TLR2/6 agonist treatment after total body irradiation in mice and nonhuman primates induces proliferation of hematopoietic progenitor cells

Abstract

Abstract Exposure to high doses of radiation, whether intentional or accidental, may cause injury or death. Therapeutics are urgently needed for mitigating injuries caused by radiation exposure. Previously, we identified a synthetic lipopeptide agonist of TLR2/6, namely fibroblast-stimulating lipopeptide (FSL-1), that prolonged survival of mice exposed to lethal ionizing radiation and mitigated hematopoietic acute radiation syndrome. Here, this agent was tested in several mouse models as well as in nonhuman primates given total body irradiation followed 24 hours later with a single subcutaneous injection of FSL-1. These studies revealed the mitigation of radiation-induced loss of platelets and red blood cells, as well as the promotion of bone marrow progenitor cell recovery. These beneficial hematopoietic outcomes were accompanied with a lack of toxicity, showcasing the safe, efficacious application of a single dose of FSL-1 for mitigating hematopoietic dysfunction resulting from radiation. By investigating the mechanism of action of FSL-1 in response to radiation, we confirmed that FSL-1 radio-mitigation activity was mediated through a TLR2/MyD88-dependent process. In FSL-1 treated irradiated mice, we found enhanced numbers of proliferating Ki67 +bone marrow cells. Finally, examination of cellular pathways in mice and nonhuman primate bone marrow cells indicated FSL-1 induced the activation of NF-kB and MAPK signaling. These data suggest that FSL-1 promotes hematopoietic progenitor cell proliferation through the activation of cell survival and activation pathways downstream of TLR2/6 stimulation, and thus may serve to mitigate the injurious consequences of radiation. Supported by grants from NIH (AI067798) and DOD Congressionally Directed Medical Research Program grant W81XWH-15-1-0574 (JMC).