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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

Proposed pathway of TLR4 activation by nPM treatment. Red: TLR4-dependent increased mRNA or protein (cytokines). Dark blue: proteins or mRNA unresponsive to nPM. White: proposed intermediates, not examined. nPM activated MyD88-dependent pathways, increasing NF-κB mRNA and increasing downstream cytokine productions of NF-κB activation. JAK/STAT pathway was also activated by nPM with TLR4 dependence. LPS-mediated TLR4 receptor activation by endocytosis was not altered by nPM treatment
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Fig9: Proposed pathway of TLR4 activation by nPM treatment. Red: TLR4-dependent increased mRNA or protein (cytokines). Dark blue: proteins or mRNA unresponsive to nPM. White: proposed intermediates, not examined. nPM activated MyD88-dependent pathways, increasing NF-κB mRNA and increasing downstream cytokine productions of NF-κB activation. JAK/STAT pathway was also activated by nPM with TLR4 dependence. LPS-mediated TLR4 receptor activation by endocytosis was not altered by nPM treatment

Mentions: Figure 9 summarizes these responses (“Inflammatory proteins” and “TLR4 pathways”) by pathway.Fig. 9


Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo
Proposed pathway of TLR4 activation by nPM treatment. Red: TLR4-dependent increased mRNA or protein (cytokines). Dark blue: proteins or mRNA unresponsive to nPM. White: proposed intermediates, not examined. nPM activated MyD88-dependent pathways, increasing NF-κB mRNA and increasing downstream cytokine productions of NF-κB activation. JAK/STAT pathway was also activated by nPM with TLR4 dependence. LPS-mediated TLR4 receptor activation by endocytosis was not altered by nPM treatment
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC5391610&req=5

Fig9: Proposed pathway of TLR4 activation by nPM treatment. Red: TLR4-dependent increased mRNA or protein (cytokines). Dark blue: proteins or mRNA unresponsive to nPM. White: proposed intermediates, not examined. nPM activated MyD88-dependent pathways, increasing NF-κB mRNA and increasing downstream cytokine productions of NF-κB activation. JAK/STAT pathway was also activated by nPM with TLR4 dependence. LPS-mediated TLR4 receptor activation by endocytosis was not altered by nPM treatment
Mentions: Figure 9 summarizes these responses (“Inflammatory proteins” and “TLR4 pathways”) by pathway.Fig. 9

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