Abstract
BackgroundExposure to traffic-related air pollution (TRAP) is associated with accelerated cognitive aging and higher dementia risk in human populations. Rodent brains respond to TRAP with activation of astrocytes and microglia, increased inflammatory cytokines, and neurite atrophy. A role for Toll-like receptor 4 (TLR4) was suggested in mouse TLR4-knockouts, which had attenuated lung macrophage responses to air pollution.MethodsTo further analyze these mechanisms, we examined mixed glial cultures (astrocytes and microglia) for RNA responses to nanoscale particulate matter (nPM; diameter <0.2 μm), a well-characterized nanoscale particulate matter subfraction of TRAP collected from a local freeway (Morgan et al. Environ Health Perspect 2011; 119,1003–1009, 2011). The nPM was compared with responses to the endotoxin lipopolysaccharide (LPS), a classic TLR4 ligand, using Affymetrix whole genome microarray in rats. Expression patterns were analyzed by significance analysis of microarrays (SAM) for fold change and by weighted gene co-expression network analysis (WGCNA) to identify modules of shared responses between nPM and LPS. Finally, we examined TLR4 activation in hippocampal tissue from mice chronically exposed to nPM.ResultsSAM and WGCNA analyses showed strong activation of TLR4 and NF-κB by both nPM and LPS. TLR4 siRNA attenuated TNFα and other inflammatory responses to nPM in vitro, via the MyD88-dependent pathway. In vivo, mice chronically exposed to nPM showed increased TLR4, MyD88, TNFα, and TNFR2 RNA, and decreased NF-κB and TRAF6 RNA TLR4 and NF-κB responses in the hippocampus.ConclusionsThese results show TLR4 activation is integral in brain inflammatory responses to air pollution, and warrant further study of TLR4 in accelerated cognitive aging by air pollution.
Highlights
Exposure to traffic-related air pollution (TRAP) is associated with accelerated cognitive aging and higher dementia risk in human populations
The results from significance analysis of microarrays (SAM) and weighted gene co-expression network analysis (WGCNA) were analyzed for enriched biological processes, by Gene Ontology (GO), and for transcription factor targets (TFTs)
Guided by results from microarray analysis, we investigated Toll-like receptor 4 (TLR4) involvement in nanoscale particulate matter (nPM) response by TLR4 knockdown in vitro, and investigated TLR4 activation in the hippocampus following chronic in vivo exposure
Summary
Exposure to traffic-related air pollution (TRAP) is associated with accelerated cognitive aging and higher dementia risk in human populations. Traffic-related air pollution (TRAP) is associated in human populations with accelerated cognitive aging [1,2,3,4] and increased risk of dementia [5,6,7,8]. TRAP-associated changes of normal aging include decreased white and grey matter [13, 14], while post mortem samples from a highly polluted Mexican City showed white matter hyperintensities and neuroinflammation [15, 16]. Rodent models given controlled exposure to TRAP particulate material (PM), showed corresponding loss of dendritic spines [17] and microglial activation [18, 19]. Mice were chronically exposed to nPM, a nano-scaled subfraction of TRAP [18, 23]
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