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Mast Cells Promote Blood Brain Barrier Breakdown and Neutrophil Infiltration in a Mouse Model of Focal Cerebral Ischemia
Abstract
Blood brain barrier (BBB) breakdown and neuroinflammation are key events in ischemic stroke morbidity and mortality. The present study investigated the effects of mast cell deficiency and stabilization on BBB breakdown and neutrophil infiltration in mice after transient middle cerebral artery occlusion (tMCAo). Adult male C57BL6/J wild type (WT) and mast cell-deficient (C57BL6/J Kit(Wsh/Wsh) (Wsh)) mice underwent tMCAo and BBB breakdown, brain edema and neutrophil infiltration were examined after 4 hours of reperfusion. Blood brain barrier breakdown, brain edema, and neutrophil infiltration were significantly reduced in Wsh versus WT mice (P<0.05). These results were reproduced pharmacologically using mast cell stabilizer, cromoglycate. Wild-type mice administered cromoglycate intraventricularly exhibited reduced BBB breakdown, brain edema, and neutrophil infiltration versus vehicle (P<0.05). There was no effect of cromoglycate versus vehicle in Wsh mice, validating specificity of cromoglycate on brain mast cells. Proteomic analysis in Wsh versus WT indicated that effects may be via expression of endoglin, endothelin-1, and matrix metalloproteinase-9. Using an in vivo model of mast cell deficiency, this is the first study showing that mast cells promote BBB breakdown in focal ischemia in mice, and opens up future opportunities for using mice to identify specific mechanisms of mast cell-related BBB injury.Journal of Cerebral Blood Flow & Metabolism advance online publication, 7 January 2015; doi:10.1038/jcbfm.2014.239.
... While receiving less attention than microglia, nonetheless mast cells within the brain represent an important source of immune signaling. Mast cells occur within the dura and meninges, and have demonstrated the ability to promote blood-brain barrier breakdown, edema, neutrophil infiltration, and hemorrhage in animal models of focal cerebral ischemia (175,176). Yet another factor, synthesized, stored, and released by mast cells, and implicated in retinal and brain barrier breakdown is the angiogenic, vascular endothelial growth factor (VEGF) (175,177) the treatment of which is discussed below. ...
... Mast cells occur within the dura and meninges, and have demonstrated the ability to promote blood-brain barrier breakdown, edema, neutrophil infiltration, and hemorrhage in animal models of focal cerebral ischemia (175,176). Yet another factor, synthesized, stored, and released by mast cells, and implicated in retinal and brain barrier breakdown is the angiogenic, vascular endothelial growth factor (VEGF) (175,177) the treatment of which is discussed below. ...
... Targeting activation of microglia (175,(273)(274)(275) and mast cells (175,276,277) has gained increasing traction as a potential therapeutic avenue for the treatment of neuralvascular degeneration due to inflammation induced small vessel disease. The interleukins are the prototypic inflammatory cytokines, which often operate in concert with other inflammatory enzymes such as TNF-a. ...
Diabetes mellitus (DM) is now recognized as a system-wide, autoimmune, inflammatory, microvascular disorder, which, in the retina and brain results in severe multifocal injury now recognized as a leading cause, world-wide, of progressive vision loss and dementia. To address this problem, resulting primarily from variations in glycemia in the prediabetic and overt diabetic states, it must be realized that, although some of the injury processes associated with diabetes may be system wide, there are varying responses, effector, and repair mechanisms that differ from organ to organ or within varying cell structures. Specifically, within the retina, and similarly within the brain cortex, lesions occur of the “neurovascular unit”, comprised of focal microvascular occlusions, inflammatory endothelial and pericyte injury, with small vessel leakage resulting in injury to astrocytes, Müller cells, and microglia, all of which occur with progressive neuronal apoptosis. Such lesions are now recognized to occur before the first microaneurysms are visible to imaging by fundus cameras or before they result in detectable symptoms or signs recognizable to the patient or clinician. Treatments, therefore, which currently are not initiated within the retina until edema develops or there is progression of vascular lesions that define the current staging of retinopathy, and in the brain only after severe signs of cognitive failure. Treatments, therefore are applied relatively late with some reduction in progressive cellular injury but with resultant minimal vision or cognitive improvement. This review article will summarize the multiple inflammatory and remediation processes currently understood to occur in patients with diabetes as well as pre-diabetes and summarize as well the current limitations of methods for assessing the structural and functional alterations within the retina and brain. The goal is to attempt to define future screening, monitoring, and treatment directions that hopefully will prevent progressive injury as well as enable improved repair and attendant function.
