Browsing by Author "Levesque, Shannon"

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    Atypical microglial response to biodiesel exhaust in healthy and hypertensive rats
    (Elsevier, 2017-03) Mumaw, Christen L.; Surace, Michael; Levesque, Shannon; Kodavanti, Urmila P.; Kodavanti, Prasada Rao S.; Royland, Joyce E.; Block, Michelle L.; Anatomy and Cell Biology, School of Medicine
    Accumulating evidence suggests a deleterious role for urban air pollution in central nervous system (CNS) diseases and neurodevelopmental disorders. Microglia, the resident innate immune cells and sentinels in the brain, are a common source of neuroinflammation and are implicated in how air pollution may exert CNS effects. While renewable energy, such as soy-based biofuel, is of increasing public interest, there is little information on how soy biofuel may affect the brain. To address this, male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were exposed to 100% Soy Biodiesel Exhaust (100SBDE; 0, 50, 150 and 500 μg/m3) by inhalation for 4 h/day for 4 weeks (5 days/week). IBA-1 staining of microglia in the substantia nigra revealed significant changes in morphology with 100SBDE exposure in rats from both genotypes, where the SHR were less sensitive. Further analysis failed to show consistent changes in pro-inflammatory cytokine expression, nitrated protein, and arginase1 expression in brain tissue from either rat strain exposed to 100SBDE. CX3CR1 and fractalkine mRNA expression were lower in the striatum of all 100SBDE exposed rats, but greater SBDE exposure was required for loss of fractalkine expression in the SHR. Together, these data support that month-long 100SBDE exposure impacts the basal ganglia with changes in microglia morphology, an impaired fractalkine axis, and an atypical activation response without traditional markers of M1 or M2 activation, where the SHR may be less sensitive to these effects.
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    Loss of NF-κB p50 function synergistically augments microglial priming in the middle-aged brain
    (BMC, 2019-03-12) Taetzsch, Thomas; Benusa, Savannah; Levesque, Shannon; Mumaw, Christen L.; Block, Michelle L.; Anatomy and Cell Biology, School of Medicine
    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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    Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors
    (Federation of American Societies for Experimental Biology, 2016-05) Mumaw, Christen L.; Levesque, Shannon; McGraw, Constance; Robertson, Sarah; Lucas, Selita; Stafflinger, Jillian E.; Campen, Matthew J.; Hall, Pamela; Norenberg, Jeffrey P.; Anderson, Tamara; Lund, Amie K.; McDonald, Jacob D.; Ottens, Andrew K.; Block, Michelle L.; Anatomy and Cell Biology, School of Medicine
    Air pollution is implicated in neurodegenerative disease risk and progression and in microglial activation, but the mechanisms are unknown. In this study, microglia remained activated 24 h after ozone (O3) exposure in rats, suggesting a persistent signal from lung to brain. Ex vivo analysis of serum from O3-treated rats revealed an augmented microglial proinflammatory response and β-amyloid 42 (Aβ42) neurotoxicity independent of traditional circulating cytokines, where macrophage-1 antigen-mediated microglia proinflammatory priming. Aged mice exhibited reduced pulmonary immune profiles and the most pronounced neuroinflammation and microglial activation in response to mixed vehicle emissions. Consistent with this premise, cluster of differentiation 36 (CD36)(-/-) mice exhibited impaired pulmonary immune responses concurrent with augmented neuroinflammation and microglial activation in response to O3 Further, aging glia were more sensitive to the proinflammatory effects of O3 serum. Together, these findings outline the lung-brain axis, where air pollutant exposures result in circulating, cytokine-independent signals present in serum that elevate the brain proinflammatory milieu, which is linked to the pulmonary response and is further augmented with age.