The Toll\u2013Like Receptor 2/6 Agonist, FSL\u20131 Lipopeptide, Therapeutically Mitigates Acute Radiation Syndrome

Cathryn J Kurkjian,Nathan D Montgomery,Ning Cheng,Hao Guo,Hong Yuan,Jenny P.-Y Ting,Joseph R Merrill,Gregory D Sempowski,W June Brickey

doi:10.1038/s41598-017-17729-9

Cathryn J Kurkjian, Nathan D Montgomery + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-17729-9

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Abstract

Risks of radiation exposure from nuclear incidents and cancer radiotherapy are undeniable realities. These dangers urgently compel the development of agents for ameliorating radiation–induced injuries. Biologic pathways mediated by myeloid differentiation primary response gene 88 (MyD88), the common adaptor for toll–like receptor (TLR) and Interleukin–1 receptor signaling, are critical for radioprotection. Treating with agonists prior to radiation enhances survival by activating TLR signaling, whereas radiomitigating TLR–activating therapeutics given after exposure are less defined. We examine the radiomitigation capability of TLR agonists and identify one that is superior for its efficacy and reduced toxic consequences compared to other tested agonists. We demonstrate that the synthetic TLR2/6 ligand Fibroblast–stimulating lipopeptide (FSL–1) substantially prolongs survival in both male and female mice when administered 24 hours after radiation and shows MyD88–dependent function. FSL–1 treatment results in accelerated hematopoiesis in bone marrow, spleen and periphery, and augments systemic levels of hematopoiesis–stimulating factors. The ability of FSL–1 to stimulate hematopoiesis is critical, as hematopoietic dysfunction results from a range of ionizing radiation doses. The efficacy of a single FSL–1 dose for alleviating radiation injury while protecting against adverse effects reveals a viable radiation countermeasures agent.

Highlights

Replenishment of hematopoietic sites is critical for recovery following radiation exposure
This study focuses on elucidating the radiomitigation effects of FSL–1, a different class of toll–like receptor (TLR) ligand that activates TLR2/6, and understanding its role in improving hematopoietic responses associated with ARS, thereby demonstrating capacity to function as medical countermeasures against radiation
To examine the role of TLR ligands as radiomitigators, C57BL/6 mice were exposed to ionizing gamma radiation (9.2 Gy) from a cesium source, followed by administration of TLR ligands via intraperitoneal (i.p.) injections one day after radiation

Summary

Introduction

Replenishment of hematopoietic sites is critical for recovery following radiation exposure. Since the seminal articles reported the unexpected finding that the TLR5 agonist flagellin provides radioprotection[13,14], other TLR ligands have been tested as radioprotectors through administration prior to partial or total body irradiation In most cases, these studies demonstrated improved survival and protection, with accelerated hematopoiesis and/or inhibition of apoptosis within the GI tract[13,15,16,17,18,19]. We determine that a single administration of FSL–1 positively impacts hematopoiesis and induces G–CSF production following acute radiation injury Overall, these data reveal that the immune stimulatory effects of FSL–1 mitigate radiation injury by accelerating hematopoietic recovery at multiple sites following radiation exposure and promoting survival. This report illuminates the benefits of FSL–1 as a potential therapeutic for victims of radiation exposure by nuclear incidents as well as for patients receiving radiotherapy

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