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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901309v1 183/8/5244    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zhou, H. Articles by Kubes, P. PubMed PubMed Citation Articles by Zhou, H. Articles by Kubes, P. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Encephalitis

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

Immunology Research Group, Department Physiology and Biophysics, University of Calgary, NW Calgary, Alberta, Canada

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- and IL-1β were detected in the plasma after LPS injection but a different profile (IL-1β but not TNF-) 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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¹ Address correspondence and reprint requests to Dr. Paul Kubes, Immunology Research Group, Department Physiology and Biophysics, University of Calgary, 3330 Hospital Drive, NW Calgary, Alberta, T2N 4N1 Canada. E-mail address: pkubes{at}ucalgary.ca

² Abbreviations used in this paper: BBB, blood-brain barrier; WT, wild type.