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1.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(8. Vyp. 2): 39-45, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31825361

RESUMO

INTRODUCTION: At the present time, there is an increased interest in the search for biological predictors of the course and outcome of ischemic stroke (IS). Numerous studies have shown the relationship between neuroinflammation (in the brain) and systemic inflammatory response (in the blood). AIM: To study the relationship of inflammatory and autoimmune markers in blood serum of patients with acute ischemic stroke (on the 1st day) with the dynamics of the severity of neurological deficit (on the 1st and 10th day) and to assess the predictive ability of these indicators. MATERIAL AND METHODS: Twenty-two patients in the acute period of IS (mean age 60±15.5 years) were examined. The severity of neurological deficit was assessed by ESS and NIHSS. The enzymatic activity of leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI), level of autoantibodies to S-100B and MBP in serum was determined. The control group consisted of 33 healthy subjects. Blood samples were carried out on the 1st day of the post-stroke period, the clinical examination was performed on the 1st and 10th day of observation. RESULTS: Depending on the dynamics of neurological symptoms by the 10th day of observation, two subgroups of patients were identified. The1st subgroup was characterized by the normalization of neurological deficit (n=10). In the 2nd group, the negative dynamics of neurological deficit/lack of any positive changes was observed (n=12). Both subgroups demonstrated the increase in the LE and α1-PI activity as compared to the control (p=0.0019, p=0.00079; p=0.038, p=0.00041, respectively). The highest LE activity was detected in the 1st subgroup (p=0.035). The high level of autoantibodies to MBP was also observed in the 1st subgroup as compared to the control and the 2nd group (p=0.047, p=0.03, respectively). The 2nd subgroup was characterized by a higher functional activity of acute phase protein α1-PI (p=0.04). Using regression analysis, a model for predicting the course of the early post-stroke period depending on the determined immunological parameters was developed. CONCLUSION: The results suggest that the studied inflammatory and autoimmune markers may be possible predictors of the course of the early post-stroke period.


Assuntos
Biomarcadores , Isquemia Encefálica , Inflamação , Acidente Vascular Cerebral , Adulto , Idoso , Doenças Autoimunes , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/imunologia , Humanos , Elastase de Leucócito/metabolismo , Pessoa de Meia-Idade , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/imunologia , alfa 1-Antitripsina
2.
BMC Neurol ; 19(1): 236, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615442

RESUMO

BACKGROUND: Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. However, it remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality. METHODS: In this study, we enrolled 458 patients with acute ischemic stroke (< 24 h after onset), 320 patients with ischemic stroke on day 10, and 216 healthy subjects. Peripheral cholinergic activity, reflected by intracellular acetylcholine (ACh) content in human peripheral blood mononuclear cells (PBMCs), was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was measured by quantitative real-time PCR and western blot. Regression analyses were used to assess associations between peripheral cholinergic function and clinical outcomes. RESULTS: Within 24 h after the onset of acute ischemic stroke, there was a rapid increase in peripheral cholinergic activity that correlated with brain infarction volume (r = 0.67, P < 0.01). Specifically, lymphocyte-derived ACh levels were significantly higher in stroke patients with pneumonia (0.21 ± 0.02 ng/106 PBMC versus 0.15 ± 0.01 ng/106 PBMC, P = 0.03). Of note, lymphocytic AChE catalytic activity was significantly lower in these patients. One-year mortality was significantly greater in patients with higher intracellular ACh levels within the first 24 h after acute stroke. CONCLUSIONS: Lymphocytes produced increased amounts of ACh in patients with acute stroke, and pneumonia was a likely result. The association between this enhanced cholinergic activity and increased risk of pneumonia/mortality suggests that increased cholinergic activity may contribute to fatal post-stroke infection.


