The TLR2/TLR6 ligand FSL-1 mitigates radiation- induced hematopoietic injury in mice and nonhuman primates

Thrombocytopenia, hemorrhage, anemia, and infection are life- threatening issues following accidental or intentional radiation exposure. Since few therapeutics are available, safe and efficacious small molecules to mitigate radiation- induced injury need to be developed. Our previous study showed the synthetic TLR2/TLR6 ligand fibroblast stimulating lipopeptide (FSL- 1) prolonged survival and provided MyD88- dependent mitigation of hematopoietic acute radiation syndrome (H- ARS) in mice. Although mice and humans differ in TLR number, expression, and function, nonhuman primate (NHP) TLRs are like those of humans; therefore, studying both animal models is critical for drug development. The objectives of this study were to determine the efficacy of FSL- 1 on hematopoietic recovery in small and large animal models subjected to sublethal total body irradiation and investigate its mechanism of action. In mice, we demonstrate a lack of adverse effects, an easy route of delivery (subcutaneous) and efficacy in promoting hematopoietic progenitor cell proliferation by FSL- 1. NHP given radiation, followed a day later with a single subcutaneous administration of FSL- 1, displayed no adversity but showed elevated hematopoietic cells. Our analyses revealed that FSL- 1 promoted red blood cell development and induced soluble effectors following radiation exposure. Cytologic analysis of bone marrow aspirates revealed a striking enhancement of mononuclear progenitor cells in FSL- 1- treated NHP. Combining the efficacy of FSL- 1 in promoting hematopoietic cell recovery with the lack of adverse effects induced by a single administration supports the application of FSL- 1 as a viable countermeasure against H- ARS.