Ruxolitinib, a selective JAK1/2 inhibitor, for the treatment of serious diseases caused by Staphylococcus aureus superantigens

Abstract

Abstract Staphylococcal superantigens (SSAgs), produced by Staphylococcus aureus, non-specifically activate 30–50% of all CD4+ and CD8+ T cells expressing certain T cell receptor (TCR) Vb gene families. SSAg-activated T cells rapidly produce large quantities of cytokines and chemokines resulting in a systemic inflammatory response syndrome (SIRS), which culminates in multi organ failure (MOF) and ultimately death. Through this process, SSAgs play a significant role in the immunopathogenesis of pneumonia, sepsis, and toxic shock syndrome. Because most cytokines produced during SIRS act through the Janus Kinase (JAK) signaling pathway, we hypothesized that therapeutics inhibiting JAK functions would attenuate SIRS, MOF, and lower mortality caused by SSAgs. We tested ruxolitinib (RUXO), an FDA-approved selective JAK 1/2 inhibitor. Several in vitro and in vivo studies were performed using HLA-DR3 transgenic mice because SSAgs bind to HLA class II molecules with higher affinity. In vitro, at 100, 10, and 1 mm concentrations, RUXO significantly inhibited SSAg-induced upregulation of CD25 and CD69 on both CD4+ and CD8+ T cell subsets as well as SSAg-induced production of IL-2, IL-17, and IFN-g in a dose-dependent manner at 24 and 48 hours. For in vivo studies, mice (5–6 per group) were gavaged with RUXO (100 mg/kg) or vehicle, twice daily on days −1, 0 and 1, challenged with SSAg (20 mg/mouse, i.p) on day 0 and euthanized on day 2. SSAg-induced SIRS, thymocyte deletion, upregulation of activation markers (CD69 and CD25), and immunopathology were significantly attenuated in RUXO-treated mice compared to vehicle-treated mice. Overall, JAK inhibitors such as ruxolitinib can be used as an adjunct to treat serious diseases caused by SSAg.