Assuntos
Acetilcolina/metabolismo , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Acetilcolina/imunologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
3.
Immunopharmacol Immunotoxicol ; 41(5): 558-564, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31542978

RESUMO

Background: The phenomenon of ischemic stroke receives maximal attention nowadays. Many studies are designed to discover new therapies for reducing debilitating consequences of this disorder. Development of stroke-related tissue damage is due to the combination of blood flow occlusion and reperfusion phase. Inflammatory pathways participate in excess oxidative stress formation after reperfusion. Modafinil is a well-known medication prescribed for sleep disorders. Recently, several studies have focused on finding new indications for modafinil treatment. Anti-inflammatory effects of modafinil through disrupting NF-κB signaling pathway is reported previously. Downregulation of inflammatory cytokines and further oxidative damage have also been mentioned in various experiments. So far, no specific experiment had been conducted to assess the anti-inflammatory effects of modafinil on ischemic stroke. Material and methods: We evaluated outcomes of acutely administered modafinil on post-stroke behaviors and histopathological features (including apoptotic caspase-3 expressing neurons) through bilateral common carotid artery occlusion in rats. Alterations in concentrations of TNFɑ and IL-1ß were assessed, together with malon di-aldehyde (MDA) to represent oxidation level. Western blotting was used to reveal the involvement of NF-κB downregulation. Considering possible alterations in blood flow and neuronal metabolism, we also assessed the effects of modafinil on cerebral glucose metabolism through PET scan. Results and discussion: Modafinil exhibited promising effects on remission of behavioral deficits and the number of degenerated neurons in ischemic hippocampus CA1 region. IL-1ß and MDA levels were downregulated in treated animals. However, no significant alteration was observed in PET results and TNFɑ between treated and non-treated ischemic brains. Decreased protein levels of NF-κB was also measured in modafinil treated animals. Conclusion: Our findings demonstrate a promising therapeutic effect of modafinil for animal models of stroke.


Assuntos
Anti-Inflamatórios/uso terapêutico , Isquemia Encefálica/complicações , Modafinila/uso terapêutico , NF-kappa B/metabolismo , Acidente Vascular Cerebral/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Masculino , NF-kappa B/genética , Tomografia por Emissão de Pósitrons , Ratos Wistar , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/imunologia
4.
Int J Mol Sci ; 20(15)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382688

RESUMO

We recently reported that neonatal ischemia induces microglia/macrophage activation three days post-ischemia. We also found that female mice sustained smaller infarcts than males three months post-ischemia. The objective of our current study was to examine whether differential acute neuroinflammatory response and infiltrated immune cells occurs between male and females after three days post-ischemia. Permanent middle cerebral artery occlusion was induced in male and female postnatal 9-day-old (P9) mice, and mice were sacrificed three days after ischemia. Brains were analyzed for mRNA transcription after microglia magnetic cell sorting to evaluate M1 and M2 markers. FACS analysis was performed to assess myeloid infiltration and microglial expression of CX3 chemokine receptor 1 (CX3CR1). Inflammatory cytokine expression and microglia/macrophage activation were analyzed via in situ hybridization combined with immunofluorescence techniques. Lesion volume and cell death were measured. An increase in microglia/macrophages occurred in male versus female mice. The cells exhibited amoeboid morphology, and TNFα and ptgs2 (Cox-2) genes were more expressed in males. More myeloid cell infiltration was found in male versus female brains. However, we did not observe sex-dependent differences in the injured volume or cell death density. Our data show that sex differences in the acute microglial and immune responses to neonatal ischemia are likely both gene- and region-specific.


Assuntos
Isquemia Encefálica/imunologia , Imunidade Inata/genética , Inflamação/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Animais Recém-Nascidos/imunologia , Encéfalo/imunologia , Encéfalo/patologia , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Feminino , Infarto da Artéria Cerebral Média , Inflamação/genética , Inflamação/patologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Caracteres Sexuais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia
5.
Nat Rev Neurol ; 15(8): 473-481, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263257

RESUMO

Ischaemic stroke elicits a strong neuroinflammatory response, but the functional relevance and therapeutic potential of neuroinflammation has only recently become apparent. In acute experimental stroke, T cells contribute to ischaemia-reperfusion injury after recanalization in an antigen-independent manner. Surprisingly, the detrimental T cell effects are platelet-dependent. Glycoprotein (GP)Ib-mediated and GPVI-mediated platelet activation, but not GPIIb-IIIa-mediated platelet aggregation, is an important checkpoint that orchestrates thrombotic and pro-inflammatory pathways, and downstream activation of coagulation factor XII is a driving force of ischaemia-reperfusion injury in acute stroke. The evidence therefore suggests that T cells interact with platelets and facilitate further infarct development through a complex process that we refer to as thrombo-inflammation. Results of clinical trials of agents that target lymphocytes support this concept. However, in the majority of patients with ischaemic stroke, recanalization cannot be achieved and the contribution of T cells in the setting of the resultant permanent ischaemia and subacute stroke is less clear and more complex. In some settings, T cells still seem to aggravate neuronal damage late after the ischaemic insult, but stroke triggers systemic immunodepression, therefore further anti-inflammatory treatments would need to be used carefully in this context. Targeting stroke-related neuroinflammation could become an effective adjunct therapy to improve outcomes after ischaemic stroke, but this approach will require caution regarding the timing and avoidance of adverse effects.


Assuntos
Plaquetas/imunologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Encefalite/imunologia , Trombose Intracraniana/imunologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/terapia , Linfócitos T/imunologia , Animais , Isquemia Encefálica/complicações , Encefalite/complicações , Humanos , Trombose Intracraniana/complicações , Microbiota/imunologia , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/complicações
6.
BMC Neurol ; 19(1): 148, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269910

RESUMO

BACKGROUND: Almost 40% of stroke patients have a poor outcome at 3 months after the index event. Predictors for stroke outcome in the early acute phase may help to tailor stroke treatment. Infection and inflammation are considered to influence stroke outcome. METHODS: In a prospective multicenter study in Germany and Spain, including 486 patients with acute ischemic stroke, we used multivariable regression analysis to investigate the association of poor outcome with monocytic HLA-DR (mHLA-DR) expression, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide-binding protein (LBP) as markers for immunodepression, inflammation and infection. Outcome was assessed at 3 months after stroke via a structured telephone interview using the modified Rankin Scale (mRS). Poor outcome was defined as a mRS score of 3 or higher which included death. Furthermore, a time-to-event analysis for death within 3 months was performed. RESULTS: Three-month outcome data was available for 391 patients. Female sex, older age, diabetes mellitus, atrial fibrillation, stroke-associated pneumonia (SAP) and higher National Institute of Health Stroke Scale (NIHSS) score as well as lower mHLA-DR levels, higher IL-6 and LBP-levels at day 1 were associated with poor outcome at 3 months in bivariate analysis. Furthermore, multivariable analysis revealed that lower mHLA-DR expression was associated with poor outcome. Female sex, older age, atrial fibrillation, SAP, higher NIHSS score, lower mHLA-DR expression and higher IL-6 levels were associated with shorter survival time in bivariate analysis. In multivariable analysis, SAP and higher IL-6 levels on day 1 were associated with shorter survival time. CONCLUSIONS: SAP, lower mHLA-DR-expression and higher IL-6 levels on day one are associated with poor outcome and shorter survival time at 3 months after stroke onset. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01079728 , March 3, 2010.


Assuntos
Isquemia Encefálica/imunologia , Antígenos HLA-DR/sangue , Interleucina-6/sangue , Pneumonia/etiologia , Acidente Vascular Cerebral/imunologia , Proteínas da Fase Aguda , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/complicações , Biomarcadores/sangue , Isquemia Encefálica/sangue , Isquemia Encefálica/complicações , Isquemia Encefálica/mortalidade , Proteínas de Transporte/sangue , Diabetes Mellitus , Feminino , Alemanha , Humanos , Tolerância Imunológica , Inflamação/complicações , Interleucina-10/sangue , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Pneumonia/mortalidade , Estudos Prospectivos , Espanha , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue
7.
Stroke ; 50(7): 1869-1878, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31177975

