Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic–Ischemic Brain Injury

Ten, Vadim S.; Yao, Jun; Ratner, Veniamin; Sosunov, Sergey A.; Fraser, Deborah A.; Botto, Marina; Sivasankar, Baalasubramanian; Morgan, B. Paul; Silverstein, Samuel C.; Stark, Raymond I.; Polin, Richard A.; Vannucci, Susan J.; Pinsky, David J.; Starkov, Anatoly A.

doi:10.1523/jneurosci.5249-09.2010

Cited by 82 publications

(88 citation statements)

References 61 publications

(66 reference statements)

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“…Controlling for complement activation is essential because previous studies have shown that manipulation of the complement cascade can strongly alter stroke outcome in different animal species. 35,36 …”

Section: Regulatory T Cells Promote Stroke 687mentioning

confidence: 99%

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Kleinschnitz

Kraft

Dreykluft

et al. 2013

Blood

304

293

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Key Points• Regulatory T cells are promoters of ischemic stroke by inducing dysfunction of the cerebral microvasculature. We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic antiinflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in IntroductionIschemic stroke induces a profound local inflammatory response involving various types of immune cells that transmigrate across the activated blood-brain barrier to invade the brain in a timed fashion. 1 Although previous research mainly focused on the role of innate immune cells, 2 recent evidence suggests that T cells, which belong to the adaptive immune system, also contribute critically to stroke development, especially in the early phase. 3 T cells have been identified in the postischemic brain as soon as 24 hours after reperfusion, 4 and Abs directed against vascular adhesion receptors expressed on the brain endothelium or leukocyte very late antigen-4 (VLA-4) expressed on lymphocytes inhibited T-cell transmigration and reduced tissue damage in models of stroke. 5 We and others showed recently that recombination activating gene (Rag1)-deficient mice, which lack functional T cells, are largely resistant against ischemic neurodegeneration. 6-8 T cellmediated brain damage became manifest by 24 hours after transient middle cerebral artery occlusion (tMCAO) and did not depend on antigen recognition or costimulation. 8 This clearly argues against TCR-driven mechanisms of tissue damage and suggests instead that T cells act detrimentally in ischemic stroke through antigenindependent pathways, at least during the early phase. Moreover, Rag1 Ϫ/Ϫ mice did not display a gross defect in thrombus formation after artificial vessel wall injury, which could easily explain the stroke protective phenotype in these animals. 8 Although the deleterious effects of T cells in stroke pathophysiology are well accepted, the functional relevance of the different T-cell subsets for stroke progression is less clear, as is their pathologic contribution at the different stages of cerebral ischemia (ie, acute versus chronic). Using adoptive cell transfer in Rag1 Ϫ/Ϫ mice, we could demonstrate that natural killer T cells (NKT cells) Submitted April 26, 2012; accepted October 27, 2012.Prepublished online as Blood First Edition paper, November 15, 2012; DOI 10.1182/blood-2012-04-426734. *C.K. and P.K. ...

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Section: Regulatory T Cells Promote Stroke 687mentioning

confidence: 99%

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Kleinschnitz

Kraft

Dreykluft

et al. 2013

Blood

304

293

View full text Add to dashboard Cite

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“…C1q knockout mice show neuroprotection coupled with attenuated oxidative brain injury, and resistance to oxygen-glucose deprivation. In contrast, post-ischemic exposure to exogenous C1q increases both mitochondrial ROS production and neuronal injury [117]. C1q receptor overexpression in cells results in caspase-3 activation, mitochondrial dysfunction, and apoptosis [118].…”

Section: Cr1mentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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“…Mitochondrial membrane potential was assayed in terms of the mitochondrial uptake of the potential-sensitive dye safranin O, as previously described (68,69). Briefly, isolated mitochondria were suspended in respiration buffer containing safranin O (1 μM).…”

Section: Mitochondrial Assaysmentioning

confidence: 99%

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

et al. 2011

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Shedding of the extracellular domain of cytokine receptors allows the diffusion of soluble receptors into the extracellular space; these then bind and neutralize their cytokine ligands, thus dampening inflammatory responses. The molecular mechanisms that control this process, and the extent to which shedding regulates cytokine-induced microvascular inflammation, are not well defined. Here, we used real-time confocal microscopy of mouse lung microvascular endothelium to demonstrate that mitochondria are key regulators of this process. The proinflammatory cytokine soluble TNF-α (sTNF-α) increased mitochondrial Ca 2+ , and the purinergic receptor P 2 Y 2 prolonged the response. Concomitantly, the proinflammatory receptor TNF-α receptor-1 (TNFR1) was shed from the endothelial surface. Inhibiting the mitochondrial Ca 2+ increase blocked the shedding and augmented inflammation, as denoted by increases in endothelial expression of the leukocyte adhesion receptor E-selectin and in microvascular leukocyte recruitment. The shedding was also blocked in microvessels after knockdown of a complex III component and after mitochondria-targeted catalase overexpression. Endothelial deletion of the TNF-α converting enzyme (TACE) prevented the TNF-α receptor shedding response, which suggests that exposure of microvascular endothelium to sTNF-α induced a Ca 2+ -dependent increase of mitochondrial H 2 O 2 that caused TNFR1 shedding through TACE activation. These findings provide what we believe to be the first evidence that endothelial mitochondria regulate TNFR1 shedding and thereby determine the severity of sTNF-α-induced microvascular inflammation.

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Complement Component C1q Mediates Mitochondria-Driven Oxidative Stress in Neonatal Hypoxic–Ischemic Brain Injury

Cited by 82 publications

References 61 publications

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Slow Excitotoxicity in Alzheimer's Disease

Activation of TNFR1 ectodomain shedding by mitochondrial Ca2+ determines the severity of inflammation in mouse lung microvessels

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