title: 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.
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.
authors.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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Yongshan
authors.initials: Y
authors.lastname: Mou
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Bernstock
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Dace
authors.initials: D
authors.lastname: Klimanis
authors.affiliation: College of Arts and Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Sixian
authors.initials: S
authors.lastname: Wang
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Maria
authors.initials: M
authors.lastname: Spatz
authors.affiliation: National Institute of Neurological Disorders and Stroke, Flow Cytometry Core Facility, Bethesda, Maryland, United States of America.
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.affiliation: Information Technology & Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kory
authors.initials: K
authors.lastname: Johnson
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.affiliation: Department of Neurology, Jinan Central Hospital affiliated with Shandong University, 105 Jiefang Road, Jinan, Shandong, 250013, P. R. China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Li
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Li
authors.affiliation: Stroke Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Hallenbeck
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D005947:Glucose / Q000276:immunology* / Q000378:metabolism; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D059372:Nucleotide Motifs; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010100:Oxygen / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D016615:Telomere
chemical_list: C408982:CPG-oligonucleotide; D002352:Carrier Proteins; C000594089:IL1B protein, rat; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; D009838:Oligodeoxyribonucleotides; D020170:Caspase 1; D005947:Glucose; D010100:Oxygen