thrombosis that was concomitant with improved regional cerebral blood flow following stroke as revealed by laser speckle imaging. Mechanistically, fibronectin containing extra domain A, a ligand for integrin α9, partially contributed to α9-mediated stroke exacerbation. Infusion of a specific anti-integrin α9 inhibitor into hyperlipidemic mice following reperfusion significantly reduced infarct volume and improved short- and long-term functional outcomes up to 28 days. CONCLUSIONS We provide genetic and pharmacological evidence for the first time that targeting myeloid-specific integrin α9β1 improves short- and long-term functional outcomes in stroke models with preexisting comorbidities by limiting cerebral thrombosis and inflammation.
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Affiliation(s)
- Nirav Dhanesha
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Manish Jain
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Amit K. Tripathi
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Prakash Doddapattar
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Mehul Chorawala
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Girish Bathla
- Department of Radiology, University of Iowa, Iowa City, Iowa, USA
| | - Manasa K. Nayak
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Madankumar Ghatge
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Steven R. Lentz
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
| | - Shigeyuki Kon
- Department of Molecular Immunology, Faculty of Pharmaceutical Sciences, Fukuyama University, Hiroshima, Japan
| | - Anil K. Chauhan
- Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, Iowa, USA
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A novel approach to treatment of thromboembolic stroke in mice: Redirecting neutrophils toward a peripherally implanted CXCL1-soaked sponge. Exp Neurol 2020; 330:113336. [PMID: 32360283 DOI: 10.1016/j.expneurol.2020.113336] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/30/2020] [Accepted: 04/28/2020] [Indexed: 11/23/2022]
Abstract
Neutrophils are considered key participants in post-ischemic stroke inflammation. They are the first white blood cells to arrive in ischemic brain and their presence in the brain tissue positively correlates with post-ischemic injury severity. CXCL1 is a neutrophil attractant chemokine and the present study evaluates whether redirecting neutrophil migration using a peripherally implanted CXCL1-soaked sponge can reduce brain inflammation and improve outcomes in a novel mouse model of thromboembolic (TE) stroke. TE stroke was induced by injection of a platelet-rich microemboli suspension into the internal carotid artery of adult C57BL/6 male mice. The model induced neuroinflammation that was associated with increases in multiple brain and serum cytokines/chemokines at the mRNA and protein levels, including very marked increases in CXCL1. In other groups of animals, an absorbable sterile hemostatic sponge, previously immersed in either saline (0.9%NaCl) or CXCL1, was implanted into subcutaneous pockets formed in the inguinal region on the left and right side following stroke surgery. Mice implanted with the sponge soaked with CXCL1 had significantly reduced neuroinflammation and infarct size after TE stroke compared to mice implanted with the sponge soaked with 0.9%NaCl. There was also reduced mortality and improved neurological deficits in the TE stroke + CXCL1 sponge group compared to the TE stroke +0.9%NaCl sponge group. In conclusion: redirecting bloodstream leukocytes toward a peripherally-implanted neutrophil chemokine CXCL1-soaked sponge improves outcomes in a novel mouse model of thromboembolic stroke. The present findings suggest a novel therapeutic strategy for patients with acute stroke.
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Neurovascular protection by peroxisome proliferator-activated receptor α in ischemic stroke. Exp Neurol 2020; 331:113323. [PMID: 32320699 DOI: 10.1016/j.expneurol.2020.113323] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/14/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. Currently, the only pharmacological therapy for ischemic stroke is thrombolysis with tissue plasminogen activator that has a narrow therapeutic window and increases the risk of intracerebral hemorrhage. New pharmacological treatments for ischemic stroke are desperately needed, but no neuroprotective drugs have successfully made it through clinical trials. Beneficial effects of peroxisome proliferator-activated receptor alpha (PPARα) activation on vascular integrity and function have been reported, and PPARα agonists have clinically been used for many years to manage cardiovascular disease. Thus, PPARα has gained interest in recent years as a target for neurovascular disease such as ischemic stroke. Accumulating preclinical evidence suggests that PPARα activation modulates several pathophysiological hallmarks of stroke such as oxidative stress, blood-brain barrier (BBB) dysfunction, and neuroinflammation to improve functional recovery. Therefore, this review summarizes the various actions PPARα exerts in neurovascular health and disease and the potential of employing exogenous PPARα agonists for future pharmacological treatment of ischemic stroke.
