Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of toll-like receptor 2 (TLR2)

Alexander N. Shakhov, Vijay K. Singh, Frederick Bone, Alec Cheney, Yevgeniy Kononov, Peter Krasnov, Troitza K. Bratanova-Toshkova, Vera V. Shakhova, Jason Young, Michael M. Weil, Angela Panoskaltsis-Mortari, Christie Orschell, Patricia S. Baker, Andrei Gudkov, Elena Feinstein

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere33044
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 27 2012

Fingerprint

Acute Radiation Syndrome
lipopeptides
Lipopeptides
Toll-Like Receptor 2
agonists
Radiation
mice
granulocyte colony-stimulating factor
cytokines
Whole-Body Irradiation
irradiation
Bone Marrow
Irradiation
Granulocyte Colony-Stimulating Factor
Cytokines
lipoproteins
bone marrow
Lipoproteins
Bone
Toll-like receptor 2

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Shakhov, A. N., Singh, V. K., Bone, F., Cheney, A., Kononov, Y., Krasnov, P., ... Feinstein, E. (2012). Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of toll-like receptor 2 (TLR2). PLoS One, 7(3), [e33044]. https://doi.org/10.1371/journal.pone.0033044

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; Baker, Patricia S.; Gudkov, Andrei; Feinstein, Elena.

In: PLoS One, Vol. 7, No. 3, e33044, 27.03.2012.

Research output: Contribution to journalArticle

Shakhov, AN, Singh, VK, Bone, F, Cheney, A, Kononov, Y, Krasnov, P, Bratanova-Toshkova, TK, Shakhova, VV, Young, J, Weil, MM, Panoskaltsis-Mortari, A, Orschell, C, Baker, PS, Gudkov, A & Feinstein, E 2012, 'Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of toll-like receptor 2 (TLR2)', PLoS One, vol. 7, no. 3, e33044. https://doi.org/10.1371/journal.pone.0033044
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 ; 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). In: PLoS One. 2012 ; Vol. 7, No. 3.
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AU - Panoskaltsis-Mortari, Angela

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