RESUMO

Background and Purpose- Cerebral ischemic stroke elicits profound responses of CD4+ T cells, which in turn significantly affect the ischemic brain injury. ACC1 (acetyl coenzyme A carboxylase 1) is a key enzyme that has been recently found to propagate CD4+ T cell-associated inflammation by mediating de novo fatty acid synthesis; however, its role in the context of ischemic stroke remains unknown. Methods- Focal cerebral ischemia was induced by transient middle cerebral artery occlusion for 60 minutes in mice. Seahorse XF glycolysis assay and targeted lipidomic profiling were used to detect metabolic changes in CD4+ T cell after stroke. CD4 cre mice were crossed with ACC1 fl/fl mice to generate the CD4+ T-cell-specific deletion of ACC1 (CD4 creACC1 fl/fl mice) mice. Pretreatment with calorie restriction (CR; with 30% reduction of food for 4 weeks before middle cerebral artery occlusion) or post-treatment with ACC1 inhibitor, soraphen A were both used to test the effect of ACC1 modulation on poststroke neuroinflammation. Results- Cerebral ischemic stroke increased glycolysis and fatty acid synthesis in peripheral CD4+ T cells, in which the expression of ACC1 was also upregulated. CR downregulated the expression of ACC1 in CD4+ T cells after stroke. Both CD4 creACC1 fl/fl mice and CR-pretreated mice exhibited significantly reduced ischemic brain injury and preserved the balance of peripheral regulatory T cells/T helper 17 (Th17) cells. Furthermore, conditional knockout of ACC1 in CD4+ T cells attenuated the protection exerted by CR both on ischemic brain injury and peripheral balance of regulatory T cells/Th17 cells. Pharmacological inhibition of ACC1 after middle cerebral artery occlusion attenuates neuroinflammation, preserves regulatory T cells/Th17 balance, and improves neurological outcomes after ischemic stroke. Conclusions- ACC1 is a novel immune metabolic modulation target to balance the regulatory T cells and Th17 cells and blunt neuroinflammation after stroke. Inhibition of ACC1 can be a previously unrecognized mechanism that underlies CR-afforded neuroprotection against cerebral ischemic stroke.


Assuntos
Acetil-CoA Carboxilase/genética , Isquemia Encefálica/tratamento farmacológico , Fatores Imunológicos/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Acetil-CoA Carboxilase/antagonistas & inibidores , Acetil-CoA Carboxilase/imunologia , Animais , Isquemia Encefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Restrição Calórica , Ácidos Graxos/biossíntese , Infarto da Artéria Cerebral Média/patologia , Inflamação/etiologia , Inflamação/prevenção & controle , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Acidente Vascular Cerebral/imunologia , Células Th17/imunologia
8.
J Neuroinflammation ; 16(1): 121, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174550

RESUMO

The NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome is a member of the NLR family of innate immune cell sensors. These are crucial regulators of cytokine secretions, which promote ischemic cell death and insulin resistance. This review summarizes recent progress regarding the NLRP3 inflammasome as a potential treatment for ischemic stroke in patients with diabetes, two complicated diseases that often occur together. Stroke worsens glucose metabolism abnormalities, and the outcomes after stroke are more serious for diabetic patients compared with those without diabetes. Inflammation contributes to organ injury after ischemic stroke and diabetes. Recent research has focused on inhibiting the activation of inflammasomes and thus reducing the maturation of proinflammatory cytokines such as interleukin (IL)-1ß and IL-18. Studies suggest that inhibition of NLRP3 prevents or alleviates both ischemic stroke and diabetes. Targeting against the assembly and activity of the NLRP3 inflammasome is a potential and novel therapy for inflammasome-associated diseases, including ischemic stroke concomitant with diabetes.


Assuntos
Isquemia Encefálica/metabolismo , Complicações do Diabetes/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Acidente Vascular Cerebral/metabolismo , Animais , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Humanos , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/imunologia
9.
World Neurosurg ; 128: e1131-e1136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31121365

RESUMO

BACKGROUND: Delayed cerebral ischemia (DCI) is a serious and frequent complication following subarachnoid hemorrhage (SAH). The pathophysiology behind DCI remains poorly understood, but inflammation has been proposed to play a significant role. This study investigated the relationship between plasma levels of some of the most important inflammatory markers and DCI, cerebral vasospasm, and functional outcome in patients with SAH. METHODS: In 90 patients with SAH, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, high sensitivity C-reactive protein (HsCRP), interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were measured in peripheral blood day 3 and day 8 after SAH. Any occurrence of DCI or infection was recorded, and computed tomography angiography was performed on day 8. Clinical outcome was assessed after 3 months. RESULTS: HsCRP on day 3 was higher in patients with angiographic vasospasm (P = 0.003), and HsCRP on day 8 was higher in patients with poor outcome (P = 0.014). No association with DCI, vasospasm, or outcome was found for any of the remaining analyzed substances. CONCLUSIONS: High plasma levels of HsCRP were significantly associated with angiographic vasospasm and clinical outcome. Plasma levels of interleukin-6, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, interleukin-8, interleukin-10, interferon gamma, and tumor necrosis factor alpha were not associated with DCI, angiographic vasospasm, or clinical outcome at 3 months.


Assuntos
Isquemia Encefálica/sangue , Isquemia Encefálica/imunologia , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/sangue , Vasoespasmo Intracraniano/imunologia , Adulto , Idoso , Biomarcadores/sangue , Isquemia Encefálica/etiologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/terapia , Resultado do Tratamento , Vasoespasmo Intracraniano/etiologia , Adulto Jovem
10.
Neurol Sci ; 40(9): 1877-1885, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31069585

RESUMO

BACKGROUND: The immune response to acute ischemic stroke (AIS) is implicated in diagnosis, prognosis, and intervention; however, the temporal dynamics of leukocytes following AIS are poorly understood. The purpose of this study was to characterize peripheral leukocyte dynamics following AIS among individuals with poor and favorable outcomes. METHODS: A retrospective chart review was conducted among patients with a diagnosis of AIS who were treated at a comprehensive stroke center across a 3-year timeframe. Groups were defined according to stroke outcomes. Patients with poor outcomes were distinguished from those with favorable outcomes by discharge National Institute of Health Stroke Score, infarct size, and Modified Rankin Scale. Leukocyte counts were compared among controls and AIS outcome groups. RESULTS: The neutrophil-lymphocyte ratio (NLR) calculated at 48-72 h post-AIS was identified as the strongest predictor of outcome. NLR was significantly higher in the poor outcome group (8.68 ± 0.93) compared with both the favorable outcome (4.5 ± 0.51, p = 0.009) and control group (4.33 ± 0.66, p < 0.001). Patients with a 48-72 h NLR ≥ 4.58 were 5.58 times more likely to have a poor outcome than AIS patients with an NLR < 4.58. CONCLUSIONS: The results of this study improve the understanding of the immune response in AIS. Low neutrophil count relative to high lymphocyte count at 48-72 h post-AIS should be considered a predictor of a favorable stroke outcome. Conversely, high neutrophil count relative to low lymphocyte count at 48-72 h post-AIS should be considered a predictor of a poor stroke outcome.


Assuntos
Isquemia Encefálica/sangue , Linfócitos , Neutrófilos , Acidente Vascular Cerebral/sangue , Idoso , Idoso de 80 Anos ou mais , Infarto Encefálico/patologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Feminino , Humanos , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia
11.
Cells ; 8(5)2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31083342

RESUMO

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain-blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators.


Assuntos
Barreira Hematoencefálica/imunologia , Edema Encefálico/imunologia , Isquemia Encefálica/imunologia , Encefalite/imunologia , Mastócitos/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Humanos , Mastócitos/citologia , Camundongos , Ratos
12.
Cell Mol Neurobiol ; 39(6): 883-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140018

RESUMO

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood-brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/patologia , Trato Gastrointestinal/patologia , Neuroproteção , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/sangue , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Inflamação/imunologia , Inflamação/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/fisiopatologia , Resveratrol/farmacologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
13.
J Neuroinflammation ; 16(1): 112, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138227

