Gene expression profiling in stroke: relevance of blood–brain interaction

Asano, Shinichi; Chantler, Paul D.; Barr, Taura L.

doi:10.1016/j.coph.2015.10.004

Cited by 26 publications

(21 citation statements)

References 63 publications

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“…This was accompanied by a greater influx of peripheral leukocytes, particularly neutrophils ( Figure 4D), which are the strongest producers of reactive oxygen species (ROS) and matrix metallopeptidases (MMPs) and promote neuronal injury and BBB disruption [124][125][126] . In agreement, an increased number of neutrophils with altered phenotypic responses was previously seen in aged male mice and human stroke patients compared to their younger counterparts 127 and an increased neutrophil to lymphocyte ratio has been associated with stroke severity and outcome 128 . Although the absence of neuroprotective signal in bulk tissue does not rule out the possibility of its presence in individual cell types, these results suggest that an increased neuroinflammation and infiltration of circulating immune cells are one of the primary drivers for the exacerbated pathology in aged mice.…”

Section: Discussionsupporting

confidence: 85%

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

Androvic

Kirdajová

Tureckova

et al. 2019

Preprint

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Section: Discussionsupporting

confidence: 85%

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

Androvic

Kirdajová

Tureckova

et al. 2019

Preprint

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“…These chemokines have important roles in WNV-induced neuroinflammation (7,35,36) and are prominently produced by activated microglia (31)(32)(33)(34); the genes were significantly downregulated after minocycline administration during WNV infection. Some proinflammatory genes do not change significantly with minocycline treatment (CXCL10 and IFN-␣), which is likely due to nonmicroglial production; notably, WNV-infected neurons are able to produce CXCL10 (66), and neurons and astrocytes have the ability to produce significant amounts of proinflammatory cytokines/chemokines during viral infections (67)(68)(69)(70).…”

Section: Discussionmentioning

confidence: 99%

Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

Quick

Seitz

Clarke

et al. 2017

J Virol

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West Nile virus (WNV) is a neurotropic flavivirus that can cause significant neurological disease. Mouse models of WNV infection demonstrate that a proinflammatory environment is induced within the central nervous system (CNS) after WNV infection, leading to entry of activated peripheral immune cells. We utilized spinal cord slice cultures (SCSC) to demonstrate that anti-inflammatory mechanisms may also play a role in WNV-induced pathology and/or recovery. Microglia are a type of macrophage that function as resident CNS immune cells. Similar to mouse models, infection of SCSC with WNV induces the upregulation of proinflammatory genes and proteins that are associated with microglial activation, including the microglial activation marker Iba1 and CC motif chemokines CCL2, CCL3, and CCL5. This suggests that microglia assume a proinflammatory phenotype in response to WNV infection similar to the proinflammatory (M1) activation that can be displayed by other macrophages. We now show that the WNV-induced expression of these and other proinflammatory genes was significantly decreased in the presence of minocycline, which has antineuroinflammatory properties, including the ability to inhibit proinflammatory microglial responses. Minocycline also caused a significant increase in the expression of anti-inflammatory genes associated with alternative anti-inflammatory (M2) macrophage activation, including interleukin 4 (IL-4), IL-13, and FIZZ1. Minocycline-dependent alterations to M1/M2 gene expression were associated with a significant increase in survival of neurons, microglia, and astrocytes in WNV-infected slices and markedly decreased levels of inducible nitric oxide synthase (iNOS). These results demonstrate that an anti-inflammatory environment induced by minocycline reduces viral cytotoxicity during WNV infection in CNS tissue. West Nile virus (WNV) causes substantial morbidity and mortality, with no specific therapeutic treatments available. Antiviral inflammatory responses are a crucial component of WNV pathology, and understanding how they are regulated is important for tailoring effective treatments. Proinflammatory responses during WNV infection have been extensively studied, but anti-inflammatory responses (and their potential protective and reparative capabilities) following WNV infection have not been investigated. Minocycline induced the expression of genes associated with the anti-inflammatory (M2) activation of CNS macrophages (microglia) in WNV-infected SCSC while inhibiting the expression of genes associated with proinflammatory (M1) macrophage activation and was protective for multiple CNS cell types, indicating its potential use as a therapeutic reagent. This culture system can uniquely address the ability of CNS parenchymal cells (neurons, astrocytes, and microglia) to respond to minocycline and to modulate the inflammatory environment and cytotoxicity in response to WNV infection without peripheral immune cell involvement.

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“…LPS is well known to induce the macrophage M1 phenotype that is characterized by increases in iNOS and decreases in Arg-1 [50] . Preclinical evidence suggests that increased expression of Arg-1 in microglia following ischemic stroke is associated with improved tissue remodeling as well as behavioral recovery [48] . Additionally, evidence has demonstrated the significant increase in the expression of the M1 microglial marker iNOS in a model of epilepsy induced by kainate in mice that causes severe damage to brain tissue [51] .…”

mentioning

confidence: 99%

“…There are 2 arginase isoforms that are encoded by separate genes with different intracellular localization: Arg-1 is a cytosolic enzyme, while Arg-2 (arginase-2) is mainly expressed in mitochondria [49] . In the CNS, Arg-1 has been recognized as a marker of the M2 macrophage phenotypic shift that is associated with neuroprotection [48] . Given that L -arginine is also an indispensable substrate for NOS in NO formation, arginase has been recently recognized as a critical regulator of NO production by competing with NOS for L -arginine.…”

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confidence: 99%

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Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

Coelho

Viau²,

Staub³

et al. 2017

Neuroimmunomodulation

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Objective: The present study evaluated the ability of rosmarinic acid (RA) to inhibit microglia activation induced by lipopolysaccharide (LPS) in the N9 murine microglial cell line, and investigated the putative mechanisms involved in this process. Methods: In all tests, N9 murine microglial cells were pretreated with RA (0.1, 1.0, and 10 μM) for 20 h and exposed to LPS (1 μM/mL) for 4 h. Cell viability was measured by Trypan blue exclusion assay. Flow cytometry was used to detect reactive oxygen species (ROS), quantify cleaved caspase-3, and analyze the mitochondrial electrochemical potential. iNOS, Arg-1, TNF-α, IL-1β, and IL-6 proteins were analyzed by Western blotting, and their antigens were detected using the chemiluminescence technique. The effect of RA on DNA was evaluated by the Comet assay. Results: RA attenuated the expression of the M1 marker iNOS and the levels of proinflammatory factors, including TNF-α, IL-1β, and IL-6; it increased the expression of the M2 marker Arg-1, and inhibited, at least in part, ROS generation and loss of mitochondrial outer membrane permeabilization through the inhibition of cleaved caspase-3 activation. RA also inhibited DNA damage, reassuring cell protection. Conclusions: The results suggested a protective effect of RA through downregulation of inflammatory cytokines and cleaved caspase-3.

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Gene expression profiling in stroke: relevance of blood–brain interaction

Cited by 26 publications

References 63 publications

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

Minocycline Has Anti-inflammatory Effects and Reduces Cytotoxicity in an Ex Vivo Spinal Cord Slice Culture Model of West Nile Virus Infection

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

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