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Mechanisms of Action of Ruxolitinib in Murine Models of Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is an often-fatal disorder characterized by the over-activation of T cells and macrophages that excessively produce pro-inflammatory cytokines, including interferon-γ (IFNγ). Previously, we reported that the Janus kinase (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 IFNγ 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 IFNγ signaling or instead by targeting signaling initiated by other pro-inflammatory cytokines. To address this question, here we compared the effects of ruxolitinibwith those obtained using an IFNγ-neutralizing antibody (αIFNγ) in two murine HLH models. In both models, ruxolitinib and αIFNγ reduced inflammation-associated anemia indicating that ruxolitinib operates in an IFNγ-dependent manner to reverse this HLH manifestation. In contrast, the number and activation status of T cells and neutrophils, and their infiltration into tissues, were significantly lessened following treatment with ruxolitinib but remained unchanged or were increased following treatment with αIFNγ. Notably, despite discontinuation of ruxolitinib, LCMV-infected Prf1 -/- mice exhibited enhanced survival compared to mice that discontinued αIFNγ. This protective effect could be mimicked by transient treatment with αIFNγ and a neutrophil-depleting antibody. Thus, ruxolitinib operates through IFNγ-dependent and independent mechanisms to dampen HLH by targeting the deleterious effects of T cells and neutrophils, the latter representing an unappreciated and understudied cell type that contributes to HLH pathogenesis.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1378 Ruxolitinib (INCB018424) Ruxolitinib (INCB018424) is the first potent, selective, JAK1/2 inhibitor to enter the clinic with IC50 of 3.3 nM/2.8 nM in cell-free assays, >130-fold selectivity for JAK1/2 versus JAK3. (94) (9)

Related Targets

JAK