... Because mast cells contain granules with vasoactive molecules and proteases, they have been implicated in BBB disruption and in promoting neutrophil extravasation in the course of cerebral ischemia [24,94,95]. Using c-kit mutant mice that show mast cells deficiency, it was shown that depletion of mast cells resulted in decreased levels of neuroinflammation, brain edema, neutrophil infiltration, and infarct size following stroke [95,96]. Repopulating meningeal mast cells by transfer of in vitro generated bone marrow-derived mast cells reverted the protective phenotype in c-kit mutant mice, and this was partially dependent upon the ability of mast cells to produce IL-6 [95]. ...
... Repopulating meningeal mast cells by transfer of in vitro generated bone marrow-derived mast cells reverted the protective phenotype in c-kit mutant mice, and this was partially dependent upon the ability of mast cells to produce IL-6 [95]. Similarly, preventing mast cell degranulation by intracerebroventricular delivery of cromoglycate reduced brain edema and neutrophil infiltration both in ischemic and hemorrhagic stroke models [94,96,97]. ...
Recent evidence implicates cranial border immune compartments in the meninges, choroid plexus, circumventricular organs, and skull bone marrow in several neuroinflammatory and neoplastic diseases. Their pathogenic importance has also been described for cardiovascular diseases such as hypertension and stroke. In this review, we will examine the cellular composition of these cranial border immune niches, the potential pathways through which they might interact, and the evidence linking them to cardiovascular disease.
... Moreover, in a model of focal cerebral ischemia, treatment of WT mice with the MCs stabilizer cromolyn (blocking the release of MC's mediators) also produced a neuroprotective effect (McKittrick et al., 2015). In that study, MC-deficient Wsh mice showed decreased neutrophil infiltration, brain-blood barrier (BBB) breakdown, and brain edema after brain ischemia as compared to WT mice (McKittrick et al., 2015). ...
... Moreover, in a model of focal cerebral ischemia, treatment of WT mice with the MCs stabilizer cromolyn (blocking the release of MC's mediators) also produced a neuroprotective effect (McKittrick et al., 2015). In that study, MC-deficient Wsh mice showed decreased neutrophil infiltration, brain-blood barrier (BBB) breakdown, and brain edema after brain ischemia as compared to WT mice (McKittrick et al., 2015). It has also been reported that mice lacking MCs or in which MC are stabilized show less damage after LPS-induced neuroinflammation (Dong et al., 2019) and surgery-induced neuroinflammation (Zhang et al., 2020). ...
