Microglial priming through the lung—brain axis: the role of air pollution‐induced circulating factors

Mumaw, Christen L.; Levesque, Shannon; McGraw, Constance; Robertson, Stewart A.; Lucas, Selitá; Stafflinger, Jillian E.; Campen, Matthew J.; Hall, Pamela R.; Norenberg, Jeffrey P.; Anderson, Tamara L.; Lund, Amie K.; McDonald, Jacob D.; Ottens, Andrew K.; Block, Michelle L.

doi:10.1096/fj.201500047

Cited by 134 publications

(117 citation statements)

References 69 publications

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“…Neurologic consequences of inhaled PM and gases have been reported in epidemiologic and toxicologic studies, but considerable uncertainty exists regarding the pathway by which toxic effects transfer from the lung to the brain (3,(32)(33)(34). The present study establishes that a circulating signal arises after pulmonary exposure to MWCNTs that leads to a BBB-dependent neuroinflammatory response.…”

Section: Discussionsupporting

confidence: 57%

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

Aragon

Topper

Tyler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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115

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Pulmonary exposure to multiwalled carbon nanotubes (MWCNTs) causes indirect systemic inflammation through unknown pathways. MWCNTs translocate only minimally from the lungs into the systemic circulation, suggesting that extrapulmonary toxicity may be caused indirectly by lung-derived factors entering the circulation. To assess a role for MWCNT-induced circulating factors in driving neuroinflammatory outcomes, mice were acutely exposed to MWCNTs (10 or 40 μg/mouse) via oropharyngeal aspiration. At 4 h after MWCNT exposure, broad disruption of the blood-brain barrier (BBB) was observed across the capillary bed with the small molecule fluorescein, concomitant with reactive astrocytosis. However, pronounced BBB permeation was noted, with frank albumin leakage around larger vessels (>10 μm), overlain by a dose-dependent astroglial scar-like formation and recruitment of phagocytic microglia. As affirmed by elevated inflammatory marker transcription, MWCNT-induced BBB disruption and neuroinflammation were abrogated by pretreatment with the rho kinase inhibitor fasudil. Serum from MWCNT-exposed mice induced expression of adhesion molecules in primary murine cerebrovascular endothelial cells and, in a wound-healing in vitro assay, impaired cell motility and cytokinesis. Serum thrombospondin-1 level was significantly increased after MWCNT exposure, and mice lacking the endogenous receptor CD36 were protected from the neuroinflammatory and BBB permeability effects of MWCNTs. In conclusion, acute pulmonary exposure to MWCNTs causes neuroinflammatory responses that are dependent on the disruption of BBB integrity.nanoparticle | blood-brain barrier | microglia | thrombospondin-1 | multiwalled carbon nanotube

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Section: Discussionsupporting

confidence: 57%

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

Aragon

Topper

Tyler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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115

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“…Recent epidemiological studies have linked traffic-related air pollution to adverse neurological outcomes [2, 30] with several toxicological reports demonstrating that PM exposure has the capacity to alter neural development [31, 32], induce neuroinflammation [33], impair cognition [34], and potentially induce neurodegeneration [35]. However, there is still much debate regarding such findings owing to inconsistent results and a lack of understanding as to how inhalation exposures lead to neurological deficits.…”

Section: Discussionmentioning

confidence: 99%

Surface area-dependence of gas-particle interactions influences pulmonary and neuroinflammatory outcomes

et al. 2016

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BackgroundDeleterious consequences of exposure to traffic emissions may derive from interactions between carbonaceous particulate matter (PM) and gaseous components in a manner that is dependent on the surface area or complexity of the particles. To determine the validity of this hypothesis, we examined pulmonary and neurological inflammatory outcomes in C57BL/6 and apolipoprotein E knockout (ApoE−/−) male mice after acute and chronic exposure to vehicle engine-derived particulate matter, generated as ultrafine (UFP) and fine (FP) sizes, with additional exposures using UFP or FP combined with gaseous copollutants derived from fresh gasoline and diesel emissions, labeled as UFP + G and FP + G.ResultsThe UFP and UFP + G exposure groups resulted in the most profound pulmonary and neuroinflammatory effects. Phagocytosis of UFP + G particles via resident alveolar macrophages was substantial in both mouse strains, particularly after chronic exposure, with concurrent increased proinflammatory cytokine expression of CXCL1 and TNFα in the bronchial lavage fluid. In the acute exposure paradigm, only UFP and UFP + G induced significant changes in pulmonary inflammation and only in the ApoE−/− animals. Similarly, acute exposure to UFP and UFP + G increased the expression of several cytokines in the hippocampus of ApoE−/− mice including Il-1β, IL-6, Tgf-β and Tnf-α and in the hippocampus of C57BL/6 mice including Ccl5, Cxcl1, Il-1β, and Tnf-α. Interestingly, Il-6 and Tgf-β expression were decreased in the C57BL/6 hippocampus after acute exposure. Chronic exposure to UFP + G increased expression of Ccl5, Cxcl1, Il-6, and Tgf-β in the ApoE−/− hippocampus, but this effect was minimal in the C57BL/6 mice, suggesting compensatory mechanisms to manage neuroinflammation in this strain.ConclusionsInflammatory responses the lung and brain were most substantial in ApoE−/− animals exposed to UFP + G, suggesting that the surface area-dependent interaction of gases and particles is an important determinant of toxic responses. As such, freshly generated UFP, in the presence of combustion-derived gas phase pollutants, may be a greater health hazard than would be predicted from PM concentration, alone, lending support for epidemiological findings of adverse neurological outcomes associated with roadway proximity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0177-x) contains supplementary material, which is available to authorized users.

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“…Rodent models given controlled exposure to TRAP particulate material (PM), showed corresponding loss of dendritic spines [17] and microglial activation [18, 19]. Brain inflammatory responses include increased IL-1α and TNFα [17, 18, 20], together with NF-κB [21] and detoxifying enzymes associated with Nrf2 [22].…”

Section: Introductionmentioning

confidence: 99%

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

Woodward

Levine

Haghani

et al. 2017

J Neuroinflammation

115

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

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Microglial priming through the lung—brain axis: the role of air pollution‐induced circulating factors

Cited by 134 publications

References 69 publications

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

Serum-borne bioactivity caused by pulmonary multiwalled carbon nanotubes induces neuroinflammation via blood–brain barrier impairment

Surface area-dependence of gas-particle interactions influences pulmonary and neuroinflammatory outcomes

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

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