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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 pro-inflammatory cytokine production and cell death in BMDM subjected to LPS and OGD.BMDM were treated with OGD, with or without 1 ng/ml LPS, A151 or C151 for 18 hours. IL-1β (A), IL-1α (B), IL-6 (C), CINC-1 (D), TNFα (E), and LDH (F) in cell culture supernatants were measured by ELISA. Data are presented as mean ± SEM from three replicates representative of three independent experiments (*, p < 0.05 compared with LPS treatment; **, p < 0.05 compared with control or C151 treatment).
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pone.0140772.g001: A151 reduced pro-inflammatory cytokine production and cell death in BMDM subjected to LPS and OGD.BMDM were treated with OGD, with or without 1 ng/ml LPS, A151 or C151 for 18 hours. IL-1β (A), IL-1α (B), IL-6 (C), CINC-1 (D), TNFα (E), and LDH (F) in cell culture supernatants were measured by ELISA. Data are presented as mean ± SEM from three replicates representative of three independent experiments (*, p < 0.05 compared with LPS treatment; **, p < 0.05 compared with control or C151 treatment).

Mentions: Brain ischemia is characterized by oxygen and glucose deprivation and inflammation within the brain. To investigate the immunomodulatory potential of A151 under ischemic conditions, BMDM were treated with A151 or C151, LPS, and OGD. A151 dramatically reduced the levels of IL-1β, IL-1α, IL-6, CINC-1, and TNFα in culture supernatants (Fig 1). This was in contrast to the effects of the control ODN C151, which only reduced the levels of IL-6 and CINC-1. Of note, neither ODN altered the levels of CINC-3, IFNγ, IL-10, or TGFβ (data not shown).


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 pro-inflammatory cytokine production and cell death in BMDM subjected to LPS and OGD.BMDM were treated with OGD, with or without 1 ng/ml LPS, A151 or C151 for 18 hours. IL-1β (A), IL-1α (B), IL-6 (C), CINC-1 (D), TNFα (E), and LDH (F) in cell culture supernatants were measured by ELISA. Data are presented as mean ± SEM from three replicates representative of three independent experiments (*, p < 0.05 compared with LPS treatment; **, 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.g001: A151 reduced pro-inflammatory cytokine production and cell death in BMDM subjected to LPS and OGD.BMDM were treated with OGD, with or without 1 ng/ml LPS, A151 or C151 for 18 hours. IL-1β (A), IL-1α (B), IL-6 (C), CINC-1 (D), TNFα (E), and LDH (F) in cell culture supernatants were measured by ELISA. Data are presented as mean ± SEM from three replicates representative of three independent experiments (*, p < 0.05 compared with LPS treatment; **, p < 0.05 compared with control or C151 treatment).
Mentions: Brain ischemia is characterized by oxygen and glucose deprivation and inflammation within the brain. To investigate the immunomodulatory potential of A151 under ischemic conditions, BMDM were treated with A151 or C151, LPS, and OGD. A151 dramatically reduced the levels of IL-1β, IL-1α, IL-6, CINC-1, and TNFα in culture supernatants (Fig 1). This was in contrast to the effects of the control ODN C151, which only reduced the levels of IL-6 and CINC-1. Of note, neither ODN altered the levels of CINC-3, IFNγ, IL-10, or TGFβ (data not shown).

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