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Kollikowski AM, Schuhmann MK, Nieswandt B, Müllges W, Stoll G, Pham M. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466-479. [PMID: 31899551 DOI: 10.1002/ana.25665] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 12/27/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization. METHODS We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines. RESULTS Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T-cell chemoattractant CXCL-11. Finally, we found evidence that short-term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation. INTERPRETATION We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466-479.
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Affiliation(s)
| | | | - Bernhard Nieswandt
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Wolfgang Müllges
- Department of Neurology, University Hospital of Würzburg, Würzburg, Germany
| | - Guido Stoll
- Department of Neurology, University Hospital of Würzburg, Würzburg, Germany
| | - Mirko Pham
- Department of Neuroradiology, University Hospital of Würzburg, Würzburg, Germany
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Hou Y, Yang D, Xiang R, Wang H, Wang X, Zhang H, Wang P, Zhang Z, Che X, Liu Y, Gao Y, Yu X, Gao X, Zhang W, Yang J, Wu C. N2 neutrophils may participate in spontaneous recovery after transient cerebral ischemia by inhibiting ischemic neuron injury in rats. Int Immunopharmacol 2019; 77:105970. [DOI: 10.1016/j.intimp.2019.105970] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/28/2019] [Accepted: 10/09/2019] [Indexed: 12/22/2022]
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Significantly Increased Accumulation of 18F-FDG Throughout the Left Middle Cerebral Artery Territory Corresponding to Acute-Phase Infarction. Clin Nucl Med 2019; 44:907-910. [PMID: 31592826 DOI: 10.1097/rlu.0000000000002796] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
A 70-year-old woman had spontaneous resolution of an embolism in her right middle cerebral artery (MCA) (day 1); another embolism occurred in her left MCA (day 3), which was promptly removed. On day 5, F-FDG PET/CT performed for staging mediastinal lymphoma showed marked FDG accumulation in the left MCA territory, whereas a defect was seen in the right insular region. Eventually, bilateral lesions developed irreversible infarction. Anaerobic metabolism and/or inflammation in acute-phase infarction were the supposed mechanism for the increased accumulation of FDG in her left MCA territory.
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Thålin C, Hisada Y, Lundström S, Mackman N, Wallén H. Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis. Arterioscler Thromb Vasc Biol 2019; 39:1724-1738. [PMID: 31315434 DOI: 10.1161/atvbaha.119.312463] [Citation(s) in RCA: 274] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.
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Affiliation(s)
- Charlotte Thålin
- From the Division of Internal Medicine, Department of Clinical Sciences, Danderyd Hospital (C.T.), Karolinska Institutet, Stockholm, Sweden
| | - Yohei Hisada
- Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill (Y.H., N.M.)
| | - Staffan Lundström
- Department of Oncology-Pathology (S.L.), Karolinska Institutet, Stockholm, Sweden.,Palliative Care Services and R&D-Unit, Stockholms Sjukhem Foundation, Sweden (S.L.)
| | - Nigel Mackman
- Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill (Y.H., N.M.)
