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Response to Lipopolysaccharide Leukocyte Recruitment Into Brain In A Requirement for Microglial TLR4 in Leukocyte Recruitment into Brain in Response to Lipopolysaccharide This information is current as Hong Zhou, Benoît M. Lapointe, Stephen R. Clark, Lori of October 1, 2021. Zbytnuik and Paul Kubes J Immunol 2006; 177:8103-8110; ; doi: 10.4049/jimmunol.177.11.8103 http://www.jimmunol.org/content/177/11/8103 Downloaded from References This article cites 47 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/177/11/8103.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology A Requirement for Microglial TLR4 in Leukocyte Recruitment into Brain in Response to Lipopolysaccharide Hong Zhou, Benoıˆt M. Lapointe, Stephen R. Clark, Lori Zbytnuik, and Paul Kubes1 To study the mechanisms involved in leukocyte recruitment induced by local bacterial infection within the CNS, we used intravital microscopy to visualize the interaction between leukocytes and the microvasculature in the brain. First, we showed that intra- cerebroventricular injection of LPS could cause significant rolling and adhesion of leukocytes in the brain postcapillary venules of wild-type mice, while negligible recruitment was observed in TLR4-deficient C57BL/10ScCr mice and CD14 knockout mice, suggesting recruitment is mediated by TLR4/CD14-bearing cells. Moreover, we observed reduced but not complete inhibition of recruitment in MyD88 knockout mice, indicating both MyD88-dependent and -independent pathways are involved. The leukocyte recruitment responses in chimeric mice with TLR4-positive microglia and endothelium, but TLR4-negative leukocytes, were com- parable to normal wild-type mice, suggesting either endothelium or microglia play a crucial role in the induction of leukocyte recruitment. LPS injection induced both microglial and endothelial activation in the CNS. Furthermore, minocycline, an effective Downloaded from inhibitor of microglial activation, completely blocked the rolling and adhesion of leukocytes in the brain and blocked TNF-␣ production in response to LPS in vivo. Minocycline did not affect activation of endothelium by LPS in vitro. TNFR p55/p75 double knockout mice also exhibited significant reductions in both rolling and adhesion in response to LPS, indicating TNF-␣ signaling is critical for the leukocyte recruitment. Our results identify a TLR4 detection system within the blood-brain barrier. The microglia play the role of sentinel cells detecting LPS thereby inducing endothelial activation and leading to efficient leukocyte recruitment to the CNS. The Journal of Immunology, 2006, 177: 8103–8110. http://www.jimmunol.org/ e have known for many years that the brain is “im- peripheral cells, including macrophages, which release cytokines mune privileged” in as much as foreign tissue grafts and other proinflammatory molecules that may impinge upon the W transplanted into the brain have significantly extended CNS. This is best exemplified by a clear activation of brain-resi- survival (1). This suggests that the immune system has restricted dent microglia when LPS is given i.p. (10). In addition, there is access to the brain (2). Although this immune compromise makes strong evidence to suggest direct activation of microglia by LPS. perfect sense from the perspective of trying to prevent collateral TLR4 is predominately expressed on microglia but not oligoden- damage in the brain in response to various insults, there are in- drocytes or neurons (11) and microglia exposed to LPS in vitro by guest on October 1, 2021 stances when very robust innate immune responses occur in the have been shown to be potently activated to release IL-1␤, TNF-␣, CNS, particularly in response to various cerebral bacterial infec- and various other proinflammatory molecules (12). More recently, tions (3–5). A disruption of this delicate balance between infection a number of studies attempting to mimic local cerebral inflamma- and inflammation is best exemplified by bacterial meningitis, tion have delivered LPS via intracerebroventricular (i.c.v.)2 ad- wherein the response is so profound it not only destroys the patho- ministration and detected robust cytokine and chemokine increases gen but often also causes profound tissue injury (6). In addition, within the brain tissue and more specifically in microglia (13). there is a growing body of evidence that susceptibility, progres- These studies suggest that microglia are sentinel cells within the sion, and relapse in chronic CNS diseases is closely associated brain, poised to detect infectious molecules causing a rapid robust with a systemic immune response to nonspecific infection (7). In- local response. deed, multiple sclerosis, neurodegenerative diseases such as Alz- The mechanism of neutrophil recruitment into the brain in re- heimer’s disease, prion-related diseases, and various other cerebral sponse to local LPS remains poorly understood due to limitations diseases may be activated, reactivated, or expedited by infection in the ability to detect neutrophil recruitment into the CNS and the and more importantly by the innate immune response to infection lack of an easy way to block microglial function. To date, a mi- (8–10). Clearly, a local inflammatory response in the CNS or a croglia-deficient mouse does not exist, and the macrophage-defi- systemic inflammatory response to a peripheral infection can have cient op/op mice have only a 30% reduction in microglia (14). In devastating effects in the brain. the last few years, a novel microglial inhibitor was identified. In Administering the prototypical TLR4 ligand, LPS, i.p. to mice 1998, Yrjanheikki et al. (15) reported that minocycline, a tetracy- reveals evidence of brain inflammation, partly via activation of cline derivative, has potent inhibitory functions in microglial ac- tivation and in brain inflammation. This has been confirmed and extended by more than 60 studies in the last 5 years. Most impor- Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary NW, Alberta, Canada tantly, the drug may have efficacy in human CNS disease (16) Received for publication July 3, 2006. Accepted for publication September 8, 2006. further underscoring the importance of understanding the mecha- The costs of publication of this article were defrayed in part by the payment of page nisms of action of this drug in brain inflammation. charges. This article must therefore be hereby marked advertisement in accordance In this study, we systematically examined neutrophil recruit- with 18 U.S.C. Section 1734 solely to indicate this fact. ment into the CNS in response to local LPS administration. We 1 Address correspondence and reprint requests to Dr. Paul Kubes, Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive, Calgary NW, Alberta, Canada, T2N 4N1. E-mail address: 2 Abbreviation used in this paper: i.c.v., intracerebroventricular; Toll/IL-1 receptor [email protected] domain-containing adapter inducing IFN-␤. Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 8104 LPS-INDUCED LEUKOCYTE RECRUITMENT IN THE BRAIN used intravital microscopy to directly visualize the behavior of the tion was used to count all infiltrated neutrophils. Neutrophils found in the leukocytes in the brain microvasculature. Using various knockout ventricles or meninges were not counted. mice as well as making chimeric mice expressing the LPS receptor on bone marrow-derived or non-bone marrow-derived cells, we Dual-radiolabeled Ab assay for P-selectin expression identified that microglia as well as cerebral endothelial cells were P-selectin expression was quantified in the brains of saline- or LPS-injected activated in response to local LPS. We also determined that mi- mice as previously described (20). Briefly, a mixture of 10 ␮gof125I- 131 nocycline, an established microglial inhibitor, blocked leukocyte labeled anti-P-selectin (RB40.34) and a dose of I-labeled nonbinding Ab (A110-1, anti-keyhole limpet hemocyanin) calculated to achieve a total 131I recruitment in an unprecedented fashion (as effectively as TLR4 activity of 4–6 ϫ 105 cpm were injected i.v. through the jugular vein. The deficiency) in response to intracerebral LPS primarily by blocking Abs were allowed to circulate for 5 min. The mouse was then perfused with production of TNF-␣ in microglia. Clearly, microglia play a dom- saline through the jugular vein to remove all circulating blood. Tissues inant role in the innate immune response to infectious agents in the were harvested, weighed, and measured for 125I and 131I activity. P-selectin 131 CNS and minocycline may be able to attenuate or dampen this
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