| First Author | Diamond T | Year | 2022 |
| Journal | PLoS One | Volume | 17 |
| Issue | 6 | Pages | e0269553 |
| PubMed ID | 35671274 | Mgi Jnum | J:327521 |
| Mgi Id | MGI:7285579 | Doi | 10.1371/journal.pone.0269553 |
| Citation | Diamond T, et al. (2022) Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-gamma in a predominantly hepatic-intrinsic manner. PLoS One 17(6):e0269553 |
| abstractText | 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-gamma 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 non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44hi CD62Llo) (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. |
