Mechanisms of Radiation-Induced Innate Immune Dysfunction and Its Countermeasures

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PROJECT DESCRIPTION: Nuclear power plant accidents, terrorism, and geopolitical instability present the risk of massive radiation exposure. As neutrophils markedly decline post-radiation exposure, macrophages assume the important role of removing most translocated or invading bacteria. However, very few studies have evaluated the effects of radiation on the phagocytic function of differentiated, non-dividing tissue resident macrophages. We have discovered that extracellular cold-inducible RNA-binding protein (eCIRP) is a novel mediator which can cause innate immune dysfunction. In our preliminary studies, we have shown an increased release of eCIRP after radiation exposure in vivo and in vitro. Deficiency in CIRP improved the survival of mice subjected to total body irradiation (TBI). Sepsis significantly worsened the survival post-TBI, but CIRP-/- mice had lower bacterial loads and improved survival after sepsis, suggesting that eCIRP’s detrimental effect may be due to the impaired bacterial clearance. Indeed, eCIRP significantly reduced macrophage phagocytosis of E. coli via cytoskeletal paralysis. eCIRP also induced the formation of macro- phage extracellular traps, and extracellular traps reduced macrophage phagocytosis of dying cells. We have identified that triggering receptor expressed on myeloid cells-1 (TREM-1) is the eCIRP receptor, and that TREM-1 activation plays a critical role in the eCIRP-mediated macrophage phagocytic dysfunction. Moreover, the 30-day survival after TBI was significantly improved in TREM-1-/- mice. Based on these novel findings, we hypothesize that eCIRP released after ionizing radiation activates TREM-1, resulting in macrophage phagocytic dysfunction and ultimately leading to sepsis and death. We have also shown that the new inhibitor M3 reduced eCIRP’s binding to TREM-1 and improved survival after sepsis. As such, we further hypothesize that inhibition of eCIRP/TREM-1 interaction with M3 restores macrophage phagocytic function, thereby improving the survival of mice subjected to radiation injury alone or complicated by sepsis. In this project, we plan to further establish the critical role of eCIRP on radiation-induced macrophage phagocytic dysfunction, determine the mechanisms by which eCIRP causes macrophage phagocytic dysfunction, and develop M3 as a novel radiation medical countermeasure targeting eCIRP-induced macrophage phagocytic dysfunction. These studies shall provide novel mechanistic insights into the pathogenesis of radiation-induced innate immune dysfunction, as well as a new medical countermeasure for victims of major radiation exposure with or without sepsis.