| | - Håkan Wallén
- Division of Cardiovascular Medicine (H.W.), Karolinska Institutet, Stockholm, Sweden
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Zeng Z, Zhang Y, Liang X, Wang F, Zhao J, Xu Z, Liu X, Liu X. Qingnao dripping pills mediate immune-inflammatory response and MAPK signaling pathway after acute ischemic stroke in rats. J Pharmacol Sci 2019; 139:143-150. [DOI: 10.1016/j.jphs.2018.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 12/06/2018] [Accepted: 12/31/2018] [Indexed: 12/17/2022] Open
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Abu-Fanne R, Stepanova V, Litvinov RI, Abdeen S, Bdeir K, Higazi M, Maraga E, Nagaswami C, Mukhitov AR, Weisel JW, Cines DB, Higazi AAR. Neutrophil α-defensins promote thrombosis in vivo by altering fibrin formation, structure, and stability. Blood 2019; 133:481-493. [PMID: 30442678 PMCID: PMC6356988 DOI: 10.1182/blood-2018-07-861237] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 10/17/2018] [Indexed: 02/06/2023] Open
Abstract
Inflammation and thrombosis are integrated, mutually reinforcing processes, but the interregulatory mechanisms are incompletely defined. Here, we examined the contribution of α-defensins (α-defs), antimicrobial proteins released from activated human neutrophils, on clot formation in vitro and in vivo. Activation of the intrinsic pathway of coagulation stimulates release of α-defs from neutrophils. α-Defs accelerate fibrin polymerization, increase fiber density and branching, incorporate into nascent fibrin clots, and impede fibrinolysis in vitro. Transgenic mice (Def++) expressing human α-Def-1 developed larger, occlusive, neutrophil-rich clots after partial inferior vena cava (IVC) ligation than those that formed in wild-type (WT) mice. IVC thrombi extracted from Def++ mice were composed of a fibrin meshwork that was denser and contained a higher proportion of tightly packed compressed polyhedral erythrocytes than those that developed in WT mice. Def++ mice were resistant to thromboprophylaxis with heparin. Inhibiting activation of the intrinsic pathway of coagulation, bone marrow transplantation from WT mice or provision of colchicine to Def++ mice to inhibit neutrophil degranulation decreased plasma levels of α-defs, caused a phenotypic reversion characterized by smaller thrombi comparable to those formed in WT mice, and restored responsiveness to heparin. These data identify α-defs as a potentially important and tractable link between innate immunity and thrombosis.
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Affiliation(s)
- Rami Abu-Fanne
- Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel
| | | | - Rustem I Litvinov
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Suhair Abdeen
- Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel
| | - Khalil Bdeir
- Department of Pathology and Laboratory Medicine and
| | - Mohamed Higazi
- Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel
| | - Emad Maraga
- Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel
| | - Chandrasekaran Nagaswami
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and
| | - Alexander R Mukhitov
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and
| | - John W Weisel
- Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; and
| | | | - Abd Al-Roof Higazi
- Department of Clinical Biochemistry, Hadassah-Hebrew University, Jerusalem, Israel
- Department of Pathology and Laboratory Medicine and
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Davis SM, Collier LA, Winford ED, Leonardo CC, Ajmo CT, Foran EA, Kopper TJ, Gensel JC, Pennypacker KR. Leukemia inhibitory factor modulates the peripheral immune response in a rat model of emergent large vessel occlusion. J Neuroinflammation 2018; 15:288. [PMID: 30322390 PMCID: PMC6190542 DOI: 10.1186/s12974-018-1326-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/05/2018] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND The migration of peripheral immune cells and splenocytes to the ischemic brain is one of the major causes of delayed neuroinflammation after permanent large vessel stroke. Other groups have demonstrated that leukemia inhibitory factor (LIF), a cytokine that promotes neural cell survival through upregulation of antioxidant enzymes, promotes an anti-inflammatory phenotype in several types of immune cells. The goal of this study was to determine whether LIF treatment modulates the peripheral immune response after stroke. METHODS Young male (3 month) Sprague-Dawley rats underwent sham surgery or permanent middle cerebral artery occlusion (MCAO). Animals were administered LIF (125 μg/kg) or PBS at 6, 24, and 48 h prior to euthanization at 72 h. Bone marrow-derived macrophages were treated with LIF (20 ng/ml) or PBS after stimulation with interferon gamma + LPS. Western blot was used to measure protein levels of CD11b, IL-12, interferon inducible protein-10, CD3, and the LIF receptor in spleen and brain tissue. ELISA was used to measure IL-10, IL-12, and interferon gamma. Isolectin was used to label activated immune cells in brain tissue sections. Statistical analysis was performed using one-way ANOVA and Student's t test. A Kruskal-Wallis test followed by Bonferroni-corrected Mann-Whitney tests was performed if data did not pass the D'Agostino-Pearson normality test. RESULTS LIF-treated rats showed significantly lower levels of the LIF receptor and interferon gamma in the spleen and CD11b levels in the brain compared to their PBS-treated counterparts. Fluorescence from isolectin-binding immune cells was more prominent in the ipsilateral cortex and striatum after PBS treatment compared to LIF treatment. MCAO + LIF significantly decreased splenic levels of CD11b and CD3 compared to sham surgery. MCAO + PBS treatment significantly elevated splenic levels of interferon inducible protein-10 at 72 h after MCAO, while LIF treatment after MCAO returned interferon inducible protein 10 to sham levels. LIF administration with interferon gamma + LPS significantly reduced the IL-12/IL-10 production ratio compared to macrophages treated with interferon gamma + LPS alone. CONCLUSIONS These data demonstrate that LIF promotes anti-inflammatory signaling through alterations of the IL-12/interferon gamma/interferon inducible protein 10 pathway.
