Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion

被引：6

作者：

Shkirkova, Kristina ^{[1
]}

Demetriou, Alexandra N. ^{[1
]}

Sizdahkhani, Saman ^{[1
]}

Lamorie-Foote, Krista ^{[1
]}

Zhang, Hongqiao ^{[2
]}

Morales, Manuel ^{[1
]}

Chen, Selena ^{[1
]}

Zhao, Lifu ^{[1
]}

Diaz, Arnold ^{[2
]}

Godoy-Lugo, Jose A. ^{[2
]}

Zhou, Beryl ^{[2
]}

Zhang, Nathan ^{[2
]}

Li, Andrew ^{[2
]}

Mack, Wendy J. ^{[3
]}

Sioutas, Constantinos ^{[4
]}

Thorwald, Max A. ^{[2
]}

Finch, Caleb E. ^{[2
]}

Pike, Christian ^{[2
]}

Mack, William J. ^{[1
]}

机构：

[1] Univ Southern Calif, Zilkha Neurogenet Inst, 1501 San Pablo St, Los Angeles, CA 90033 USA

[2] Univ Southern Calif, Leonard Davis Sch Gerontol, Los Angeles, CA USA

[3] Univ Southern Calif, Keck Sch Med, Dept Populat & Publ Hlth Sci, Los Angeles, CA USA

[4] Univ Southern Calif, Rossier Sch Educ, Los Angeles, CA USA

来源：

STROKE | 2024年 / 55卷 / 04期

基金：

美国国家卫生研究院;

关键词：

carotid stenosis; mice; microglia; toll-like receptor 4; white matter; AIR-POLLUTION; NEUROTOXICITY;

D O I：

10.1161/STROKEAHA.124.046412

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：1090 / 1093

页数：4

共 21 条

[21] Argon mediates protection by interleukin-8 suppression via a TLR2/TLR4/STAT3/NF-B pathway in a model of apoptosis in neuroblastoma cells invitro and following ischemia-reperfusion injury in rat retina invivo
Ulbrich, Felix
Lerach, Teresa
Biermann, Julia
Kaufmann, Kai B.
Lagreze, Wolf A.
Buerkle, Hartmut
Loop, Torsten
Goebel, Ulrich
JOURNAL OF NEUROCHEMISTRY, 2016, 138 (06) : 859 - 873

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