Interferon-γ Mediates Anemia but Is Dispensable for Fulminant Toll-like Receptor 9-Induced Macrophage Activation Syndrome and Hemophagocytosis in Mice

ObjectiveMacrophage activation syndrome (MAS) is a devastating cytokine storm syndrome complicating many inflammatory diseases and characterized by fever, pancytopenia, and systemic inflammation. It is clinically similar to hemophagocytic lymphohistiocytosis (HLH), which is caused by viral infection of a host with impaired cellular cytotoxicity. Murine models of MAS and HLH illustrate that interferon- (IFN) is the driving stimulus for hemophagocytosis and immunopathology. This study was undertaken to investigate the inflammatory contributors to a murine model of Toll-like receptor 9 (TLR-9)-induced fulminant MAS. MethodsWild-type, transgenic, and cytokine-inhibited mice were treated with an IL-10 receptor blocking antibody and a TLR-9 agonist, and parameters of MAS were evaluated. ResultsFulminant MAS was characterized by dramatic elevations in IFN, IL-12, and IL-6 levels. Increased serum IFN levels were associated with enhanced IFN production within some hepatic cell populations but also with decreased numbers of IFN-positive cells. Surprisingly, IFN-knockout mice developed immunopathology and hemophagocytosis comparable to that seen in wild-type mice. However, IFN-knockout mice did not become anemic and had greater numbers of splenic erythroid precursors. IL-12 neutralization phenocopied disease in IFN-knockout mice. Interestingly, type I IFNs contributed to the severity of hypercytokinemia and weight loss, but their absence did not otherwise affect MAS manifestations. ConclusionThese data demonstrate that both fulminant MAS and hemophagocytosis can arise independently of IFN, IL-12, or type I IFNs. They also suggest that IFN-mediated dyserythropoiesis, not hemophagocytosis, is the dominant cause of anemia in fulminant TLR-9-induced MAS. Thus, our data establish a novel mechanism for the acute anemia of inflammation, but suggest that a variety of triggers can result in hemophagocytic disease.