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Affiliation(s)
- Stephanie M. Davis
- Department of Neurology, University of Kentucky, 741 S. Limestone BBSRB B457, Lexington, KY 40536-0905 USA
| | - Lisa A. Collier
- Department of Neurology, University of Kentucky, 741 S. Limestone BBSRB B457, Lexington, KY 40536-0905 USA
| | - Edric D. Winford
- Department of Neuroscience, University of Kentucky, 800 Rose St. Lexington, Lexington, KY 40536 USA
| | - Christopher C. Leonardo
- Department of Molecular Pharmacology and Physiology, University of South Florida, 12901 Bruce B. Downs Blvd MDC 8, Tampa, FL 33612 USA
| | - Craig T. Ajmo
- Department of Molecular Pharmacology and Physiology, University of South Florida, 12901 Bruce B. Downs Blvd MDC 8, Tampa, FL 33612 USA
| | - Elspeth A. Foran
- Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd MDC 7, Tampa, FL 33612 USA
| | - Timothy J. Kopper
- Department of Physiology, University of Kentucky, 800 Rose St. MS508, Lexington, KY 40536 USA
- Spinal Cord and Brain Injury Repair Center, University of Kentucky, 741 S. Limestone BBSRB B463, Lexington, KY 40536 USA
| | - John C. Gensel
- Department of Physiology, University of Kentucky, 800 Rose St. MS508, Lexington, KY 40536 USA
- Spinal Cord and Brain Injury Repair Center, University of Kentucky, 741 S. Limestone BBSRB B463, Lexington, KY 40536 USA
| | - Keith R. Pennypacker
- Department of Neurology, University of Kentucky, 741 S. Limestone BBSRB B457, Lexington, KY 40536-0905 USA
- Department of Neuroscience, University of Kentucky, 800 Rose St. Lexington, Lexington, KY 40536 USA
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Kothur K, Troedson C, Webster R, Bandodkar S, Chu S, Wienholt L, Pope A, Mackay MT, Dale RC. Elevation of cerebrospinal fluid cytokine/chemokines involved in innate, T cell, and granulocyte inflammation in pediatric focal cerebral arteriopathy. Int J Stroke 2018; 14:154-158. [DOI: 10.1177/1747493018799975] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Aim To determine the role of inflammation in pediatric transient focal cerebral arteriopathy using cerebrospinal fluid cytokine/chemokines as biomarkers. Methods We measured 32 cytokine/chemokines in acute cerebrospinal fluid collected from children with stroke due to focal cerebral arteriopathy (n = 5) using multiplex immunoassay and compared with two patients with arterial ischemic stroke due to other causes (non-focal cerebral arteriopathy group, vertebral dissection, n = 1; cryptogenic, n = 1), pediatric encephalitis (n = 43), and non-inflammatory neurological disease controls (n = 20). Results Median age in the focal cerebral arteriopathy group was 9.3 years (range, 2.8–13 years). In the focal cerebral arteriopathy group (n = 5), four patients had middle cerebral ± distal carotid arteriopathy; one patient had posterior circulation arteriopathy. The median time from symptom onset to cerebrospinal fluid sampling was four days (range, 0.6–7 days). Only IL-6, IL-8, CXCL1, and CXCL10 levels were significantly higher in the acute cerebrospinal fluid of focal cerebral arteriopathy patients compared to non-inflammatory neurological disease controls and non-focal cerebral arteriopathy stroke. In contrast to focal cerebral arteriopathy, a broad array of Th1, Th2, Treg, Th17, B-cell related, and other broad spectrum cytokine/chemokines were elevated in encephalitis. Conclusion The elevated cerebrospinal fluid cytokine/chemokines support innate, T cell, and granulocyte inflammatory mechanisms in children with focal cerebral arteriopathy. This warrants larger cohort studies to discriminate primary inflammatory signals of the arteriopathy from secondary inflammation due to the stroke itself.
