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Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.
Shkirkova, Kristina; Demetriou, Alexandra N; Sizdahkhani, Saman; Lamorie-Foote, Krista; Zhang, Hongqiao; Morales, Manuel; Chen, Selena; Zhao, Lifu; Diaz, Arnold; Godoy-Lugo, Jose A; Zhou, Beryl; Zhang, Nathan; Li, Andrew; Mack, Wendy J; Sioutas, Constantinos; Thorwald, Max A; Finch, Caleb E; Pike, Christian; Mack, William J.
Afiliação
  • Shkirkova K; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Demetriou AN; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Sizdahkhani S; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Lamorie-Foote K; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Zhang H; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Morales M; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Chen S; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Zhao L; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Diaz A; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Godoy-Lugo JA; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Zhou B; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Zhang N; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Li A; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Mack WJ; Zilkha Neurogenetic Institute (K.S., A.N.D., S.S., K.L.-F., M.M., S.C., L.Z., W.J.M.), University of Southern California, Los Angeles.
  • Sioutas C; Department of Population and Public Health Sciences, Keck School of Medicine (W.J.M.), University of Southern California, Los Angeles.
  • Thorwald MA; Viterbi School of Engineering (C.S.), University of Southern California, Los Angeles.
  • Finch CE; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Pike C; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
  • Mack WJ; Leonard Davis School of Gerontology (H.Z., A.D., J.A.G.-L., B.Z., N.Z., A.L., M.A.T., C.E.F., C.P.), University of Southern California, Los Angeles.
Stroke ; 55(4): 1090-1093, 2024 Apr.
Article em En | MEDLINE | ID: mdl-38299349
ABSTRACT

BACKGROUND:

Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures.

METHODS:

Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively.

RESULTS:

Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers.

CONCLUSIONS:

i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Isquemia Encefálica / Estenose das Carótidas / Aldeídos / Substância Branca Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Isquemia Encefálica / Estenose das Carótidas / Aldeídos / Substância Branca Limite: Animals Idioma: En Ano de publicação: 2024 Tipo de documento: Article