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Abstract
BackgroundWhile 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.MethodsMale 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.ResultsPeripheral 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.ConclusionsThese 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.
Highlights
While Nuclear factor kappa-light-chain-enhancer of activated B cells (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
An asterisk indicates significant difference (P < 0.05) from the 1.5–3.0-month-old group and a dagger indicates a significant difference between mouse strains. n = 3–7 only the 16.0–18.0-month-old NF-κB p50−/− mice were significantly higher than the genotype augmented Tumor necrosis factor alpha (TNFα) levels in 1.5–3.0-month-old NF-κB p50−/− mice
We address the role of NF-κB p50 in regulating microglia in the aging brain and reveal that (1) NF-κB p50 activity in response to a pro-inflammatory triggers changes across the lifespan, which decreases in older mice; (2) aging synergistically amplifies pro-inflammatory priming due to loss of NF-κB p50 function in microglia and the brain in middle-aged mice; and (3) NF-κB p65 expression is reduced in the middle-aged brain and NF-κB p65 activity in response to LPS decreases in the middle-aged NF-κB p50−/− brain, despite the presence of exaggerated neuroinflammation
Summary
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. While the causes driving the enhanced sensitivity of aging microglia to proinflammatory stimuli are poorly understood, age-related microglial priming is predicted to be an interaction between the microglial responses to increasingly deleterious changes in the CNS environment [25] and intrinsic microglial characteristics associated with aging [12]. Several factors are implicated in the process of age-induced microglial priming, including upregulation of innate immune receptors on microglia responsible for the detection of pro-inflammatory stimuli [12, 25], enhanced peripheral inflammation/circulating cytokine production that transfers to the brain to impact neuroinflammation [26], and elevated states of oxidative stress in the aged brain [27,28,29]. The intrinsic signaling mechanisms that shift microglia into a primed state as the brain ages remain unclear
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