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Affiliation(s)
- Kavitha Kothur
- Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The University of Sydney, Sydney, Australia
- TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia
| | - Christopher Troedson
- TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia
| | - Richard Webster
- TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia
| | - Sushil Bandodkar
- Department of Biochemistry, The Children’s Hospital at Westmead, Sydney, Australia
| | - Stephanie Chu
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Louise Wienholt
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia
| | - Alun Pope
- Statistical Consulting, The University of Sydney, Sydney, Australia
| | - Mark T Mackay
- Department of Neurology, Royal Children’s Hospital, and University of Melbourne, Victoria, Australia
| | - Russell C Dale
- Neuroimmunology Group, Institute for Neuroscience and Muscle Research, The University of Sydney, Sydney, Australia
- TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Sydney, Australia
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Boese AC, Le QSE, Pham D, Hamblin MH, Lee JP. Neural stem cell therapy for subacute and chronic ischemic stroke. Stem Cell Res Ther 2018; 9:154. [PMID: 29895321 PMCID: PMC5998588 DOI: 10.1186/s13287-018-0913-2] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Neural stem cells (NSCs) play vital roles in brain homeostasis and exhibit a broad repertoire of potentially therapeutic actions following neurovascular injury. One such injury is stroke, a worldwide leading cause of death and disability. Clinically, extensive injury from ischemic stroke results from ischemia-reperfusion (IR), which is accompanied by inflammation, blood-brain barrier (BBB) damage, neural cell death, and extensive tissue loss. Tissue plasminogen activator (tPA) is still the only US Food and Drug Administration-approved clot-lysing agent. Whereas the thrombolytic role of tPA within the vasculature is beneficial, the effects of tPA (in a non-thrombolytic role) within the brain parenchyma have been reported as harmful. Thus, new therapies are needed to reduce the deleterious side effects of tPA and quickly facilitate vascular repair following stroke. The Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies "focus on drugs/devices/treatments with multiple mechanisms of action and that target multiple pathways". Thus, based on multifactorial ischemic cascades in various stroke stages, effective stroke therapies need to focus on targeting and ameliorating early IR injury as well as facilitating angiogenesis, neurogenesis, and neurorestorative mechanisms following stroke. This review will discuss the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury and will emphasize both the subacute and chronic phase of ischemic stroke.
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Affiliation(s)
- Austin C Boese
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Quan-Son Eric Le
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Dylan Pham
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Milton H Hamblin
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Jean-Pyo Lee
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, 70112, USA. .,Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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Larson TA. Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair. Front Endocrinol (Lausanne) 2018; 9:205. [PMID: 29760681 PMCID: PMC5936772 DOI: 10.3389/fendo.2018.00205] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/12/2018] [Indexed: 01/16/2023] Open
Abstract
Sex steroidal hormones coordinate the development and maintenance of tissue architecture in many organs, including the central nervous systems (CNS). Within the CNS, sex steroids regulate the morphology, physiology, and behavior of a wide variety of neural cells including, but not limited to, neurons, glia, endothelial cells, and immune cells. Sex steroids spatially and temporally control distinct molecular networks, that, in turn modulate neural activity, synaptic plasticity, growth factor expression and function, nutrient exchange, cellular proliferation, and apoptosis. Over the last several decades, it has become increasingly evident that sex steroids, often in conjunction with neuroinflammation, have profound impact on the occurrence and severity of neuropsychiatric and neurodegenerative disorders. Here, I review the foundational discoveries that established the regulatory role of sex steroids in the CNS and highlight recent advances toward elucidating the complex interaction between sex steroids, neuroinflammation, and CNS regeneration through adult neurogenesis. The majority of recent work has focused on neuroinflammatory responses following acute physical damage, chronic degeneration, or pharmacological insult. Few studies directly assess the role of immune cells in regulating adult neurogenesis under healthy, homeostatic conditions. As such, I also introduce tractable, non-traditional models for examining the role of neuroimmune cells in natural neuronal turnover, seasonal plasticity of neural circuits, and extreme CNS regeneration.
