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

机译：Toll样受体2（TLR2）的合成脂肽激动剂对小鼠急性辐射综合症的预防和缓解。

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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.
机译：细菌脂蛋白（BLP）通过激活包含Toll样受体2（TLR2）的异二聚体受体复合物，在哺乳动物中诱导先天免疫应答。 TLR2信号传导导致抗凋亡因子，抗氧化剂和细胞因子的核因子-κB（NF-κB）依赖性上调，所有这些都与辐射防护有关。在这里，我们证明了模拟天然存在的支原体BLP结构的合成脂肽（sLP）在辐射前48小时至辐射后24小时之间给予致命的全身辐射（TBI）后，可显着提高小鼠存活率。 sLP有效的TBI剂量范围表明sLP主要影响急性放射综合症的造血（HP）成分。确实，sLP治疗加速了受辐照小鼠的骨髓（BM）和脾细胞的恢复，并改善了血小板减少症。 sLP不能提高照射的TLR2基因敲除小鼠的存活率，证实sLP介导的放射防护需要TLR2。但是，sLP在野生型背景上含有TLR2无BM的嵌合小鼠中具有放射防护能力，这表明sLP对HP系统的放射防护至少部分是间接的，并且是在非BM细胞中引发的。 sLP注射导致强烈瞬时诱导多种在造血中具有已知作用的细胞因子，包括粒细胞集落刺激因子（G-CSF），角质形成细胞趋化因子（KC）和白介素6（IL-6）。 sLP诱导的细胞因子，特别是G-CSF，可能是sLP辐射防护/缓解活性的介质。这项研究说明了基于LP的TLR2激动剂在国防和医学领域的抗辐射预防和治疗方面的强大潜力。

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