Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-gamma in a predominantly hepatic-intrinsic manner

Interferon gamma (IFN-gamma) is the main cytokine driving organ dysfunction in Familial Hemophagocytic Lymphohistiocytosis (FHL). Blockade of IFN-gamma pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-gamma receptor (IFN-gamma-R). However, whether IFN-y induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a IFNgR(-/-) bone marrow chimeric model, this study showed that non-hematopoietic IFN-gamma response is critical for development of FHL hepatitis in LCMV-infected Prf1(-/-) mice. Lack of hepatic IFN-gamma responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-gamma nonhematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44(hi) CD62L(io)) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-gamma response results in increased hepatic transcription of type 1 immune response and oxidative stress response pathways, while decreasing transcription of genes involved in extracellular matrix (ECM) production. In summary, these findings demonstrate that there is a hepatic transcriptional response to IFN-gamma, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.