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Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2).
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (3), pp. e33044. Date of Electronic Publication: 2012 Mar 27. - Publication Year :
- 2012
-
Abstract
- 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.
- Subjects :
- Acute Radiation Syndrome etiology
Acute Radiation Syndrome metabolism
Animals
Bacterial Proteins metabolism
Biomimetic Materials chemical synthesis
Biomimetic Materials pharmacology
Bone Marrow drug effects
Bone Marrow pathology
Bone Marrow radiation effects
Cytokines blood
Dose-Response Relationship, Radiation
Female
Granulocyte Colony-Stimulating Factor blood
HEK293 Cells
Hematopoietic System radiation effects
Humans
Kaplan-Meier Estimate
Lipopeptides chemical synthesis
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred ICR
Mice, Knockout
Mycoplasma metabolism
Spleen drug effects
Spleen pathology
Spleen radiation effects
Thrombocytopenia etiology
Thrombocytopenia prevention & control
Time Factors
Toll-Like Receptor 2 genetics
Toll-Like Receptor 2 metabolism
Whole-Body Irradiation adverse effects
Acute Radiation Syndrome prevention & control
Hematopoietic System drug effects
Lipopeptides pharmacology
Toll-Like Receptor 2 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22479357
- Full Text :
- https://doi.org/10.1371/journal.pone.0033044