Mechanisms of action of ruxolitinib in murine models of hemophagocytic lymphohistiocytosis

Abstract

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

Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease : a case report

“…In line with a putative pathogenic role of IFNγ signaling, a high frequency of MAS was reported. The observation in our patient of (1) elevated frequency of Th1 cells, main producers of IFNγ3, and (2) a clinical response to ruxolitinib, blocking the IFNγ signalling, although not selectively,4 5 is consistent with this hypothesis. Although no definite conclusion can be drawn from this single case, our report suggests that ruxolitinib may represent a valid therapeutic option to be tested early in patients with s-AJI associated with severe early-onset lung disease.…”

JAK/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation

“…Beginning on day 4 after LCMV infection, we treated mice with vehicle, DEX, or DEX in combination with RUX at a dose that mediated a measurable reduction in pSTAT5 (supplemental Figure 2F). Consistent with prior reports, 15,25 all LCMV-infected vehicle-treated mice lost weight and died by 2 weeks postinfection ( Figure 4A-B). Although LCMV-infected mice treated with DEX exhibited slightly longer survival, all animals eventually succumbed to disease.…”

“…RUX also has the potential to inhibit the activity of cytokines that contribute to disease pathogenesis, but do not modulate DEX sensitivity, such as IFN-g. IFN-g did not promote DEX resistance in our model, but is currently under investigation as a therapeutic target in HLH. 25 Thus, our work, in conjunction with the established role for CD8 T cells as drivers of HLH, suggests that combining DEX and RUX has the dual potential to enhance DEX-induced apoptosis and attenuate other cytokine-mediated contributions to disease progression.…”

The Rheumatologist’s Role in COVID-19

“…It has been reported that the anti-IL-6R antibody tocilizumab has been beneficial in treating Chinese COVID-19 patients with CSS 17 . In addition, small molecule inhibitors of Janus kinases (JAK), such as the JAK1/2 inhibitor, ruxolitinib, are capable of blocking signaling downstream of IL-6, IFN-g, and other cytokines 18,19 . Thus there may be a variety of targeted cytokine inhibitors available that may benefit patients with COVID-19-induced CSS ( Table 2).…”