Signaling through TLR5 mitigates lethal radiation damage by neutrophil-dependent release of MMP-9

Abstract

Acute radiation syndrome (ARS) is a major cause of lethality following radiation disasters. A TLR5 agonist, entolimod, is among the most powerful experimental radiation countermeasures and shows efficacy in rodents and non-human primates as a prophylactic (radioprotection) and treatment (radiomitigation) modality. While the prophylactic activity of entolimod has been connected to the suppression of radiation-induced apoptosis, the mechanism by which entolimod functions as a radiomitigator remains poorly understood. Uncovering this mechanism has significant and broad-reaching implications for the clinical development and improvement of TLR5 agonists for use as an effective radiation countermeasure in scenarios of mass casualty resulting from accidental exposure to ionizing radiation. Here, we demonstrate that in contrast to radioprotection, neutrophils are essential for the radiomitigative activity of entolimod in a mouse model of lethal ARS. Neutrophils express functional TLR5 and rapidly exit the bone marrow (BM), accumulate in solid tissues, and release MMP-9 following TLR5 stimulation which is accompanied by an increase in the number of active hematopoietic pluripotent precursors (HPPs) in the BM. Importantly, recombinant MMP-9 by itself has radiomitigative activity and, in the absence of neutrophils, accelerates the recovery of the hematopoietic system. Unveiling this novel TLR5-neutrophil-MMP-9 axis of radiomitigation opens new opportunities for the development of efficacious radiation countermeasures to treat ARS following accidental radiation disasters.

Population structure, genetic diversity and prolificacy in pishan red sheep under an extreme desert environment

“…PRS live in desert environments, and after natural and artificial selection, it forms the characteristics of perennial estrus and the early onset of puberty. TLR5 can effectively alleviate the stimulation caused by radiation ( Brackett et al, 2021 ), and SOX10 independently regulates the expression of IRF1 in melanoma through the JAK-STAT signaling pathway ( Yokoyama et al, 2021 ). ATP6V0A can affect fetal brain development ( Aoto et al, 2021 ).…”