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Affiliation(s)
- Tracy A. Larson
- Department of Biology, University of Virginia, Charlottesville, VA, United States
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Yilmaz E, Bayram Kacar A, Bozpolat A, Zararsiz G, Gorkem BS, Karakukcu M, Patiroglu T, Gumus H, Ozdemir MA, Ozcan A, Per H, Unal E. The relationship between hematological parameters and prognosis of children with acute ischemic stroke. Childs Nerv Syst 2018; 34:655-661. [PMID: 29209887 DOI: 10.1007/s00381-017-3673-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 11/27/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Stroke is rarely seen in children, but it is a major cause of morbidity and mortality. Therefore, there is a need for inexpensive and noninvasive diagnostic methods for estimating the prognosis. Although the prognostic importance of hematological parameters in acute ischemic stroke were reported in adult studies, there is a lack in pediatric ages. The aim of the study is to investigate the relationship between hematological parameters and prognosis of acute ischemic stroke in children. METHODS Retrospectively scanned in the study were 106 pediatric patients with acute ischemic stroke who managed at the Medical Faculty of Erciyes University, Kayseri, between the years of 2000 and 2014. White blood count (WBC); neutrophil, lymphocyte, and platelet count; mean platelet volume (MPV); platelet distribution width (PDW); neutrophil count/lymphocyte count (N/L) ratio values obtained from the measurements and initial symptoms; demographical features; risk factors; neurological examination; and clinical follow-up were recorded. Their hematological parameters were compared with those of 106 age and sex-matched healthy individuals. RESULTS MPV and PDW values were found similar in patient and control groups, and the platelet count was found significantly low in the control group (p = 0,028). WBC, neutrophil count, and N/L ratio were found considerably high in the patient group (p < 0.001). Lymphocyte count, however, was found significantly low in the control group (p < 0.001). No statistically significant difference was detected in WBC, neutrophil count, lymphocyte count, platelet count, N/L ratio, and MPV and PDW values between the group with sequelae and the one without sequelae. In addition, it was determined that WBC, neutrophil count, lymphocyte count, platelet count, N/L ratio, and MPV and PDW values in the univariate Cox-regression analysis of the patient group had no effect on survival and disease-free survival. When receiver operating characteristic curve was applied, it was observed that the area below WBC, N/L ratio curve was important in the patient group in terms of predicting acute ischemic stroke. CONCLUSION The values of WBC, neutrophil count, and N/L ratio differ significantly from those of the control group. The WBC and N/L ratio may help for an earlier diagnosis in children with acute ischemic stroke. WBC, thrombocyte count, MPV, PDW, and N/L ratio do not constitute a risk in overall survival, disease-free survival, and sequelae development.
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Affiliation(s)
- Ebru Yilmaz
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Ayse Bayram Kacar
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Erciyes University, Kayseri, Turkey
| | - Adil Bozpolat
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Gokmen Zararsiz
- Faculty of Medicine, Department of Biostatistics and Medical Informatics, Erciyes University, Kayseri, Turkey
| | - Burcu S Gorkem
- Faculty of Medicine, Department of Radiology, Division of Pediatric Radiology, Erciyes University, Kayseri, Turkey
| | - Musa Karakukcu
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Turkan Patiroglu
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Hakan Gumus
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Erciyes University, Kayseri, Turkey
| | - Mehmet Akif Ozdemir
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Alper Ozcan
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey
| | - Huseyin Per
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Erciyes University, Kayseri, Turkey
| | - Ekrem Unal
- Faculty of Medicine, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Erciyes University, 38039, Talas, Kayseri, Turkey.
