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

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.

Lactobacillus rhamnosusGG protects the intestinal epithelium from radiation injury through release of lipoteichoic acid, macrophage activation and the migration of mesenchymal stem cells

“…Here again the likely explanation is that LGG is confined to the intestinal lumen and the bone marrow would not be exposed to LGG or LTA. TLR2 activation can induce radioprotection in the bone marrow as previously demonstrated by parenteral administration of the synthetic TLR2 agonist PAM3-CSK422; however, in this study it was not clear which cells were responding to the PAM3-CSK4.…”

“…To determine if LGG-CM contains a TLR2 agonist, we incubated HEK-Blue cells expressing TLR2 and HEK-Blue null cells with media, LGG-CM or PAM3-CSK4, a synthetic TLR2 agonist 22. Incubation of HEK-Blue cells expressing TLR2 with LGG-CM resulted in NFκB activation indicating that LGG-CM contains a TLR2 agonist (figure 1A).…”

Colony-stimulating factors for the treatment of the hematopoietic component of the acute radiation syndrome (H-ARS): A review

“…These new countermeasures include agents such as 5-androstenediol (5-AED/Neumune Ò ) [24,25], CBLB502 (truncated flagellin: Entolimod™) [26], CBLB612 and CBLB613 (both lipopeptides of mycoplasma origin) [27,28], vitamin E isomers and their derivatives (d-tocotrienol [29,30], c-tocotrienol [31], and a-tocopherol succinate [32,33]). Further, we have demonstrated in mice, that the administration of a G-CSF antibody completely abrogates the radioprotective efficacy of some radiation countermeasures (e.g., Fig.…”

Radiation takes its Toll

“…A TLR5 agonist derived from flagellin for instance can protect mice and nonhuman primates from both gastrointestinal and hematological toxicity when given before 8–13Gy whole body irradiation (WBI) with the liver being the central coordinator of this response [87–89]. Driving TLR 2, 3, 4 and 9 has similar radioprotective effects [70, 90–92] and TLR 2, 4, 5 and 9 signaling can also trigger mitigation, post radiation exposure [70, 88, 92–94] all within the range of 4.5–13Gy of WBI, depending on the experimental model and the end-point investigated. Whether or not the mechanisms behind radiation protection are identical to the ones that confer mitigation is not entirely clear but chemical library screening suggests this is not necessarily the case [95, 96].…”