Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

摘要

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the overactivation of T cells and macrophages that excessively produce proinflammatory cytokines, including interferon-gamma (IFN-gamma). 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(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV). Ruxolitinib inhibits signaling downstream of IFN-gamma, 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-gamma 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-gamma-neutralizing antibody (alpha IFN-gamma) in 2 murine HLH models. In both models, ruxolitinib and alpha IFN-gamma reduced inflammation-associated anemia, indicating that ruxolitinib operates in an IFN-gamma-dependent 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 alpha IFN-gamma. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1(-/-) mice exhibited enhanced survival compared with mice in which alpha IFN-gamma was discontinued. This protective effect could be mimicked by transient treatment with alpha IFN-gamma and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFN-gamma-dependent 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.