Browsing by Author "Kodavanti, Urmila P."

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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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    Diesel exhaust impairs TREM2 to dysregulate neuroinflammation
    (BMC, 2020-11-22) Greve, Hendrik J.; Mumaw, Christen L.; Messenger, Evan J.; Kodavanti, Prasada R. S.; Royland, Joyce L.; Kodavanti, Urmila P.; Block, Michelle L.; Pharmacology and Toxicology, School of Medicine
    BACKGROUND: Air pollution has been linked to neurodegenerative diseases, including Alzheimer's disease (AD), and the underlying neuroimmune mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglia (DAM) cells, where loss-of-function TREM2 mutations are associated with an increased risk of AD. At present, the basic function of TREM2 in neuroinflammation is a point of controversy. Further, the impact of air pollution on TREM2 and the DAM phenotype is largely unknown. Using diesel exhaust (DE) as a model of urban air pollution exposure, we sought to address its impact on TREM2 expression, the DAM phenotype, the association of microglia with the neurovasculature, and the role of TREM2 in DE-induced neuroinflammation. METHODS: WYK rats were exposed for 4 weeks to DE (0, 50, 150, 500 μg/m3) by inhalation. DE particles (DEP) were administered intratracheally once (600 μg/mouse) or 8 times (100 μg/mouse) across 28 days to male mice (Trem2+/+, Trem2-/-, PHOX+/+, and PHOX-/-). RESULTS: Rats exposed to DE exhibited inverted-U patterns of Trem2 mRNA expression in the hippocampus and frontal cortex, while TREM2 protein was globally diminished, indicating impaired TREM2 expression. Analysis of DAM markers Cx3Cr1, Lyz2, and Lpl in the frontal cortex and hippocampus showed inverted-U patterns of expression as well, supporting dysregulation of the DAM phenotype. Further, microglial-vessel association decreased with DE inhalation in a dose-dependent manner. Mechanistically, intratracheal administration of DEP increased Tnf (TNFα), Ncf1 (p47PHOX), and Ncf2 (p67PHOX) mRNA expression in only Trem2+/+ mice, where Il1b (IL-1β) expression was elevated in only Trem2-/- mice, emphasizing an important role for TREM2 in DEP-induced neuroinflammation. CONCLUSIONS: Collectively, these findings reveal a novel role for TREM2 in how air pollution regulates neuroinflammation and provides much needed insight into the potential mechanisms linking urban air pollution to AD.
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    The bidirectional lung brain-axis of amyloid-β pathology: ozone dysregulates the peri-plaque microenvironment
    (Oxford University Press, 2023) Greve, Hendrik J.; Dunbar, August L.; Garza Lombo, Carla; Ahmed, Chandrama; Thang, Morrent; Messenger, Evan J.; Mumaw, Christen L.; Johnson, James A., Jr.; Kodavanti, Urmila P.; Oblak, Adrian L.; Block, Michelle L.; Pharmacology and Toxicology, School of Medicine
    The mechanisms underlying how urban air pollution affects Alzheimer's disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain's parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.
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    The Use of Standardized Diesel Exhaust Particles in Alzheimer’s Disease Research
    (IOS Press, 2021) Block, Michelle L.; Kodavanti, Urmila P.; Pharmacology and Toxicology, School of Medicine
    The mechanisms underlying how urban air pollution exposure conveys Alzheimer's disease risk and affects plaque pathology is largely unknown. Because particulate matter, the particle component of urban air pollution, varies across location, pollution source, and time, a single model representative of all ambient particulate matter is unfeasible for research investigating the role of ar pollution in central nervous system diseases. More specifically, the investigation of several models of particulate matter with enrichment of source-specific components are essential to employ, in order to more fully understand what characteristics of particulate matter affects Alzheimer's disease, including standardized diesel exhaust particles.