{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:41:21Z","timestamp":1790833281023,"version":"4.1.0"},"reference-count":54,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-\u03b3 (IFN-\u03b3). Previously, we reported that the JAK inhibitor ruxolitinib dampens T-cell activation and lessens inflammation in a model of HLH in which perforin-deficient (Prf1\u2212\/\u2212) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-\u03b3, as well as several other JAK-dependent cytokines. As a consequence, it remained unclear whether ruxolitinib was exerting its beneficial effects in HLH by inhibiting IFN-\u03b3 signaling or by targeting signaling initiated by other proinflammatory cytokines. To address this question, we compared the effects of ruxolitinib with those obtained using an IFN-\u03b3\u2013neutralizing antibody (\u03b1IFN-\u03b3) in 2 murine HLH models. In both models, ruxolitinib and \u03b1IFN-\u03b3 reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-\u03b3\u2013dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, as well as their infiltration into tissues, were significantly reduced following treatment with ruxolitinib, but they remained unchanged or were increased following treatment with \u03b1IFN-\u03b3. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1\u2212\/\u2212 mice exhibited enhanced survival compared with mice in which \u03b1IFN-\u03b3 was discontinued. This protective effect could be mimicked by transient treatment with \u03b1IFN-\u03b3 and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-\u03b3\u2013dependent and -independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, with the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.<\/jats:p>","DOI":"10.1182\/blood.2019000761","type":"journal-article","created":{"date-parts":[[2019,4,24]],"date-time":"2019-04-24T02:15:16Z","timestamp":1556072116000},"page":"147-159","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":138,"title":["Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis"],"prefix":"10.1182","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9708-6810","authenticated-orcid":false,"given":"Sabrin","family":"Albeituni","sequence":"first","affiliation":[{"name":"Department of Oncology 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