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Enzmann GU, Pavlidou S, Vaas M, Klohs J, Engelhardt B. ICAM-1 null C57BL/6 Mice Are Not Protected from Experimental Ischemic Stroke. Transl Stroke Res 2018; 9:608-621. [PMID: 29399739 DOI: 10.1007/s12975-018-0612-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 01/19/2018] [Accepted: 01/19/2018] [Indexed: 11/29/2022]
Abstract
Accumulation of neutrophils in the brain is a hallmark of cerebral ischemia and considered central in exacerbating tissue injury. Intercellular adhesion molecule (ICAM)-1 is upregulated on brain endothelial cells after ischemic stroke and considered pivotal in neutrophil recruitment as ICAM-1-deficient mouse lines were found protected from experimental stroke. Translation of therapeutic inhibition of ICAM-1 into the clinic however failed. This prompted us to investigate stroke pathogenesis in Icam1tm1Alb C57BL/6 mutants, a true ICAM-1null mouse line. Performing transient middle cerebral artery occlusion, we found that absence of ICAM-1 did not ameliorate stroke pathology at acute time points after reperfusion. Near-infrared imaging showed comparable accumulation of neutrophils in the ischemic hemispheres of ICAM-1null and wild type C57BL/6 mice. We also isolated equal numbers of neutrophils from the ischemic brains of ICAM-1null and wild type C57BL/6 mice. Immunostaining of the brains showed neutrophils to equally accumulate in the leptomeninges and brain parenchymal vessels of ICAM-1null and wild type C57BL/6 mice. In addition, the lesion size was comparable in ICAM-1null and wild type mice. Our study demonstrates that absence of ICAM-1 neither inhibits cerebral ischemia-induced accumulation of neutrophils in the brain nor provides protection from ischemic stroke.
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Affiliation(s)
- Gaby U Enzmann
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland
| | - Sofia Pavlidou
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland
| | - Markus Vaas
- Institute for Biomedical Engineering, ETH and University of Zurich, 8093, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Jan Klohs
- Institute for Biomedical Engineering, ETH and University of Zurich, 8093, Zurich, Switzerland.,Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Britta Engelhardt
- Theodor Kocher Institute, University of Bern, Freiestrasse 1, 3012, Bern, Switzerland.
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Thom V, Arumugam TV, Magnus T, Gelderblom M. Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury. Front Immunol 2017; 8:875. [PMID: 28824617 PMCID: PMC5534474 DOI: 10.3389/fimmu.2017.00875] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/10/2017] [Indexed: 12/31/2022] Open
Abstract
Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg.
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Affiliation(s)
- Vivien Thom
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thiruma V Arumugam
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Tim Magnus
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mathias Gelderblom
- Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Petrovic-Djergovic D, Goonewardena SN, Pinsky DJ. Inflammatory Disequilibrium in Stroke. Circ Res 2017; 119:142-58. [PMID: 27340273 DOI: 10.1161/circresaha.116.308022] [Citation(s) in RCA: 204] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2016] [Accepted: 05/25/2016] [Indexed: 01/01/2023]
Abstract
Over the past several decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. Understanding the benefits of timely reperfusion has led to the development of thrombolytic therapy as the cornerstone of current management of ischemic stroke, but there remains much to be learned about mechanisms of neuronal ischemic and reperfusion injury and associated inflammation. For ischemic stroke, novel therapeutic targets have continued to remain elusive. When considering modern molecular biological techniques, advanced translational stroke models, and clinical studies, a consistent pattern emerges, implicating perturbation of the immune equilibrium by stroke in both central nervous system injury and repair responses. Stroke triggers activation of the neuroimmune axis, comprised of multiple cellular constituents of the immune system resident within the parenchyma of the brain, leptomeninges, and vascular beds, as well as through secretion of biological response modifiers and recruitment of immune effector cells. This neuroimmune activation can directly impact the initiation, propagation, and resolution phases of ischemic brain injury. To leverage a potential opportunity to modulate local and systemic immune responses to favorably affect the stroke disease curve, it is necessary to expand our mechanistic understanding of the neuroimmune axis in ischemic stroke. This review explores the frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke.
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Affiliation(s)
- Danica Petrovic-Djergovic
- From the Departments of Internal Medicine (D.P.-D., S.N.G., D.J.P.) and Molecular and Integrative Physiology (D.J.P.), University of Michigan, Ann Arbor
| | - Sascha N Goonewardena
- From the Departments of Internal Medicine (D.P.-D., S.N.G., D.J.P.) and Molecular and Integrative Physiology (D.J.P.), University of Michigan, Ann Arbor
| | - David J Pinsky
- From the Departments of Internal Medicine (D.P.-D., S.N.G., D.J.P.) and Molecular and Integrative Physiology (D.J.P.), University of Michigan, Ann Arbor.