RESUMO

BACKGROUND: Ischemic stroke provokes a neuroinflammatory response and simultaneously promotes release of epinephrine and norepinephrine by the sympathetic nervous system. This increased sympathetic outflow can act on ß2-adrenergic receptors expressed by immune cells such as brain-resident microglia and monocyte-derived macrophages (MDMs), but the effect on post-stroke neuroinflammation is unknown. Thus, we investigated how changes in ß2-adrenergic signaling after stroke onset influence the microglia/MDM stroke response, and the specific importance of microglia/MDM ß2-adrenergic receptors to post-stroke neuroinflammation. METHODS: To investigate the effects of ß2-adrenergic receptor manipulation on post-stroke neuroinflammation, we administered the ß2-adrenergic receptor agonist clenbuterol to mice 3 h after the onset of photothrombotic stroke. We immunostained to quantify microglia/MDM numbers and proliferation and to assess morphology and activation 3 days later. We assessed stroke outcomes by measuring infarct volume and functional motor recovery and analyzed gene expression levels of neuroinflammatory molecules. Finally, we evaluated changes in cytokine expression and microglia/MDM response in brains of mice with selective knockout of the ß2-adrenergic receptor from microglia and monocyte-lineage cells. RESULTS: We report that clenbuterol treatment after stroke onset causes enlarged microglia/MDMs and impairs their proliferation, resulting in reduced numbers of these cells in the peri-infarct cortex by 1.7-fold at 3 days after stroke. These changes in microglia/MDMs were associated with increased infarct volume in clenbuterol-treated animals. In mice that had the ß2-adrenergic receptor specifically knocked out of microglia/MDMs, there was no change in morphology or numbers of these cells after stroke. However, knockdown of ß2-adrenergic receptors in microglia and MDMs resulted in increased expression of TNFα and IL-10 in peri-infarct tissue, while stimulation of ß2-adrenergic receptors with clenbuterol had the opposite effect, suppressing TNFα and IL-10 expression. CONCLUSIONS: We identified ß2-adrenergic receptor signaling as an important regulator of the neuroimmune response after ischemic stroke. Increased ß2-adrenergic signaling after stroke onset generally suppressed the microglia/MDM response, reducing upregulation of both pro- and anti-inflammatory cytokines, and increasing stroke size. In contrast, diminished ß2-adrenergic signaling in microglia/MDMs augmented both pro- and anti-inflammatory cytokine expression after stroke. The ß2-adrenergic receptor may therefore present a therapeutic target for improving the post-stroke neuroinflammatory and repair process.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Isquemia Encefálica/imunologia , Mediadores da Inflamação/imunologia , Receptores Adrenérgicos beta 2/imunologia , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/imunologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores Adrenérgicos beta 2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
14.
PLoS One ; 14(5): e0215482, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048856

RESUMO

Although T cells play important roles in the pathophysiology of ischemic stroke, the dynamics of T cells remains unclear. In cancer, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) contribute to the maintenance of the tumor microenvironment by suppressing T cells. However, the presence of these cells has never been examined in ischemic brain. Therefore, we examined the temporal and spatial profiles of PMN-MDSCs, which are defined as the CD11b+Ly6ClowLy6G+ cells with higher expression levels of Nox2 and C/EBP Homologous Protein (CHOP) mRNA than normal neutrophil. Fluorescence-activated cell sorter (FACS) analysis showed that the count of CD11b+Ly6ClowLy6G+ cells was increased in the ischemic hemisphere and bone marrow at 72 hours, as well as in the spleen 24 hours after transient middle cerebral artery occlusion in mice. In contrast, the contralateral hemisphere, normal bone marrow, and normal spleen contained few CD11b+Ly6ClowLy6G+ cells. Real-time reverse transcription polymerase chain reaction revealed that CD11b+Ly6ClowLy6G+ cells sorted from brain and spleen 72 hours after ischemia had greater expression of Nox2 and CHOP mRNA than neutrophils in bone marrow, suggesting that these cells constitute PMN-MDSCs. Immunohistochemistry showed that CD11b+Ly6G+ cells were located in the ischemic core and border zone, indicating that PMN-MDSCs might be endemic to these regions. Although neutrophils are believed to invade infarct regions 48-72 hours after ischemia, the present study suggested that some of these cells are in fact PMN-MDSCs. Further studies on the function of PMN-MDSCs might unveil the unknown mechanisms of T cell activation and recruitment in ischemic stroke.


Assuntos
Isquemia Encefálica/patologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/metabolismo , Animais , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Isquemia Encefálica/imunologia , Isquemia Encefálica/veterinária , Antígeno CD11b/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Neutrófilos/citologia , Neutrófilos/imunologia , Baço/citologia , Baço/imunologia , Baço/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
15.
Front Med ; 13(4): 420-426, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30929189

