NF‐κB and innate immunity in ischemic stroke

Harari, Olivier; Liao, James K.

doi:10.1111/j.1749-6632.2010.05735.x

Cited by 270 publications

(214 citation statements)

References 51 publications

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“…NF-κB is a master regulator of inflammation and immune responses [21]. It is potently activated in brain tissues from stroke patients and ischemic insulted animals [22]. The activation of NF-κB induces a Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The pro-survival effect of NF-κB in neurons is mediated through the upregulation of several antiapoptotic proteins, including superoxide dismutase [25], Bcl-2, and Bcl-xL [26]. Studies have shown that the spatial and temporal control of NF-κB activation may determine whether it promotes neuronal death or survival [22]; however, the precise mechanisms underlying its effect in ischemic injury remains to be fully defined [24,[27][28][29]. Using neurons obtained from p65 +/− knockout mice, we showed the knockdown of NF-κB p65 moderately exacerbated OGD/R-induced neuronal cell death.…”

Section: Discussionmentioning

confidence: 99%

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Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

Das

Roy

et al. 2018

Mol Neurobiol

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Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has long been implicated in neuronal injury caused by acute ischemia/ reperfusion (I/R). However, its precise role and regulatory mechanisms remain obscure. Here, we investigated the role of the CaMKII family in neuronal survival during I/R. Our data indicated that CAMK2D/CaMKIIδ and CAMK2G/CaMKIIγ were selectively upregulated in a time-dependent manner at both transcriptional and protein levels after acute ischemia. Overexpression of CaMKIIδ promoted neuronal survival, while their depletion exacerbated ischemic neuronal death. Similar to CaMKIIδ, knockdown of CAMKIIγ resulted in significant neuronal death after I/R. We further identified CaMKIIδ 2 as the subtype that is selectively induced by I/R in primary neurons. The induction of CaMKIIδ was controlled in part by a pair of long non-coding RNAs (lncRNAs), C2dat1 and C2dat2. C2dat2, similar to C2dat1, was upregulated by I/R and cooperated with C2dat1 to modulate CaMKIIδ expression. Knockdown of C2dat1/2 blocked OGD/R-induced CaMKIIδ expression and decreased neuronal survival but did not affect the levels of CaMKIIγ, indicating specific targeting of CAMK2D by C2dat1/2. Mechanistically, I/R-induced CaMKIIδ and CaMKIIγ caused the upregulation of IKKα/β and further activation of the NF-κB signaling pathway to protect neurons from ischemic damage. Genetically, downregulating p65 subunit of NF-κB in mice increased I/R-induced neuronal death by blocking the activity of CaMKII/IKK/IκBα/NF-κB signaling axis. In summary, CaMKIIδ and CaMKIIγ are novel I/R-induced genes that promote neuronal survival during ischemic injury. The upregulation of these CaMKII kinases led to activation of the NF-κB signaling pathway, which protects neurons from ischemic damage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

Das

Roy

et al. 2018

Mol Neurobiol

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“…The DAMPs act on TLR4 of microglia to activate the MyD88/NF-kB signaling pathway, which produces inflammatory factors that contribute to inflammatory injury and aggravate neurologic impairments (7). Thus, inhibition of TLR4 signaling strongly protects against cerebral ischemia (7,15).…”

Section: Discussionmentioning

confidence: 99%

“…Patten-associated molecular patterns and damage-associated molecular patterns (DAMPs) activate TLRs and induce the expression of NF-kB-dependent proinflammatory cytokines and/or type I IFN, and these molecules participate in pathophysiological processes (5). DAMPs released from ischemic neurons can activate the TLR4/MyD88/NF-kB signaling pathway in the neighboring microglia and induce the release of proinflammatory cytokines, which gives rise to the degeneration and apoptosis of neurons (6)(7)(8). Recent studies have shown that modification of the TLR-mediated NF-kB signaling pathway significantly attenuates ischemic injuries to the organs.…”

mentioning

confidence: 99%

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

Wang

Huang

Chen

et al. 2014

The Journal of Immunology

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Recent reports have shown that preconditioning with the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) protects against cerebral ischemia/reperfusion (I/R) injury. However, it is unclear whether poly(I:C) treatment after cerebral I/R injury is also effective. We used mouse/rat middle cerebral artery occlusion and cell oxygen-glucose deprivation models to evaluate the therapeutic effects and mechanisms of poly(I:C) treatment. Poly(I:C) was i.p. injected 3 h after ischemia (treatment group). Cerebral infarct volumes and brain edemas were significantly reduced, and neurologic scores were significantly increased. TNF-α and IL-1β levels were markedly decreased, whereas IFN-β levels were greatly increased, in the ischemic brain tissues, cerebral spinal fluid, and serum. Injuries to hippocampal neurons and mitochondria were greatly reduced. The numbers of TUNEL-positive and Fluoro-Jade B+ cells also decreased significantly in the ischemic brain tissues. Poly(I:C) treatment increased the levels of Hsp27, Hsp70, and Bcl2 and decreased the level of Bax in the ischemic brain tissues. Moreover, poly(I:C) treatment attenuated the levels of TNF-α and IL-1β in serum and cerebral spinal fluid of mice stimulated by LPS. However, the protective effects of poly(I:C) against cerebral ischemia were abolished in TLR3−/− and TLR4−/−mice. Poly(I:C) downregulated TLR4 signaling via TLR3. Poly(I:C) treatment exhibited obvious protective effects 14 d after ischemia and was also effective in the rat permanent middle cerebral artery occlusion model. The results suggest that poly(I:C) exerts therapeutic effects against cerebral I/R injury through the downregulation of TLR4 signaling via TLR3. Poly(I:C) is a promising new drug candidate for the treatment of cerebral infarcts.

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“…Many attempts have been made to explore the mechanisms underlying this intrinsic neuroprotection of ischemic preconditioning. Postischemic inflammation is a significant factor that increases damage associated with ischemic brain injury [3,4] . Many studies have shown that the prevention of the inflammatory response might be a contributing mechanism by which IPC induces protection against brain ischemia [5,6] .…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo

et al. 2012

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Aim: To examine the neuroprotective effects of the Toll-like receptor 3 (TLR3) agonist Poly I:C in acute ischemic models in vitro and in vivo. Methods: Primary astrocyte cultures subjected to oxygen-glucose deprivation (OGD) were used as an in vitro simulated ischemic model. Poly I:C was administrated 2 h before OGD. Cell toxicity was measured using MTT assay and LDH leakage assay. The levels of TNFα, IL-6 and interferon-β (IFNβ) in the media were measured using ELISA. Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF) protein levels were detected using Western blot analysis. A mouse middle cerebral artery occlusion (MCAO) model was u sed for in vivo study. The animals were administered Poly I:C (0.3 mg/kg, im) 2 h before MCAO, and examined with neurological deficit scoring and TTC staining. The levels of TNFα and IL-6 in ischemic brain were measured using ELISA. Results: Pretreatment with Poly I:C (10 and 20 μg/mL) markedly attenuated OGD-induced astrocyte injury, and significantly raised the cell viability and reduced the LDH leakage. Poly I:C significantly upregulated TRIF expression accompanied by increased downstream IFNβ production. Moreover, Poly I:C significantly suppressed the pro-inflammatory cytokines TNFα and IL-6 production. In mice subjected to MCAO, administration of Poly I:C significantly attenuated the neurological deficits, reduced infarction volume, and suppressed the increased levels of TNFα and IL-6 in the ischemic striatum and cortex. Conclusion: Poly I:C pretreatment exerts neuroprotective and anti-inflammatory effects in the simulated cerebral ischemia models, and the neuroprotection is at least in part due to the activation of the TLR3-TRIF pathway.

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NF‐κB and innate immunity in ischemic stroke

Cited by 270 publications

References 51 publications

Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

Ischemic Injury-Induced CaMKIIδ and CaMKIIγ Confer Neuroprotection Through the NF-κB Signaling Pathway

Polyinosinic-Polycytidylic Acid Has Therapeutic Effects against Cerebral Ischemia/Reperfusion Injury through the Downregulation of TLR4 Signaling via TLR3

Toll-like receptor 3 agonist Poly I:C protects against simulated cerebral ischemia in vitro and in vivo

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