The JAK inhibitor ruxolitinib abrogates immune hepatitis instigated by concanavalin A in mice

Therapeutics that impair the innate immune responses of the liver during the inWammatory cytokine storm like that occurring in COVID-19 are greatly needed. Much interest is currently directed toward Janus kinase (JAK) in- hibitors as potential candidates to mitigate this life-threatening complication. Accordingly, this study investi- gated the inWuence of the novel JAK inhibitor ruxolitinib (RXB) on concanavalin A (Con A)-induced hepatitis and systemic hyperinWammation in mice to simulate the context occurring in COVID-19 patients. Mice were orally treated with RXB (75 and 150 mg/kg) 2 h prior to the intravenous administration of Con A (20 mg/kg) for a pe- riod of 12 h. The results showed that RXB pretreatments were efVcient in abrogating Con A-instigated hepatocel- lular injury (ALT, AST, LDH), necrosis (histopathology), apoptosis (cleaved caspase-3) and nuclear proliferation due to damage (PCNA). The protective mechanism of RXB were attributed to i) prevention of Con A-enhanced hepatic production and systemic release of the proinWammatory cytokines TNF-α, IFN-γ and IL-17A, which coin- cided with decreasing inVltration of immune cells (monocytes, neutrophils), ii) reducing Con A-induced hepatic overexpression of IL-1β and CD98 alongside NF-κB activation, and iii) lessening Con A-induced consumption of GSH and GSH peroxidase and generation of oxidative stress products (MDA, 4-HNE, NOx) in the liver. In sum- mary, JAK inhibition by RXB led to eminent protection of the liver against Con A-deleterious manifestations pri- marily via curbing the inWammatory cytokine storm driven by TNF-α, IFN-γ and IL-17A.