Huntington´s disease (HD) is a pathological condition that can be studied in mice by the administration of quinolinic acid (QUIN), an agonist of the N ‐methyl‐ d ‐aspartate receptor (NMDAR) that induces NMDAR‐mediated cytotoxicity and neuroinflammation. Mast cells (MCs) participate in numerous inflammatory processes through the release of important amounts of histamine (HA). In this study, we aimed to characterize the participation of MCs and HA in the establishment of neural and oxidative damage in the QUIN‐induced model of HD. C57BL6/J mice (WT), MC‐deficient c‐Kit W‐sh/W‐sh (Wsh) mice and Wsh mice reconstituted by intracerebroventricular (i.c.v.) injection of 5 × 10 ⁵ bone marrow‐derived mast cells (BMMCs), or i.c.v. administered with HA (5 µg) were used. All groups of animals were intrastriatally injected with 1 µL QUIN (30 nmol/µL) and 3 days later, apomorphine‐induced circling behavior, striatal GABA levels and the number of Fluoro‐Jade positive cells, as indicators of neuronal damage, were determined. Also, lipid peroxidation (LP) and reactive oxygen species production (ROS), as markers of oxidative damage, were analyzed. Wsh mice showed less QUIN‐induced neuronal and oxidative damage than WT and Wsh‐MC reconstituted animals. Histamine administration restored the QUIN‐induced neuronal and oxidative damage in the non‐reconstituted Wsh mice to levels equivalent or superior to those observed in WT mice. Our results demonstrate that MCs and HA participate in the neuronal and oxidative damages observed in mice subjected to the QUIN ‐induced model of Huntington's disease.
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... Brain mast cells are located perivascularly in proximity to neurons and microglia in the CNS and are the first responder to injury. Despite their small numbers, the activation of mast cells following an cerebral ischemic event had a dramatic effect on BBB breakdown [81], whereas a tibial fracture surgery may induce brain mast cell degranulation, microglial activation and neuroinflammation [82]. Based on these investigations, the brain mast cell stabilizers cromolyn (also disodium cromoglycate) was injected into rats undergoing open tibial fracture surgery, showing attenuation of surgery-induced cognitive impairments as well as astrocyte activation and microglia-astrocyte communication [83]. ...
Perioperative neurocognitive disorders (PND) is a common postoperative complication associated with regional or general anesthesia and surgery. Growing evidence in both patient and animal models of PND suggested that neuroinflammation plays a critical role in the development and progression of this problem, therefore, mounting efforts have been made to develop novel therapeutic approaches for PND by targeting specific factors or steps alongside the neuroinflammation. Multiple studies have shown that perioperative anti-neuroinflammatory strategies via administering pharmacologic agents or performing nonpharmacologic approaches exert benefits in the prevention and management of PND, although more clinical evidence is urgently needed to testify or confirm these results. Furthermore, long-term effects and outcomes with respect to cognitive functions and side effects are needed to be observed. In this review, we discuss recent preclinical and clinical studies published within a decade as potential preventive and therapeutic approaches targeting neuroinflammation for PND.
... In the case of a cerebrovascular accident (CVA), it is noticed that after the ischemic event, microglia, mast cells, and astrocytes are activated, which increase the permeability of the BBB, facilitating the recruitment of cytokines from the periphery to the brain [60,61]. Activated monocytes and macrophages produce cytokines, free radicals, metalloproteinases, nitric oxide, and many other factors that participate in the reaction through the hypoxemic stimulus [62]. The authors point out that in this context, at lower concentrations, VEGF plays its role in a moderate way by stimulating angiogenesis and preventing neuronal death while decreasing the cytotoxic effect of glutamate, thus increasing cell survival [63][64][65] in addition to effecting its antiinflammatory action and promoting neuroplasticity, further increasing the migration and proliferation of neuronal precursor cells. ...
VEGF is an important neurotrophic and vascular factor involved in mental disorders. The objective of this study was to verify the effect of genetic polymorphisms in the VEGF pathway on the risk for depression, symptom intensity, and suicide attempts. To examine the association between the VEGF pathway and depression, we genotyped polymorphisms and measured the plasma concentrations of VEGF, KDR, and FLT1 proteins. The participants were 160 patients with depression and 114 healthy controls. The questionnaires that assessed the clinical profile of the patients were the MINI-International Neuropsychiatric Interview, GRID-HAMD21, CTQ, BSI, and the number of suicide attempts. Genotyping of participants was performed using the real-time PCR and protein measurements were performed using the enzyme-linked immunosorbent assay (ELISA). VEGF and its inhibitors were reduced in depression. Individuals with depression and displaying the homozygous AA of the rs699947 polymorphism had higher plasma concentrations of VEGF (p-value = 0.006) and were associated with a greater number of suicide attempts (p-value = 0.041). Individuals with depression that were homozygous for the G allele of the FLT1 polymorphism rs7993418 were associated with lower symptom severity (p-value = 0.040). Our results suggest that VEGF pathway polymorphisms are associated with the number of suicide attempts and the severity of depressive symptoms.
