Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain

Thomas Taetzsch, Savannah Benusa, Shannon Levesque, Christen L. Mumaw, Michelle Block

Research output: Contribution to journalArticle

Abstract

Background: While NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood. Methods: Male NF-κB p50 +/+ and NF-κB p50 -/- mice at three different ages (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later. Results: Peripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50 +/+ and NF-κB p50 -/- mice of three different age groups (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50 -/- mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50 +/+ mice at all ages. Notably, the 16.0-18.0-month-old (middle aged) NF-κB p50 -/- mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5-3.0 month old, young adult) NF-κB p50 -/- mice. The 16.0-18.0-month-old LPS-treated NF-κB p50 -/- mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50 -/- mice exhibited decreased brain NF-κB p65 expression and activity. Conclusions: These findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.

Original languageEnglish (US)
Article number60
JournalJournal of Neuroinflammation
Volume16
Issue number1
DOIs
StatePublished - Mar 12 2019

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Brain
Microglia
Mesencephalon
Inbred C57BL Mouse
Transcription Factor RelA
Central Nervous System Diseases
Interleukin-1
Young Adult
Reactive Oxygen Species
Age Groups
Cytokines
Inflammation
Injections
DNA
Serum

Keywords

  • Aging
  • Microglia
  • NF-κB
  • Priming

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain. / Taetzsch, Thomas; Benusa, Savannah; Levesque, Shannon; Mumaw, Christen L.; Block, Michelle.

In: Journal of Neuroinflammation, Vol. 16, No. 1, 60, 12.03.2019.

Research output: Contribution to journalArticle

Taetzsch, Thomas ; Benusa, Savannah ; Levesque, Shannon ; Mumaw, Christen L. ; Block, Michelle. / Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain. In: Journal of Neuroinflammation. 2019 ; Vol. 16, No. 1.
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abstract = "Background: While NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood. Methods: Male NF-κB p50 +/+ and NF-κB p50 -/- mice at three different ages (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later. Results: Peripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50 +/+ and NF-κB p50 -/- mice of three different age groups (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50 -/- mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50 +/+ mice at all ages. Notably, the 16.0-18.0-month-old (middle aged) NF-κB p50 -/- mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5-3.0 month old, young adult) NF-κB p50 -/- mice. The 16.0-18.0-month-old LPS-treated NF-κB p50 -/- mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50 -/- mice exhibited decreased brain NF-κB p65 expression and activity. Conclusions: These findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.",
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T1 - Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain

AU - Taetzsch, Thomas

AU - Benusa, Savannah

AU - Levesque, Shannon

AU - Mumaw, Christen L.

AU - Block, Michelle

PY - 2019/3/12

Y1 - 2019/3/12

N2 - Background: While NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood. Methods: Male NF-κB p50 +/+ and NF-κB p50 -/- mice at three different ages (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later. Results: Peripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50 +/+ and NF-κB p50 -/- mice of three different age groups (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50 -/- mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50 +/+ mice at all ages. Notably, the 16.0-18.0-month-old (middle aged) NF-κB p50 -/- mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5-3.0 month old, young adult) NF-κB p50 -/- mice. The 16.0-18.0-month-old LPS-treated NF-κB p50 -/- mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50 -/- mice exhibited decreased brain NF-κB p65 expression and activity. Conclusions: These findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.

AB - Background: While NF-κB p50 function is impaired in central nervous system disease, aging in non-CNS tissues, and response to reactive oxygen species, the role of NF-κB p50 in aging-associated microglial pro-inflammatory priming is poorly understood. Methods: Male NF-κB p50 +/+ and NF-κB p50 -/- mice at three different ages (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were treated with LPS (5 mg/kg, IP) to trigger peripheral inflammation, where circulating cytokines, neuroinflammation, microglia morphology, and NF-κB p50/p65 function in brain tissue were determined 3 h later. Results: Peripheral LPS injection in 9-month-old C57BL/6 mice resulted in lower NF-κB p50 DNA binding of nuclear extracts from the whole brain, when compared to 3-week-old C57BL/6 mice, revealing differences in LPS-induced NF-κB p50 activity in the brain across the mouse lifespan. To examine the consequences of loss NF-κB p50 function with aging, NF-κB p50 +/+ and NF-κB p50 -/- mice of three different age groups (1.5-3.0 month old, 8.0-11.0 month old, and 16.0-18.0 month old) were injected with LPS (5 mg/kg, IP). NF-κB p50 -/- mice showed markedly elevated circulating, midbrain, and microglial TNFα when compared to NF-κB p50 +/+ mice at all ages. Notably, the 16.0-18.0-month-old (middle aged) NF-κB p50 -/- mice exhibited synergistically augmented LPS-induced serum and midbrain TNFα when compared to the younger (1.5-3.0 month old, young adult) NF-κB p50 -/- mice. The 16.0-18.0-month-old LPS-treated NF-κB p50 -/- mice also had the highest midbrain IL-1β expression, largest number of microglia with changes in morphology, and greatest elevation of pro-inflammatory factors in isolated adult microglia. Interestingly, aging NF-κB p50 -/- mice exhibited decreased brain NF-κB p65 expression and activity. Conclusions: These findings support that loss of NF-κB p50 function and aging in middle-aged mice may interact to excessively augment peripheral/microglial pro-inflammatory responses and point to a novel neuroinflammation signaling mechanism independent the NF-κB p50/p65 transcription factor in this process.

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KW - Microglia

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