A Toll-like Receptor 5 agonist entolimod mitigates radiation damage through a neutrophil-dependent mechanism

Abstract

Abstract The increased risk of exposure to life-threating nuclear and radiation emergencies warrants the development of FDA-approved medical radiation countermeasures (MRC) as radio mitigators, which can be used after exposure to total body irradiation. Currently, Neupogen and Neulasta are the only FDA-approved radio mitigators but are unfortunately limited by adverse side effects and the need for additional medical supportive care. Bacterial flagellin, the natural agonist of Toll-like receptor (TLR) 5, and apharmacologically optimized derivative entolimod developed by us have powerful activity as a single agent MRC in rodents and non-human primates. Currently entolimod is being developed as a MRC under the FDA’s Animal Efficacy Rule, which guides development of drugs for which efficacy testing in humans would be unethical. The lack of induction of cytokine storm post systemically administered entolimod was demonstrated in rodents, non-human primates, and Phase I clinical trials involving nearly 200 subjects. Entolimod stimulates TLR5 on hepatocytes followed by activation of immunoregulatory signaling pathways, production of pro-inflammatory cytokines, and rapid recruitment of immune cells to the liver. Neutrophils are among the first immune cells that are rapidly recruited to both non-lymphoid and lymphoid tissues post-entolimod. We found that this entolimod-elicited neutrophil response was essential to mitigating radiation damage by promoting the recovery of hematopoietic stem cells in the bone marrow. This work underscores the underappreciated importance of TLR5-elicited neutrophils in promoting there generation of hematopoiesis following total body irradiation.