Hemophagocytosis causes a consumptive anemia of inflammation

Cytopenias of uncertain etiology are commonly observed in patients during severe inflammation. Hemophagocytosis, the histological appearance of blood-eating macrophages, is seen in the disorder hemophagocytic lymphohistiocytosis and other inflammatory contexts. Although it is hypothesized that these phenomena are linked, the mechanisms facilitating acute inflammation-associated cytopenias are unknown. We report that interferon gamma (IFN-gamma) is a critical driver of the acute anemia observed during diverse microbial infections in mice. Furthermore, systemic exposure to physiologically relevant levels of IFN-gamma is sufficient to cause acute cytopenias and hemophagocytosis. Demonstrating the significance of hemophagocytosis, we found that IFN-gamma acts directly on macrophages in vivo to alter endocytosis and provoke blood cell uptake, leading to severe anemia. These findings define a unique pathological process of broad clinical and immunological significance, which we term the consumptive anemia of inflammation.