Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo

摘要

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 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.