Abstract
BackgroundAir 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.MethodsWYK 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−/−).ResultsRats 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.ConclusionsCollectively, 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.
Highlights
Air pollution is rapidly increasing in prevalence in multiple countries and is a major contributor to the global burden of disease [1]
Intratracheal (IT) diesel exhaust particle administration To examine the functional significance of triggering receptor expressed on myeloid cells 2 (TREM2) loss in DE particles (DEP)-induced neuroinflammation, an intratracheal (IT) model of DEP administration was used in mice, as we have previously reported that DEP IT administration has a central nervous system (CNS) Tumor necrosis factor alpha (TNFα) response similar to DE inhalation [37]
Diesel exhaust exposure induces neuroinflammation and impairs TREM2 expression To begin to understand more about how urban air pollution could affect CNS diseases like Alzheimer’s disease (AD), we first assessed whether DE-induced neuroinflammation was associated with TREM2 abnormalities, as inactivating mutations are a risk factor for AD [20, 21, 54]
Summary
Air pollution is rapidly increasing in prevalence in multiple countries and is a major contributor to the global burden of disease [1]. Increasing reports indicate that multiple forms of air pollution, including diesel exhaust (DE), trigger neuroinflammation and augment microglial pro-inflammatory responses both in vitro and in vivo [12, 16]. These studies, and others, have led to the neuroinflammation hypothesis, which posits that the air pollution-induced elevation in cytokines and reactive oxygen species (ROS) in the CNS may mediate the detrimental effects of air pollution on the brain [17]. 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. 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−/−)
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