RESUMO

This article presents a synopsis of the current data on the mechanisms of blood-brain barrier (BBB) alteration and autoimmune response in acute ischemic stroke. Most researchers confirm the relationship between the severity of immunobiochemical changes and clinical outcome of acute ischemic stroke. Ischemic stroke is accompanied by aseptic inflammation, which alters the brain tissue and exposes the co-stimulatory molecules of the immune system and the neuronal antigens. To date, BBB is not considered the border between the immune system and central nervous system, and the local immune subsystems are found within and behind the BBB. BBB disruption contributes to the leakage of brain autoantigens and induction of secondary autoimmune response to neuronal antigens and long-term inflammation. Glymphatic system function is altered and jeopardized both in hemorrhagic and ischemic stroke types. The receptors of innate immunity (toll-like receptor-2 and toll-like receptor-4) are also involved in acute ischemia-reperfusion injury. Immune response is related to the key processes of blood clotting and fibrinolysis. At the same time, the stroke-induced immune activation may promote reparation phenomena in the brain. Subsequent research on the reduction of the acute ischemic brain injury through the target regulation of the immune response is promising.


Assuntos
Autoimunidade , Barreira Hematoencefálica/imunologia , Isquemia Encefálica/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Autoantígenos/imunologia , Humanos , Imunidade Inata , Inflamação , Camundongos
16.
Neurology ; 92(20): e2375-e2384, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31004072

RESUMO

OBJECTIVE: We studied circulating interleukin (IL)-6, IL-8, and IL-10 concentrations and incident ischemic stroke risk in a biracial cohort, and determined if these cytokines mediated the racial disparity in stroke incidence affecting the black population. METHODS: The Reasons for Geographic and Racial Differences in Stroke study enrolled 30,237 black and white men and women age ≥45 in 2003-2007. We measured baseline IL-6, IL-8, and IL-10 in a case-cohort study of 557 participants with incident stroke over 5.4 years and 951 participants in a cohort sample. RESULTS: IL-6, but not IL-8 or IL-10, was higher in cases compared to the cohort sample (mean 4.5 vs 3.7 ng/mL; p < 0.001). Only IL-6 was associated with stroke risk factors. Adjusting for age, sex, and race, the hazard ratio (HR; 95% confidence interval) for incident stroke for the highest vs lowest quartile of IL-6 was 2.4 (1.6-3.4). HRs for the highest vs lowest quartiles of IL-8 and IL-10 were 1.5 (1.0-2.1) and 1.4 (1.0-1.9), respectively. After additional adjustment for stroke risk factors, only higher IL-6 remained associated with stroke risk (HR 2.0; 1.2-3.1). Associations did not differ by race. Mediation analyses showed that IL-6 mediated the black-white disparity in stroke risk, but mediation was via IL-6 associations with stroke risk factors. CONCLUSIONS: In this biracial population-based sample, IL-6 was strongly associated with risk of incident stroke and mediated the racial disparity in stroke via inflammatory effects of risk factors. Further study on the clinical utility of IL-6 measurement in stroke risk assessment would be helpful.


Assuntos
Isquemia Encefálica/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Acidente Vascular Cerebral/imunologia , Afro-Americanos/estatística & dados numéricos , Idoso , Isquemia Encefálica/etnologia , Estudos de Casos e Controles , Citocinas/imunologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Acidente Vascular Cerebral/etnologia
17.
J Vis Exp ; (145)2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30882779

RESUMO

In this study, a middle cerebral artery (MCA) occlusion mouse model is employed to study cerebral ischemia-reperfusion. A reproducible and reliable mouse model is useful for investigating the pathophysiology of cerebral ischemia-reperfusion and determining potential therapeutic strategies for patients with stroke. Variations in the anatomy of the circle of Willis of C57BL/6 mice affects their infarct volume after cerebral-ischemia-induced injury. Studies have indicated that distal MCA occlusion (MCAO) can overcome this problem and result in a stable infarct size. In this study, we establish a two-vessel occlusion mouse model of cerebral ischemia-reperfusion through the interruption of the blood flow to the right MCA. We distally ligate the right MCA and right common carotid artery (CCA) and restore blood flow after a certain period of ischemia. This ischemia-reperfusion injury induces an infarct of stable size and a behavioral deficit. Peripheral immune cells infiltrate the ischemic brain within the 24 h infiltration period. Additionally, the neuronal loss in the cortical area is less for a longer reperfusion duration. Therefore, this two-vessel occlusion model is suitable for investigating the immune response and neuronal recovery during the reperfusion period after cerebral ischemia.