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Bivard A, Lincz LF, Maquire J, Parsons M, Levi C. Platelet microparticles: a biomarker for recanalization in rtPA-treated ischemic stroke patients. Ann Clin Transl Neurol 2017; 4:175-179. [PMID: 28275651 PMCID: PMC5338157 DOI: 10.1002/acn3.392] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 11/27/2016] [Accepted: 12/17/2016] [Indexed: 01/05/2023] Open
Abstract
Objectives Identification of a biomarker for acute recanalization could have significant clinical impact. Methods We prospectively collected baseline, 24‐h, and 90‐day clinical and imaging data from consecutive ischemic stroke patients who fulfilled standard clinical eligibility criteria for treatment with intravenous recombinant tissue plasminogen activator (rtPA). Computed tomography angiography was acquired at 24 h and assessed using the thrombolysis is myocardial infarction (TIMI) scale with a score of 2b/3 indicating recanalization. Blood samples collected at 24 h after stroke symptom onset were used to measure the inflammatory biomarkers of glycoprotein IIb (CD41) expressing microparticles (MP), C‐reactive protein (CRP), COX 2, APOE, and Angiopoietin 1. Analysis was performed using linear regression and Pearson's correlation coefficient. Results A total of 57 patients met study eligibility criteria and had sufficient data and sample quality to be analyzed. Circulating levels of platelet derived CD41 + MP were significantly related to reperfusion (Pearson correlation, PC: 0.554, P < 0.001) and recanalization (PC: 0.495, P < 0.001) as well as related with 3‐month modified Rankin Score (PC: 0.483, P < 0.001). CRP was significantly negatively correlated with recanalization on 24 h CTA (PC: −0.292, P = 0.041). Backward logistic regression with CRP and CD41 + MP increased the association with reperfusion (r2 = 0.357 P < 0.001). Interpretation There is a significant relationship between the inflammatory biomarkers CD41 + MP and CRP and recanalization.
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Affiliation(s)
- Andrew Bivard
- Departments of Neurology John Hunter Hospital University of Newcastle Newcastle Australia
| | - Lisa F Lincz
- Hunter Haematology Research Group Calvary Mater Newcastle hospital Waratah Australia
| | - Jane Maquire
- Departments of Neurology John Hunter Hospital University of Newcastle Newcastle Australia
| | - Mark Parsons
- Departments of Neurology John Hunter Hospital University of Newcastle Newcastle Australia
| | - Christopher Levi
- Departments of Neurology John Hunter Hospital University of Newcastle Newcastle Australia
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Martinez B, Peplow PV. Immunomodulators and microRNAs as neurorestorative therapy for ischemic stroke. Neural Regen Res 2017; 12:865-874. [PMID: 28761412 PMCID: PMC5514854 DOI: 10.4103/1673-5374.208540] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Most of all strokes are ischemic due to occlusion of a vessel, and comprise two main types, thrombotic and embolic. Inflammation and immune response play an important role in the outcome of ischemic stroke. Pharmaceutical and cell-based therapies with immunomodulatory properties could be of benefit in treating ischemic stroke. Possible changes in microRNAs brought about by immunomodulatory treatments may be important. The pharmaceutical studies described in this review have identified several differentially regulated miRNAs associated with disregulation of mRNA targets or the upregulation of several neuroprotective genes, thereby highlighting the potential neuroprotective roles of specific miRNAs such as miR-762, -1892, -200a, -145. MiR-124, -711, -145 are the strongly associated miRNAs predicted to mediate anti-inflammatory pathways and microglia/macrophage M2-like activation phenotype. The cell-based therapy studies reviewed have mainly utilized mesenchymal stem cells or human umbilical cord blood cells and shown to improve functional and neurological outcomes in stroke animals. MiR-145 and miR-133b were implicated in nerve cell remodeling and functional recovery after stroke. Human umbilical cord blood cells decreased proinflammatory factors and promoted M2 macrophage polarization in stroke diabetic animals.
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Affiliation(s)
- Bridget Martinez
- Department of Molecular and Cellular Biology, University of California, Merced, CA, USA
| | - Philip V Peplow
- Department of Anatomy, University of Otago, Dunedin, New Zealand
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