Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2)
| Autor: | Christie M. Orschell, Vera V. Shakhova, Vijay K. Singh, Troitza K. Bratanova-Toshkova, Peter Krasnov, Patricia Stanhope Baker, Alexander N. Shakhov, Yevgeniy Kononov, Alec Cheney, Michael M. Weil, Andrei V. Gudkov, Angela Panoskaltsis-Mortari, Elena Feinstein, Jason A. Young, Frederick Bone |
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| Rok vydání: | 2011 |
| Předmět: |
Time Factors
Anatomy and Physiology genetic structures lcsh:Medicine Kaplan-Meier Estimate Mice Mycoplasma Biomimetic Materials Bone Marrow Immune Physiology Granulocyte Colony-Stimulating Factor Receptor lcsh:Science Mice Knockout Toll-like receptor Mice Inbred BALB C Mice Inbred ICR Multidisciplinary Animal Models Granulocyte colony-stimulating factor Haematopoiesis medicine.anatomical_structure Acute Radiation Syndrome Cytokines Female Whole-Body Irradiation Research Article Hematopoietic System Immunology Biology Lipopeptides Model Organisms Downregulation and upregulation Bacterial Proteins medicine Animals Humans Innate immune system lcsh:R Immunity Radiobiology Dose-Response Relationship Radiation Thrombocytopenia eye diseases Toll-Like Receptor 2 Mice Inbred C57BL TLR2 HEK293 Cells Cancer research lcsh:Q Bone marrow sense organs Spleen |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 3, p e33044 (2012) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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