Assuntos
Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/patologia , Traumatismo por Reperfusão/patologia , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora , Neurônios/patologia , Traumatismo por Reperfusão/fisiopatologia
18.
Proc Natl Acad Sci U S A ; 116(12): 5558-5563, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30819895

RESUMO

CD3+CD4-CD8- T cells (double-negative T cells; DNTs) have diverse functions in peripheral immune-related diseases by regulating immunological and inflammatory homeostasis. However, the functions of DNTs in the central nervous system remain unknown. Here, we found that the levels of DNTs were dramatically increased in both the brain and peripheral blood of stroke patients and in a mouse model in a time-dependent manner. The infiltrating DNTs enhanced cerebral immune and inflammatory responses and exacerbated ischemic brain injury by modulating the FasL/PTPN2/TNF-α signaling pathway. Blockade of this pathway limited DNT-mediated neuroinflammation and improved the outcomes of stroke. Our results identified a critical function of DNTs in the ischemic brain, suggesting that this unique population serves as an attractive target for the treatment of ischemic stroke.


Assuntos
Isquemia Encefálica/imunologia , Complexo CD3/imunologia , Acidente Vascular Cerebral/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso de 80 Anos ou mais , Animais , Encéfalo/imunologia , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Cell Mol Neurobiol ; 39(3): 451-460, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30778712

RESUMO

Various studies demonstrate that CD137 (TNFRSF9, 4-1BB) promotes atherosclerosis and vascular inflammation in experimental models via interactions with the CD137 ligand (CD137L). However, the exact role of CD137 in ischemic stroke remains unclear. In this study, we analyzed dynamic changes of peripheral CD137 expression on T cells in a mouse model of cerebral ischemia-middle cerebral artery occlusion (MCAO), as well as alternation of neurological function, infarct size and cerebral inflammatory status after inhibition of the CD137/CD137L pathway using an anti-CD137L monoclonal antibody. MCAO mice showed elevated surface expression of CD137 on T cells in both peripheral blood and lymphoid tissues during early cerebral ischemia. Remarkably, blockade of the CD137/CD137L pathway reduced the post-ischemic brain damage. Our findings indicate that enhanced CD137 costimulation occurs in early cerebral ischemia and promotes T cell activation, which in turn upregulates inflammatory immune response and possibly exerting deleterious effects on cerebral ischemia.


Assuntos
Ligante 4-1BB/metabolismo , Isquemia Encefálica/metabolismo , Ligante 4-1BB/sangue , Animais , Linfócitos B/metabolismo , Isquemia Encefálica/etiologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Membrana Celular/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/patologia , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
20.
J Immunol ; 202(6): 1704-1714, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30710045

RESUMO

Glycine is a simple nonessential amino acid known to have neuroprotective properties. Treatment with glycine results in reduced infarct volume of the brain, neurologic function scores, and neuronal and microglial death in ischemic stroke injury. Neuroinflammation has been considered a major contributor to cerebral ischemia-induced brain damage. However, the role of glycine in neuroinflammation following ischemic stroke is unclear. The present study aimed to determine whether neuroinflammation is involved in the neuroprotective effects of glycine in cerebral ischemia injury. Ischemic stroke promotes M1 microglial polarization. Interestingly, we found that the injection of glycine in rats after injury can inhibit ischemia-induced inflammation and promote M2 microglial polarization in vivo (Sprague-Dawley rats) and in vitro (cortical microglia and BV-2 cells). We show that glycine suppresses Hif-1α by inhibiting the upregulation of NF-κB p65 after ischemia-reperfusion injury, resulting in the inhibition of proinflammatory activity. The activation of AKT mediates the inhibition of NF-κB p65/Hif-1α signaling by glycine. Moreover, we confirm that glycine-regulated AKT activation is mediated by the inhibition of PTEN in a PTEN depletion cell line, U251 cells. Glycine modulates microglial polarization after ischemic stroke, which indirectly inhibits ischemia-induced neuronal death and functional recovery. Taken together, our findings provide a new understanding of glycine in neuroprotection by inhibiting M1 microglial polarization and promoting anti-inflammation by suppressing NF-κB p65/Hif-1α signaling.


Assuntos
Encéfalo/efeitos dos fármacos , Glicina/farmacologia , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/imunologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Isquemia Encefálica/imunologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Fator de Transcrição RelA/metabolismo
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