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

View Article: PubMed Central - PubMed

ABSTRACT

Background: Exposure 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.

Methods: To 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.

Results: SAM 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.

Conclusions: These 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12974-017-0858-x) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Hippocampal responses to nPM exposure in vivo. Mouse in vivo: Chronic nPM exposure induced components of the TLR4 pathway in hippocampus. mRNA responses by q-PCR are given, shown in relation to pathway (Fig. 7). a TLR4 mRNA was induced by nPM (p < 0.05). b MyD88 mRNA was increased by nPM (p < 0.05). c TRAF6 mRNA was decreased by nPM (p < 0.0001). d NF-κB was decreased by nPM (p < 0.05). e TNFα mRNA was increased by nPM (p < 0.01). f TNFR2 mRNA was increased by nPM (p < 0.05). n = 7
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Fig11: Hippocampal responses to nPM exposure in vivo. Mouse in vivo: Chronic nPM exposure induced components of the TLR4 pathway in hippocampus. mRNA responses by q-PCR are given, shown in relation to pathway (Fig. 7). a TLR4 mRNA was induced by nPM (p < 0.05). b MyD88 mRNA was increased by nPM (p < 0.05). c TRAF6 mRNA was decreased by nPM (p < 0.0001). d NF-κB was decreased by nPM (p < 0.05). e TNFα mRNA was increased by nPM (p < 0.01). f TNFR2 mRNA was increased by nPM (p < 0.05). n = 7

Mentions: To investigate TLR4 involvement in vivo, we examined TLR4-associated responses in the hippocampus of adult mice chronically exposed to nPM for 150 h over 10 weeks. TLR4 and MyD88 RNAs were increased by this nPM exposure (2.1× and 1.4×, respectively) (Fig. 11a, b), while NF-κB and TRAF6 were decreased (0.8× and 0.75×, respectively) (Fig. 11c, d). Increases were observed for TNFα (10×) (Fig. 11e) and TNFR2 (1.6×) (Fig. 11f). There was no response of TNFR1, c-Fos, or c-Jun (not shown).Fig. 11


Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo
Hippocampal responses to nPM exposure in vivo. Mouse in vivo: Chronic nPM exposure induced components of the TLR4 pathway in hippocampus. mRNA responses by q-PCR are given, shown in relation to pathway (Fig. 7). a TLR4 mRNA was induced by nPM (p < 0.05). b MyD88 mRNA was increased by nPM (p < 0.05). c TRAF6 mRNA was decreased by nPM (p < 0.0001). d NF-κB was decreased by nPM (p < 0.05). e TNFα mRNA was increased by nPM (p < 0.01). f TNFR2 mRNA was increased by nPM (p < 0.05). n = 7
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5391610&req=5

Fig11: Hippocampal responses to nPM exposure in vivo. Mouse in vivo: Chronic nPM exposure induced components of the TLR4 pathway in hippocampus. mRNA responses by q-PCR are given, shown in relation to pathway (Fig. 7). a TLR4 mRNA was induced by nPM (p < 0.05). b MyD88 mRNA was increased by nPM (p < 0.05). c TRAF6 mRNA was decreased by nPM (p < 0.0001). d NF-κB was decreased by nPM (p < 0.05). e TNFα mRNA was increased by nPM (p < 0.01). f TNFR2 mRNA was increased by nPM (p < 0.05). n = 7
Mentions: To investigate TLR4 involvement in vivo, we examined TLR4-associated responses in the hippocampus of adult mice chronically exposed to nPM for 150 h over 10 weeks. TLR4 and MyD88 RNAs were increased by this nPM exposure (2.1× and 1.4×, respectively) (Fig. 11a, b), while NF-κB and TRAF6 were decreased (0.8× and 0.75×, respectively) (Fig. 11c, d). Increases were observed for TNFα (10×) (Fig. 11e) and TNFR2 (1.6×) (Fig. 11f). There was no response of TNFR1, c-Fos, or c-Jun (not shown).Fig. 11

View Article: PubMed Central - PubMed

ABSTRACT

Background: Exposure 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.

Methods: To further analyze these mechanisms, we examined mixed glial cultures (astrocytes and microglia) for RNA responses to nanoscale particulate matter (nPM; diameter &lt;0.2&nbsp;&mu;m), a well-characterized nanoscale particulate matter subfraction of TRAP collected from a local freeway (Morgan et al. Environ Health Perspect 2011; 119,1003&ndash;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.

Results: SAM and WGCNA analyses showed strong activation of TLR4 and NF-&kappa;B by both nPM and LPS. TLR4 siRNA attenuated TNF&alpha; and other inflammatory responses to nPM in vitro, via the MyD88-dependent pathway. In vivo, mice chronically exposed to nPM showed increased TLR4, MyD88, TNF&alpha;, and TNFR2 RNA, and decreased NF-&kappa;B and TRAF6 RNA TLR4 and NF-&kappa;B responses in the hippocampus.

Conclusions: These 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.

Electronic supplementary material: The online version of this article (doi:10.1186/s12974-017-0858-x) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus