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Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides
The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation res...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610686/ https://www.ncbi.nlm.nih.gov/pubmed/23555964 http://dx.doi.org/10.1371/journal.pone.0060388 |
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author | Hines, Dustin J. Choi, Hyun B. Hines, Rochelle M. Phillips, Anthony G. MacVicar, Brian A. |
author_facet | Hines, Dustin J. Choi, Hyun B. Hines, Rochelle M. Phillips, Anthony G. MacVicar, Brian A. |
author_sort | Hines, Dustin J. |
collection | PubMed |
description | The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would prevent downstream immune signaling in the brain and suppress the induction of sickness behavior. We used interfering peptides to block TLR4 activation and confirmed their efficacy in preventing second messenger activation and cytokine production normally induced by LPS treatment. Further, these peptides blocked morphological changes in microglia that are typically induced by LPS. We also demonstrated that intraperitoneal (i.p.) injection of Tat-TLR4 interfering peptides prevented LPS-induced sickness behavior, as assessed in home cage behavior and with the intracranial self-stimulation paradigm. These newly synthesised peptides inhibit TLR4 signaling thereby preventing changes in behavior and motivation caused by inflammatory stimuli. These peptides highlight the roll of TLR4 and microglia morphology changes in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies. |
format | Online Article Text |
id | pubmed-3610686 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36106862013-04-03 Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides Hines, Dustin J. Choi, Hyun B. Hines, Rochelle M. Phillips, Anthony G. MacVicar, Brian A. PLoS One Research Article The innate immune receptor Toll-like 4 (TLR4) is the receptor activated by lipopolysaccharide (LPS), and TLR4-LPS interaction is well known to induce an innate immune response, triggering sickness behavior. Within the brain, TLR4 is highly expressed in brain microglia, and excessive inflammation resulting from activation of this pathway in the brain has been implicated in depressive disorders and neurodegenerative pathologies. We hypothesized that blocking LPS-induced activation of TLR4 would prevent downstream immune signaling in the brain and suppress the induction of sickness behavior. We used interfering peptides to block TLR4 activation and confirmed their efficacy in preventing second messenger activation and cytokine production normally induced by LPS treatment. Further, these peptides blocked morphological changes in microglia that are typically induced by LPS. We also demonstrated that intraperitoneal (i.p.) injection of Tat-TLR4 interfering peptides prevented LPS-induced sickness behavior, as assessed in home cage behavior and with the intracranial self-stimulation paradigm. These newly synthesised peptides inhibit TLR4 signaling thereby preventing changes in behavior and motivation caused by inflammatory stimuli. These peptides highlight the roll of TLR4 and microglia morphology changes in sickness behavior, and thus may be of therapeutic value in limiting the deleterious impact of excessive inflammation in specific CNS pathologies. Public Library of Science 2013-03-28 /pmc/articles/PMC3610686/ /pubmed/23555964 http://dx.doi.org/10.1371/journal.pone.0060388 Text en © 2013 Hines et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hines, Dustin J. Choi, Hyun B. Hines, Rochelle M. Phillips, Anthony G. MacVicar, Brian A. Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title | Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title_full | Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title_fullStr | Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title_full_unstemmed | Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title_short | Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides |
title_sort | prevention of lps-induced microglia activation, cytokine production and sickness behavior with tlr4 receptor interfering peptides |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610686/ https://www.ncbi.nlm.nih.gov/pubmed/23555964 http://dx.doi.org/10.1371/journal.pone.0060388 |
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