The role of the lectin-like oxLDL receptor (LOX-1) in traffic-generated air pollution exposure-mediated alteration of the brain microvasculature in Apolipoprotein (Apo) E knockout mice

Abstract

Recent studies have shown a strong correlation between air pollution-exposure and detrimental outcomes in the central nervous system, including alterations in blood brain barrier (BBB) integrity, neuroinflammation, and neurodegeneration. However, the mechanisms mediating these pathologies have not yet been fully elucidated. We have previously reported that exposure to traffic-generated air pollution results in increased circulating oxidized low-density lipoprotein (oxLDL), associated with alterations in BBB integrity, in atherosclerotic Apolipoprotein E null (ApoE) mice. Thus, we investigated the role of the lectin-like oxLDL receptor (LOX)-1 in mediating these deleterious effects in ApoE mice exposed to a mixture of gasoline and diesel engine exhaust (MVE: 100 PM µg/m) for 6 h/d, 7d/week, for 30 d by inhalation. Concurrent with exposures, a subset of mice were treated with neutralizing antibodies to LOX-1 (LOX-1 Ab) i.p., or IgG (control) i.p., every other day during exposures. Resulting brain microvascular integrity, tight junction (TJ) protein expression, matrix metalloproteinase (MMP)-9/-2 activity, ROS, and markers of cellular adhesion and monocyte/macrophage sequestration were assessed. MVE-exposure resulted in decreased BBB integrity and alterations in microvascular TJ protein expression, associated with increased LOX-1 expression, MMP-9/-2 activities, and lipid peroxidation, each of which was attenuated with LOX-1 Ab treatment. Furthermore, MVE-exposure induced cerebral microvascular ROS and adhesion molecules, expression of which was not normalized through LOX-1 Ab-treatment. Such findings suggest that alterations in brain microvascular structure and integrity observed with MVE-exposure may be mediated, at least in part, via LOX-1 signaling.

Exposure to traffic-generated air pollutants mediates alterations in brain microvascular integrity in wildtype mice on a high-fat diet

“…Three mo-old male C57BL/6 mice were placed on either normal mouse chow or a HF diet (TD88137 Custom Research Diet, Harlan Teklad, Madison, WI; 21.2% fat content by weight, 1.5g/kg cholesterol content) beginning 30 days prior to initiation of exposure. Mice were randomly grouped to be exposed by whole-body inhalation to a mixture of whole gasoline engine exhaust and diesel engine exhaust (MVE: 30 µg PM/m 3 gasoline engine emissions + 70 µg PM/m 3 diesel engine) or filtered-air (controls) for 6 h/d, 7 d/wk, for a period of 30 d. MVE was created by combining exhaust from a 1996 GM gasoline engine and a Yanmar diesel generator system, and exposures chemistries and PM characterized, as previously reported (McDonald et al, 2004; McDonald et al, 2008; Lund et al, 2011; Oppenheim et al, 2013; Mumaw et al, 2016; Lucero et al, 2017.). Particle size distribution was measured with a Fast Mobility Particle Sizer (FMPS, TSI, St. Paul, MN) for the ∼10–500 nm size range and an Aerodynamic Particle Sizer (TSI, St Paul, MN) to measure the 0.5–20 µm size range.…”

“…increase ox-LDL) (Ikeda et al, 1995), higher levels of which are associated with progression of cardiovascular disease, atherosclerotic plaque growth, as well as poorer prognostic outcome in stroke (Ishigaki et al, 2009). Additionally, our laboratory has previously reported that inhalation exposure to a mixture of gasoline and diesel engine exhaust (MVE) resulted in increased circulating ox-LDL in atherosclerotic Apolipoprotein (Apo)E −/− mice, which was associated with increased expression of microvascular LOX-1 and ROS (Lund et al, 2011; Lucero et al, 2017). Furthermore, exposure to air pollution has also been associated with altered BBB integrity and permeability in both laboratory studies and human exposures (Oppenheim et al, 2013; Calderón-Garcidueñas et al, 2016).…”

“…Furthermore, exposure to air pollution has also been associated with altered BBB integrity and permeability in both laboratory studies and human exposures (Oppenheim et al, 2013; Calderón-Garcidueñas et al, 2016). Exposure to MVE, specifically, has been reported to result in a disruption of the BBB, associated with increased MMP-9 expression and activity and decreased TJ protein (occludin and claudin-5) expression, in the cerebral vasculature of ApoE −/− mice (Oppenheim et al, 2015; Lucero et al, 2017). Importantly, alterations in the integrity of the BBB can lead to exacerbated pathology and/or hemorrhagic transformation during an ischemic stroke (Turner and Sharp, 2016).…”

“…We have previously reported the effects of traffic-generated air pollutants (MVE) in mediating microvascular toxicity and BBB disruption, associated with LOX-1 signaling, in atherosclerotic ApoE −/− mice (Oppenheim et al, 2013; Lucero et al, 2017). However, to date, there is very little information on whether inhaled traffic-generated pollutants promote similar detrimental effects on the cerebral vasculature in a wildtype animal model and/or whether a HF diet may exacerbate any of the observed exposure-mediated outcomes.…”

Aging Exacerbates Neuroinflammatory Outcomes Induced by Acute Ozone Exposure

“…Localization of particulate matter in the CNS has been demonstrated after high dose exposures but has only been experimentally linked to neuroinflammation and pathology in an associative manner. However, indirect inflammatory effects due to pulmonary damage may be carried into circulation, as demonstrated mechanistically in several recent studies of both particulate and gaseous inhaled toxicants (Aragon et al, 2017;Channell et al, 2012;Lucero et al, 2017;Robertson et al, 2013;Schisler et al, 2015). For exposures to lower doses of inhaled toxicants, this may be the likely mechanism of neuroinflammatory effects.…”