Treatment of Experimental Candida Sepsis with a Janus Kinase Inhibitor Controls Inflammation and Prolongs Survival

Abstract

e Janus kinases (JAK) are intracellular tyrosine kinases that transduce cytokine-mediated signals to the nucleus, promoting gene expression. Cytokines play a major role in microbial sepsis, which is often associated with uncontrolled inflammation leading to death. JAK inhibitors have been used for the treatment of several autoimmune diseases by modulating immune response, but they have never been tested against microbial sepsis. Ruxolitinib is a small-molecule inhibitor of JAK1/2 proteins, which are involved in the downstream signaling pathway of the vast majority of proinflammatory and anti-inflammatory cytokines. We therefore studied the effect of ruxolitinib in a mouse model of sepsis due to Candida albicans. When ruxolitinib therapy (50 mg/kg [of body weight]/day) was started 1 day before infection, the median survival time was reduced by 3 days, the fungal loads in all organs were higher, the inflammation was significantly less, and serum tumor necrosis factor alpha (TNF-␣) and interleukin 10 (IL-10) levels and IL-10/TNF-␣ ratios were higher than in controls. When ruxolitinib therapy (50 to 1.5 mg/kg/day) was started 1 day after infection, an inverted-U relationship was found, with 6.25 mg/kg/day prolonging median survival time by 6 days, resulting in similar fungal loads, less inflammation, and similar cytokine levels but higher IL-10/TNF-␣ ratios than the controls. The optimal dose of ruxolitinib controlled infection and prolonged survival with less inflammation than in control animals. Administration of JAK inhibitors may be a promising therapeutic adjunct that needs further investigation.

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

“…However, mouse models show conflicting data on the effect of JAK inhibitors in invasive candidiasis [17, 18]. In 1 study, tofacitinib was associated with reduced survival [17].…”

“…In 1 study, tofacitinib was associated with reduced survival [17]. In a different study, administration of ruxolitinib 50 mg/kg/d starting a day before Candida injection was associated with reduced survival, but administration of 6.25 mg/kg/d beginning on the second day of the infection was associated with increased survival [18]. Despite their relative specificity to JAK proteins in humans, JAK inhibitors might have a similar effect as staurosporine in eukaryotes.…”

Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease

“…13 Given the ubiquity of the JAK/STAT system in inflammatory processes, modulation with JAKinibs has been studied in various settings, including rheumatologic disease, 13,14 hematological malignancies, 15,16 solid tumor malignancies, 17 and septic shock. 18 Currently, there are a large number of clinical trials involving JAK and STAT inhibitors in all of these disease areas. JAKinibs with FDA approvals or in clinical trials for hematologic diseases are partially listed in Table 2.…”

Balanced control of both hyper and hypo-inflammatory phases as a new treatment paradigm in sepsis

“…On the contrary, mice treated with the optimal dose of Ruxo had the same fungal load but lower inflammation score as compared with placebo, meaning that increased survival is due to prevention of excessive tissue injury and not to an antifungal effect of the study drug. Interestingly, mice treated with the optimal dose of Ruxo had a balanced serum TNF-α/IL-10 ratio equal to one, as a further proof of the concept that a balance between pro-and anti-inflammatory signalling is required for a successful outcome (24).…”