Cited by 174Neuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function StudiesImmune Response and Inflammation

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Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation

Zhou, Hong, Andonegui, Graciela, Wong, Connie H Y, Kubes, Paul·2009·The Journal of Immunology

DOI 10.4049/jimmunol.0901309

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Abstract

Brain inflammation is a frequent consequence of sepsis and septic shock. We imaged leukocyte recruitment in brain postcapillary venules induced by i.p. administration of LPS as a simple model of systemic inflammation. The i.p. injection of LPS (0.5 mg/kg) induced significant leukocyte rolling and adhesion in brain postcapillary venules of wild-type (WT) mice and more than 90% were neutrophils. However, no emigrated neutrophils were detected in brain parenchyma. High levels of TNF-α and IL-1β were detected in the plasma after LPS injection but a different profile (IL-1β but not TNF-α) was detected in the brain. LPS caused no recruitment in TLR4 knockout mice. In chimeric mice with TLR4-expressing resident cells but TLR4-deficient bone marrow-derived circulating cells, neutrophil rolling and adhesion was similar to WT mice. This observation is consistent with a requirement for resident cells in the LPS-induced neutrophil recruitment into brain microvessels. Transgenic mice engineered to express TLR4 exclusively on endothelial cells had a similar level of leukocyte recruitment in brain as WT mice in response to LPS. High dose LPS (10 mg/kg) led to neutrophil infiltration in the brain parenchyma in WT mice. High KC and MIP-2 production was observed from brain parenchyma microglial cells, and CXCR2 knockout mice failed to recruit neutrophils. However, neither neutrophil infiltration nor KC or MIP-2 was observed in endothelial TLR4 transgenic mice in response to this LPS dose. Our results demonstrate that direct endothelial activation is sufficient to mediate leukocyte rolling and adhesion in cerebral microvessels but not sufficient for emigration to brain parenchyma.

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Authors: Zhou, H., Andonegui, G., Wong, C. H. Y., & Kubes, P.
Affiliations: University of Calgary (CA)
ORCID: Zhou, Hong
Andonegui, Graciela
Wong, Connie H Y
Kubes, Paul
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2009-10
Volume: 183
Issue: 8
Pages: 5244-5250
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.0901309
OpenAlex: W2128021781
Cited by: 174
References: 27
Citations by year: 2026: 4 · 2025: 6 · 2024: 11 · 2023: 7 · 2022: 12 · 2021: 13 · 2020: 12 · 2019: 7 · 2018: 12 · 2017: 12 · 2016: 14 · 2015: 14 · 2014: 3 · 2013: 17 · 2012: 12
FWCI: 6.39
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: neutrophil recruitment, cerebral microvasculature, systemic inflammation, sepsis, septic shock, leukocyte rolling and adhesion, postcapillary venules, LPS, TNF-α, IL-1β, CXCR2, microglia, chimeric mice, TLR4 knockout mice
MeSH terms: Animals, Brain, Cell Adhesion, Cell Movement, Central Nervous System, Encephalitis, Endothelium, Vascular, Lipopolysaccharides, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Tumor Necrosis Factor-alpha, Mice, Knockout, Lipopolysaccharide Receptors, P-Selectin, Neutrophil Infiltration, Receptors, Interleukin-8B, Toll-Like Receptor 4, Mice, Interleukin-1beta, Chemokine CXCL1, Chemokine CXCL2, Microvessels

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Role of Endothelial TLR4 for Neutrophil Recruitment into Central Nervous System Microvessels in Systemic Inflammation

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