Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of...

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Main Authors: Shakhov, Alexander N., Singh, Vijay K., Bone, Frederick, Cheney, Alec, Kononov, Yevgeniy, Krasnov, Peter, Bratanova-Toshkova, Troitza K., Shakhova, Vera V., Young, Jason, Weil, Michael M., Panoskaltsis-Mortari, Angela, Orschell, Christie M., Baker, Patricia S., Gudkov, Andrei, Feinstein, Elena
Format: Online
Language:English
Published: Public Library of Science 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314012/
id pubmed-3314012
recordtype oai_dc
spelling pubmed-33140122012-04-04 Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2) Shakhov, Alexander N. Singh, Vijay K. Bone, Frederick Cheney, Alec Kononov, Yevgeniy Krasnov, Peter Bratanova-Toshkova, Troitza K. Shakhova, Vera V. Young, Jason Weil, Michael M. Panoskaltsis-Mortari, Angela Orschell, Christie M. Baker, Patricia S. Gudkov, Andrei Feinstein, Elena Research Article Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios. Public Library of Science 2012-03-27 /pmc/articles/PMC3314012/ /pubmed/22479357 http://dx.doi.org/10.1371/journal.pone.0033044 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Shakhov, Alexander N.
Singh, Vijay K.
Bone, Frederick
Cheney, Alec
Kononov, Yevgeniy
Krasnov, Peter
Bratanova-Toshkova, Troitza K.
Shakhova, Vera V.
Young, Jason
Weil, Michael M.
Panoskaltsis-Mortari, Angela
Orschell, Christie M.
Baker, Patricia S.
Gudkov, Andrei
Feinstein, Elena
spellingShingle Shakhov, Alexander N.
Singh, Vijay K.
Bone, Frederick
Cheney, Alec
Kononov, Yevgeniy
Krasnov, Peter
Bratanova-Toshkova, Troitza K.
Shakhova, Vera V.
Young, Jason
Weil, Michael M.
Panoskaltsis-Mortari, Angela
Orschell, Christie M.
Baker, Patricia S.
Gudkov, Andrei
Feinstein, Elena
Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
author_facet Shakhov, Alexander N.
Singh, Vijay K.
Bone, Frederick
Cheney, Alec
Kononov, Yevgeniy
Krasnov, Peter
Bratanova-Toshkova, Troitza K.
Shakhova, Vera V.
Young, Jason
Weil, Michael M.
Panoskaltsis-Mortari, Angela
Orschell, Christie M.
Baker, Patricia S.
Gudkov, Andrei
Feinstein, Elena
author_sort Shakhov, Alexander N.
title Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
title_short Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
title_full Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
title_fullStr Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
title_full_unstemmed Prevention and Mitigation of Acute Radiation Syndrome in Mice by Synthetic Lipopeptide Agonists of Toll-Like Receptor 2 (TLR2)
title_sort prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of toll-like receptor 2 (tlr2)
description Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios.
publisher Public Library of Science
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314012/
_version_ 1611517260444205056

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