Limits...
Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.

Zhao J, Mou Y, Bernstock JD, Klimanis D, Wang S, Spatz M, Maric D, Johnson K, Klinman DM, Li X, Li X, Hallenbeck JM - PLoS ONE (2015)

Bottom Line: Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells.In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion.Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jinan Central Hospital affiliated with Shandong University, 105 Jiefang Road, Jinan, Shandong, 250013, P. R. China; Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

A151 reduced depolarization of mitochondrial membrane potential (MMP) in BMDM subjected to LPS and OGD.(A) FACS analysis of cells stained with JC-1. (B) The percentage of cells with depolarized MMP was reduced by A151 treatment. Data are presented as mean ± SEM from three replicates representative of three independent experiments (**, p < 0.05 compared with control or C151 treatment).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608557&req=5

pone.0140772.g003: A151 reduced depolarization of mitochondrial membrane potential (MMP) in BMDM subjected to LPS and OGD.(A) FACS analysis of cells stained with JC-1. (B) The percentage of cells with depolarized MMP was reduced by A151 treatment. Data are presented as mean ± SEM from three replicates representative of three independent experiments (**, p < 0.05 compared with control or C151 treatment).

Mentions: Mitochondrial dysfunction has been linked to NLRP3 inflammasome activation and we observed that A151 reduces NLRP3 protein expression [50]. We therefore sought to determine whether A151 could ameliorate BMDM mitochondrial dysfunction. To accomplish this we used the JC-1 assay to study the mitochondrial membrane potential (MMP) and found that A151 reduced the depolarization of MMP (Fig 3). Compared with C151 treatment, A151 reduced the percentage of cells with depolarized MMP from 15.8 ± 2.8% to 7.4 ± 0.9% (p<0.05).


Synthetic Oligodeoxynucleotides Containing Multiple Telemeric TTAGGG Motifs Suppress Inflammasome Activity in Macrophages Subjected to Oxygen and Glucose Deprivation and Reduce Ischemic Brain Injury in Stroke-Prone Spontaneously Hypertensive Rats.

Zhao J, Mou Y, Bernstock JD, Klimanis D, Wang S, Spatz M, Maric D, Johnson K, Klinman DM, Li X, Li X, Hallenbeck JM - PLoS ONE (2015)

A151 reduced depolarization of mitochondrial membrane potential (MMP) in BMDM subjected to LPS and OGD.(A) FACS analysis of cells stained with JC-1. (B) The percentage of cells with depolarized MMP was reduced by A151 treatment. Data are presented as mean ± SEM from three replicates representative of three independent experiments (**, p < 0.05 compared with control or C151 treatment).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608557&req=5

pone.0140772.g003: A151 reduced depolarization of mitochondrial membrane potential (MMP) in BMDM subjected to LPS and OGD.(A) FACS analysis of cells stained with JC-1. (B) The percentage of cells with depolarized MMP was reduced by A151 treatment. Data are presented as mean ± SEM from three replicates representative of three independent experiments (**, p < 0.05 compared with control or C151 treatment).
Mentions: Mitochondrial dysfunction has been linked to NLRP3 inflammasome activation and we observed that A151 reduces NLRP3 protein expression [50]. We therefore sought to determine whether A151 could ameliorate BMDM mitochondrial dysfunction. To accomplish this we used the JC-1 assay to study the mitochondrial membrane potential (MMP) and found that A151 reduced the depolarization of MMP (Fig 3). Compared with C151 treatment, A151 reduced the percentage of cells with depolarized MMP from 15.8 ± 2.8% to 7.4 ± 0.9% (p<0.05).

Bottom Line: Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells.In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion.Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jinan Central Hospital affiliated with Shandong University, 105 Jiefang Road, Jinan, Shandong, 250013, P. R. China; Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.

ABSTRACT
The immune system plays a fundamental role in both the development and pathobiology of stroke. Inflammasomes are multiprotein complexes that have come to be recognized as critical players in the inflammation that ultimately contributes to stroke severity. Inflammasomes recognize microbial and host-derived danger signals and activate caspase-1, which in turn controls the production of the pro-inflammatory cytokine IL-1β. We have shown that A151, a synthetic oligodeoxynucleotide containing multiple telemeric TTAGGG motifs, reduces IL-1β production by activated bone marrow derived macrophages that have been subjected to oxygen-glucose deprivation and LPS stimulation. Further, we demonstrate that A151 reduces the maturation of caspase-1 and IL-1β, the levels of both the iNOS and NLRP3 proteins, and the depolarization of mitochondrial membrane potential within such cells. In addition, we have demonstrated that A151 reduces ischemic brain damage and NLRP3 mRNA levels in SHR-SP rats that have undergone permanent middle cerebral artery occlusion. These findings clearly suggest that the modulation of inflammasome activity via A151 may contribute to a reduction in pro-inflammatory cytokine production by macrophages subjected to conditions that model brain ischemia and modulate ischemic brain damage in an animal model of stroke. Therefore, modulation of ischemic pathobiology by A151 may have a role in the development of novel stroke prevention and therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus