Project Summary/Abstract Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal disorder associated with anemia, thrombocytopenia, and leukopenia and systemic hyperinflammation. Secondary HLH can be triggered by a range of diseases, including infections, cancer, or rheumatic disease. When triggered by rheumatic disease, it is often referred to as macrophage activation syndrome (MAS). HLH/MAS involves a hyperinflammatory response in which activated macrophages phagocytose red blood cells, white blood cells and platelets. Research in the Hamerman lab has revealed a critical role for cell-intrinsic Toll-like receptor (TLR) 7 signaling in the development of inflammatory hemophagocytes, a monocyte-derived macrophage that drives HLH/MAS in a mouse model. IRF5, which mediates TLR7 signaling in monocytes, contributes to differentiation of these hemophagocytes in the mouse although the signals driving differentiation of these cells in humans are unknown. This application aims to elucidate the role of IRF5 in the development of inflammatory hemophagocytes in both mice (Aim 1) and humans (Aim 2) and to further define the mechanism of cells of the monocyte lineage in cytokine storm syndromes. The proposed research will result in a better understanding of the role of myeloid cells in secondary HLH and may provide novel therapeutic targets or approaches. The fellowship training will take place at the Benaroya Research Institute, which focuses on understanding immune-mediated diseases, under the guidance of Dr. Jessica Hamerman and Dr. Jane Buckner. The training plan described in the supporting documents will provide essential steps toward preparing me for a career as an independent scientist. At the completion of my postdoctoral training, I will be able to transition to independence as a physician scientist.