... Brain ischemia leads to an immediate local inflammatory reaction with activation of microglia, astrocytes, and endothelial cells, as well as the further release of pro-inflammatory cytokines (2). These nonspecific alterations post-ischemia could result in blood-brain barrier dysfunction and infiltration of peripheral inflammatory cells and cytokines into the brain, which may further increase tissue injury (3). ...
Background
Blood-based prognostic biomarkers of acute ischemic stroke (AIS) are limiting. Calprotectin is suggested to be involved in directing post-stroke inflammatory conditions. However, the pathological alteration of circulating calprotectin in AIS is yet to be thoroughly elucidated. Therefore, this study aimed to investigate the levels and clinical relevance of calprotectin in AIS.
Methods
This study recruited 271 patients with AIS within 24 h since symptom onset and 145 non-stroke healthy controls (HC) from February 1, 2018, to Dec 31, 2020. Patients were followed up for 2 weeks for observation of functional outcomes, as determined by the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Plasma calprotectin concentrations were determined by ELISA.
Results
Plasma calprotectin concentrations were significantly higher in patients with AIS compared with controls [patients vs. control: median (IQR) 54.2 (39.01–99.04) vs. 50.04 (35.42–61.22), p < 0.001]. Besides, patients with poor prognosis, as defined by mRS ≥ 3, had significantly higher calprotectin levels than patients with good prognosis [poor prognosis patients vs. good prognosis patients: median (IQR) 61.99 (47.52–108) vs. 43.36 (33.39–60.2), p < 0.001]. Plasma calprotectin levels were positively associated with the disease severity of AIS, as reflected by infarction volume and NIHSS score at baseline. Furthermore, baseline calprotectin was found to be independently associated with poor prognosis [odds ratio (OR): 1.02, 95% CI: 1.01–1.03] and disease progression (OR: 1.03, 95% CI: 1.02–1.04) of AIS during a 2-week follow-up, with adjustment of possible confounding factors.
Conclusion
Plasma calprotectin is associated with short-term functional outcomes of AIS.
... Histamine by its virtue increases edema formation in general, together with circulating platelet aggregating factor (PAF) from neutrophils and monocytes, upon enhancing nitric oxide (NO) production, and by VE-cadherin rearrangement in endothelia [88] . In the mouse model of focal cerebral ischemia, lack of MCs in C57BL6/J mice, similarly to intraventricular MC stabilization using cromoglycate, significantly decreased edema formation upon transient -45 minute-middle cerebral artery occlusion [89] . The study demonstrates the contribution of mast cells to increased BBB permeability, vasogenic edema, and ischemia-reperfusion injury to disease pathology. ...
During the past decades, populous expansion in mast cell scientific literature came forth with more, than forty-four thousand PubMed publications available to date. Such surge is due to the appreciation of the momentous role of mast cells in the evolution of species, in the development and maintenance of vital physiological functions, such as reproduction, homeostasis, and fluids, diverse immunological roles, and the potential of far-reaching effects despite minute numbers. While the emerging knowledge of the importance of mast cells in equilibrium comes of age when looking at the matter from an evolutionary perspective, the recognition of mast cells beyond detrimental performance in allergies and asthma, during protection against parasites, falters. Beyond well known classical functions, mast cells can process and present antigens,can serve as a viral reservoir, can respond to hormones and xenobiotics,initiate antiviral and antibacterial responses, phagocytosis, apoptosis, and participate in important developmental cornerstones. During evolution,upon the development of a sophisticated niche of innate and adaptive cell populations, certain mast cell functions became partially transmutable,yet the potency of mast cells remained considerable. Reviewing mast cells enables us to reflect on the certitude, that our sophisticated, complex physiology is rooted deeply in evolution, which we carry ancient remnants of, ones that may have decisive roles in our functioning. This communication sets out the goal of characterizing mast cells, particularly the aspects less in limelight yet of immense significance, without the aspiration exhaust it all.
Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell’s role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.
Depression is a common and recurrent mental illness with a complicated etiology, but the specific pathogenesis is not clear. Breast cancer increases susceptibility to depression, which leads to a poor prognosis. Rapid advances in the understanding of tumor immunology and neuroimmunology have provided new evidence for the pathogenesis of depression. Dysfunction of immune cells and cytokines cause depression by affecting tryptophan metabolism, serotonin levels, and blood–brain barrier permeability. Dysregulation of cytokines or intestinal flora may be shared between patients with depression and breast cancer. This review presents an overview of immune dysregulation in breast cancer patients with depression and proposes future alternative research directions and interventions.
Neuroinflammation mediated by activation of microglia and interruption of the blood-brain barrier (BBB) is an important factor that contributes to neuron death and infarct area diffusion in ischemia reperfusion injury. Finding novel molecules to regulate neuroinflammation is of significant clinical value. We have previously shown that adjudin, a small molecule compound known to possess antispermatogenic function, attenuates microglia activation by suppression of the NF-kappaB pathway. In this study we continued to explore whether adjudin could be neuroprotective by using the transient middle cerebral artery occlusion (tMCAO) model. Adjudin treatment after reperfusion significantly decreased the infarction volume and neuroscore compared to the vehicle group. Staining of CD11b showed that adjudin markedly inhibited microglial activation in both the cortex and the striatum, accompanied by a reduction in the expression and release of cytokines TNF-alpha, IL-1beta and IL-6. Concomitantly, adjudin noticeably prevented BBB disruption after ischemia and reperfusion, as indicated by the reduction of IgG detection in the brain cortex and striatum versus the vehicle group. This finding was also corroborated by immunofluorescence staining and immunoblotting of tight junction-related proteins ZO-1, JAM-A and Occludin, where the reduction of these proteins could be attenuated by adjudin treatment. Moreover, adjudin obviously inhibited the elevated MMP-9 activity after stroke. Together these data demonstrate that adjudin protects against cerebral ischemia reperfusion injury, and we present an effective neuroinflammation modulator with clinical potential.
To develop a simple, relatively noninvasive small-animal model of reversible regional cerebral ischemia, we tested various methods of inducing infarction in the territory of the right middle cerebral artery (MCA) by extracranial vascular occlusion in rats. In preliminary studies, 60 rats were anesthetized with ketamine and different combinations of vessels were occluded; blood pressure and arterial blood gases were monitored. Neurologic deficit, mortality rate, gross pathology, and in some instances, electroencephalogram and histochemical staining results were evaluated in all surviving rats. The principal procedure consisted of introducing a 4-0 nylon intraluminal suture into the cervical internal carotid artery (ICA) and advancing it intracranially to block blood flow into the MCA; collateral blood flow was reduced by interrupting all branches of the external carotid artery (ECA) and all extracranial branches of the ICA. In some groups of rats, bilateral vertebral or contralateral carotid artery occlusion was also performed. India ink perfusion studies in 20 rats documented blockage of MCA blood flow in 14 rats subjected to permanent occlusion and the restoration of blood flow to the MCA territory in six rats after withdrawal of the suture from the ICA. The best method of MCA occlusion was then selected for further confirmatory studies, including histologic examination, in five additional groups of rats anesthetized with halothane. Seven of eight rats that underwent permanent occlusion of the MCA had resolving moderately severe neurologic deficits (Grade 2 of 4) and unilateral infarcts averaging 37.6 +/- 5.5% of the coronal sectional area at 72 hours after the onset of occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Background:
Epidemiological studies have shown a strong association between systemic inflammatory diseases, particularly allergic diseases, and cardiovascular diseases. However, the relationship between atopic dermatitis (AD) and ischemic stroke remains unclear.
