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Diesel Exhaust Impairs TREM2 to Dysregulate Neuroinflammation
Citation:
Greve, H., C. Mumaw, E. Messenger, Prasada Rao Kodavanti, J. Royland, U. Kodavanti, AND M. Block. Diesel Exhaust Impairs TREM2 to Dysregulate Neuroinflammation. Journal of Neuroinflammation. BioMed Central Ltd, London, Uk, 17(1):351, (2020). https://doi.org/10.1186/s12974-020-02017-7
Impact/Purpose:
Currently, the mechanisms underlying how urban air pollution regulates neuroinflammation and why urban air pollution is associated with Alzheimer's disease (AD) are largely unknown. To begin to address these issues, murine models of diesel exhaust exposure were employed to understand the impact of urban air pollution on TREM2 expression, the DAM phenotype, and the microglial association with the neurovasculature during neuroinflammation. The mechanistic role of TREM2 in diesel exhaust particle-induced neuroinflammation was examined. The 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.
Description:
Background: Air pollution has been linked to neurodegenerative diseases, including Alzheimer’s disease (AD), but the underlying mechanisms remain poorly understood. TREM2 is a myeloid cell membrane receptor that is a key regulator of disease-associated microglial (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. Objective: 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 (12 mg/kg) or 8 times (2 mg/kg) 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.
