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. 2024 Apr;55(4):1090-1093.
doi: 10.1161/STROKEAHA.124.046412. Epub 2024 Feb 1.

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

Kristina Shkirkova #  1 , Alexandra N Demetriou #  1 , Saman Sizdahkhani #  1 , Krista Lamorie-Foote  1 , Hongqiao Zhang  2 , Manuel Morales  1 , Selena Chen  1 , Lifu Zhao  1 , Arnold Diaz  2 , Jose A Godoy-Lugo  2 , Beryl Zhou  2 , Nathan Zhang  2 , Andrew Li  2 , Wendy J Mack  1   3 , Constantinos Sioutas  4 , Max A Thorwald  2 , Caleb E Finch  2 , Christian Pike  2 , William J Mack
Affiliations

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

Kristina Shkirkova et al. Stroke. 2024 Apr.

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.

Keywords: carotid stenosis; mice; microglia; toll-like receptor 4; white matter.

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Conflict of interest statement

Disclosures Dr Mack is a consultant to Rebound Therapeutics, Viseon, Imperative Care, Integra, Q’Apel, Medtronic, Stryker, Stream Biomedical, Spartan Micro, and Egret and an investor in Cerebrotech, Q’Apel, Endostream, Viseon, Rebound, Stream Biomedical, Truvic, Spartan Micro, Radical Catheters, Vastrax, and Borvo. The other authors report no conflicts.

Figures

Figure 1:
Figure 1:. Corpus Callosum Immunofluorescence.
Graph depicts immunofluorescence integrated density levels (A. 4-HNE; B. 8-OHdG; C. Iba-1; D. dMBP). Data were analyzed using one-way ANOVA with Tukey’s test, with significance defined at two-sided alpha of 0.05. Significant comparisons relevant to study hypothesis/outcomes are displayed; Supplemental Tables 2–5 present complete ANOVA results. * p<0.05, ** p<0.01, **** p<0.0001. FA, filtered air; i-mTLR4-ko, inducible macrophage/microglial TLR4 knockout; DEP, diesel exhaust particulate; BCAS, bilateral carotid artery stenosis.
See this image and copyright information in PMC

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