Method:
The study identified 20,323 AD patients and 20,323 comorbidity-matched subjects between 2005 and 2008. The two cohorts were followed until 31 December 2009. Ischemic stroke and other cardiovascular events were determined.
Results:
During the follow-up period, 301 (1.48%) patients in the AD cohort and 228 (1.12%) matched subjects experienced ischemic stroke. After multivariate adjustment, patients with AD had a 1.33-fold (95% confidence interval (CI), 1.12-1.59; P = 0.001) increased incidence of ischemic stroke. Adjusted hazard ratios for the risk of ischemic stroke in patients with mild, moderate, and severe AD were 1.20 (95% CI, 1.00-1.45; P = 0.052), 1.64 (95% CI, 1.23-2.19; P = 0.001), and 1.71 (95% CI, 1.15-2.56; P = 0.008), respectively. The log-rank test showed a higher cumulative incidence of ischemic stroke in the severe AD group than in the moderate and mild AD groups during the follow-up period (P < 0.001).
Conclusions:
AD may be an independent risk factor for ischemic stroke, and risk of ischemic stroke increases with AD severity.
We review recent advances in the treatment and prevention of acute ischemic stroke, including the current state of endovascular therapy in light of five randomized controlled trials published this past year. Although no benefit of endovascular therapy over IV t-PA has been demonstrated, endovascular therapy is an appropriate treatment for acute ischemic stroke patients within the t-PA window who are ineligible for IV t-PA but have a large vascular occlusion. These trials reveal promises and current limitations of endovascular therapy, and comparison of reperfusion therapies remains an important area of research. One common theme is the strong association between a faster time to reperfusion, improved outcome, and reduced mortality. Primary and secondary stroke prevention trials emphasize the importance of aggressive management of medical risk factors as part of any preventative strategy. New oral anticoagulants, for example, offer cost-effective risk reduction in patients with atrial fibrillation, and may represent an opportunity for those with cryptogenic stroke. We highlight areas of unmet need and promising research in stroke, including the need to deliver proven therapies to more patients, and the need to recruit patients into clinical trials that better define the role of endovascular and other stroke therapies. Finally, improvement in strategies to recover speech, cognition, and motor function has the potential to benefit far more stroke patients than any acute stroke therapy, and represents the greatest opportunity for research in the coming century. ANN NEUROL 2013. © 2013 American Neurological Association.
Mast cells (MCs) are an important part of the innate immune system and are abundant in barrier organs such as the skin. They are known primarily for initiating allergic reactions, but many other biological functions have now been described for these cells. Studies have indicated that during wound repair, MCs enhance acute inflammation, stimulate reepithelialization and angiogenesis and promote scarring. MCs have also been linked to abnormal healing, with high numbers of MCs observed in chronic wounds, hypertrophic scars and keloids. Although MCs have gained attention in the wound healing field, several unique features of MCs have yet to be examined in the context of cutaneous repair. These include the ability of MCs to: (i) produce anti-inflammatory mediators; (ii) release mediators without degranulating; and (iii) change their phenotype. Recent findings highlight the complexity of MCs and suggest that more information is needed to understand their complete range of activities during repair.
This study investigated whether anti-CD40 Ab and 8-oxo-dG attenuate mast cell migration and EAE development. Anti-CD40 Ab and 8-oxo-dG reduced EAE scores, mast cell numbers, expression of adhesion molecules, OX40L and Act1, levels of TNF-α, LTs, expression of cytokines, and co-localization of Treg cells and mast cells, all of which are increased in EAE-brain tissues. Each treatment enhanced Treg cells, expression of OX40, and cytokines related to suppressive function of Treg cells in EAE brain tissues. Act-BMMCs with Treg cells reduced expression of OX40L and CCL2/CCR2, VCAM-1, PECAM-1, [Ca(2+)]i levels, release of mediators, various signaling molecules, Act1 related to IL-17a signals versus those in act-BMMCs without Treg cells. The data suggest that IL-10- and IL-35-producing Foxp3(+)-Treg cells, enhanced by anti-CD40 Ab or 8-oxo-dG, suppress migration of mast cells through down-regulating the expression of adhesion molecules, and suppress mast cell activation through cell-to-cell cross-talk via OX40/OX40L in EAE development.
Several clinical trials and experimental studies that could have a major impact on the treatment of patients with ischaemic stroke were published in 2012. The studies cover all therapeutic options, including stroke prevention, recanalization and thrombolysis, neuroprotection, and promising new therapeutic approaches focused on neurorepair.
Mast cells (MCs) are found abundantly in the brain and the meninges and play a complex role in neuroinflammatory diseases, such as stroke and multiple sclerosis. Here, we show that MC-deficient Kit(W)/Kit(W-v) mice display increased neurodegeneration in the lesion area after brain trauma. Furthermore, MC-deficient mice display significantly more brain inflammation, namely an increased presence of macrophages/microglia, as well as dramatically increased T-cell infiltration at days 4 and 14 after injury, combined with increased astrogliosis at day 14 following injury. The number of proliferating Ki67(+) macrophages/microglia and astrocytes around the lesion area is more than doubled in these MC-deficient mice. In parallel, MC-deficient Kit(W-sh/W-sh) mice display increased presence of macrophages/microglia at day 4, and persistent astrogliosis at day 4 and 14 after brain trauma. Further analysis of mice deficient in one of the most relevant MC proteases, i.e., mouse mast cell protease 4 (mMCP-4), revealed that astrogliosis and T-cell infiltration are significantly increased in mMCP-4-knockout mice. Finally, treatment with an inhibitor of mMCP-4 significantly increased macrophage/microglia numbers and astrogliosis. These data suggest that MCs exert protective functions after trauma, at least in part via mMCP-4, by suppressing exacerbated inflammation via their proteases.-Hendrix, S., Kramer, P., Pehl, D., Warnke, K., Boato, F., Nelissen, S., Lemmens, E., Pejler, G., Metz, M., Siebenhaar, F., Maurer, M. Mast cells protect from post-traumatic brain inflammation by the mast cell-specific chymase mouse mast cell protease-4.
THE purpose of our study was to determine whether inhibiting the action of tumor necrosis factor-α (TNFα) attenuates brain injury and reduces inflammatory responses in the mouse during ischemia and reperfusion. Mice underwent middle cerebral artery occlusion (MCAO) for 1 h followed by 23 h reperfusion. Monoclonal neutralizing anti-murine TNFα antibody (mAb) was administrated intraventricularly in the mouse with temporary MCAO. Infarct volume in the anti-TNFα mAb treated mice was significantly smaller than that in the control group (p < 0.05). The number of intercellular adhesion molecule-1 (ICAM-1)-positive vessels in the ischemic area of the anti-TNFα mAb-treated group was significantly less than that in the control group. Our study demonstrated that blocking TNFα reduced brain injury and attenuated ICAM-1 expression during transient cerebral ischemia.
Throughout the history of research on stroke pathophysiology, focus has shifted from purely vascular concepts to the insight that a complex interplay of biochemical and molecular mechanisms involving practically any cell type of the brain ("neurovascular unit") partakes in either salvage or demise of the tissue after a stroke. In addition, it was realized that peripheral immune cells play important roles, not only after their invasion into the brain but also because of stroke-induced effects on the immune system that can result in infections. Indeed, outcome of stroke patients is not only dictated by nonmodifiable factors, such as severity of stroke, age, or premorbidity, but also by modifiable factors largely related to medical complications, such as infections and possibly sarcopenia. The highly successful concept of stroke units attests to the benefits of treating stroke comprehensively. Breakthroughs in improving outcome after stroke will only result from approaches that target not only the brain, but also systemic effects of stroke.