Myeloid reprogramming in response to acute radiation tissue damage

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We have discovered the striking emergence of a novel subpopulation of myeloid cells after whole body and local irradiation that expresses both granulocytic (Ly6G) and monocytic (Ly6C) lineage markers at high levels. This immature phenotype is not normally evident in peripheral organs at baseline but is mobilized from bone marrow myeloerythroid progenitor cells. Their phenotype suggests that they may be granulocyte-derived myeloid suppressor cells, as does their co-expression of PDL-1, PD-1, and CD39. We hypothesize that they are an endogenous mechanism to minimize collateral damage from radiation-induced tissue damage and inflammation. Importantly, depletion of this subset increases vulnerability to hematopoietic acute radiation syndrome in mice and obliterates the action of radiation mitigator drugs that we have tested. Our goal is to illuminate the fate and function of these myeloid cells and the role they play in acute and chronic radiation tissue damage in animal models. We are mindful that myeloid cells tend to be exquisitely sensitive to rapidly changing environments and that their phenotype and function adapt accordingly; in keeping with the plasticity that is a hallmark of this lineage. Our hypothesis is that these cells sense and respond to damage- associated molecules and cytokines released in the aftermath of radiation exposure, that they feed back to the bone marrow driving self-sustaining loops of inflammation and myeloid lineage reprogramming which skews the immune balance away from lymphopoiesis and towards myelopoiesis. In the long term, persistent myeloid skewing affects hematopoiesis and perhaps function of other organs. The most likely culprit for mediating this rapid radiation-induced myeloid surge is IL-6, but other factors are probably important. We will pursue these avenues using a tool box of multi-color flow cytometry, Ly6G-depleting antibody, adoptive cell transfer and loss of function genetic mouse models that will allow us to finely dissect the role of this response in acute and late radiation damage. As part of the study, we will verify if these cells have inherent radiation mitigating capabilities. Finally, these cells persist systemically and probably contribute to delayed normal tissue and tumor responses to radiation therapy. We will therefore determine how they might shape persistent inflammatory states and immune dysfunction. With these studies we hope to gain a deeper understanding of the interactions between radiation tissue damage, immune responses and the recovery processes with the ultimate goal of reprogramming the myeloid system to better aid balanced normal tissue recovery after localized and whole body radiation exposures.