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Blockade of IFN-\u03b3 pathway ameliorates FHL hepatitis, both in animal models and in humans with FHL. Hepatocytes are known to express IFN-\u03b3 receptor (IFN-\u03b3-R). However, whether IFN-\u03b3 induced hepatitis in FHL is a lymphocyte or liver intrinsic response to the cytokine has yet to be elucidated. Using a <jats:italic>IFNgR<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> bone marrow chimeric model, this study showed that non-hematopoietic IFN-\u03b3 response is critical for development of FHL hepatitis in LCMV-infected <jats:italic>Prf1<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Lack of hepatic IFN-\u03b3 responsiveness results in reduced hepatitis as measured by hepatomegaly, alanine aminotransferase (ALT) levels and abrogated histologic endothelial inflammation. In addition, IFN-\u03b3 non-hematopoietic response was critical in activation of lymphocytes by soluble interleukin 2 receptor (sIL-2r) and recruitment of CD8+ effector T lymphocytes (CD8+ CD44<jats:sup>hi<\/jats:sup> CD62L<jats:sup>lo<\/jats:sup>) (Teff) and inflammatory monocytes. Lastly, non-hematopoietic IFN-\u03b3 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-\u03b3, likely critical in the pathogenesis of FHL hepatitis and hepatic specific responses could be a therapeutic target in this disorder.<\/jats:p>","DOI":"10.1371\/journal.pone.0269553","type":"journal-article","created":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T17:30:04Z","timestamp":1654623004000},"page":"e0269553","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":10,"title":["Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-\u03b3 in a predominantly hepatic-intrinsic manner"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1904-5351","authenticated-orcid":true,"given":"Tamir","family":"Diamond","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas N.","family":"Burn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7151-6085","authenticated-orcid":true,"given":"Mailyn A.","family":"Nishiguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Minichino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Chase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niansheng","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Portia A.","family":"Kreiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward M.","family":"Behrens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,6,7]]},"reference":[{"issue":"2","key":"pone.0269553.ref001","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.pcl.2012.03.002","article-title":"Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes","volume":"59","author":"SW Canna","year":"2012","journal-title":"Pediatric Clinics of North America"},{"issue":"3","key":"pone.0269553.ref002","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1182\/blood-2003-10-3413","article-title":"An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder.","volume":"104","author":"MB Jordan","year":"2004","journal-title":"Blood"},{"issue":"12","key":"pone.0269553.ref003","doi-asserted-by":"crossref","first-page":"e0226043","DOI":"10.1371\/journal.pone.0226043","article-title":"The interferon-gamma pathway is selectively up-regulated in the liver of patients with secondary hemophagocytic lymphohistiocytosis","volume":"14","author":"G Prencipe","year":"2019","journal-title":"PLoS One"},{"issue":"1","key":"pone.0269553.ref004","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/art.40683","article-title":"Brief Report: Interferon-gamma-Mediated Immunopathology Potentiated by Toll-Like Receptor 9 Activation in a Murine Model of Macrophage Activation Syndrome","volume":"71","author":"LK Weaver","year":"2019","journal-title":"Arthritis Rheumatol"},{"issue":"4","key":"pone.0269553.ref005","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1016\/j.jaci.2017.07.021","article-title":"Neutralization of IFN-gamma reverts clinical and laboratory features in a mouse model of macrophage activation syndrome","volume":"141","author":"G Prencipe","year":"2018","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"pone.0269553.ref006","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.cytogfr.2014.10.001","article-title":"Hemophagocytic lymphohistiocytosis (HLH): A heterogeneous spectrum of cytokine-driven immune disorders","volume":"26","author":"E Brisse","year":"2015","journal-title":"Cytokine Growth Factor Rev"},{"issue":"21","key":"pone.0269553.ref007","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1182\/blood.2019002289","article-title":"Emapalumab for the treatment of relapsed\/refractory hemophagocytic lymphohistiocytosis","volume":"134","author":"N. 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