7D). We further identified a positive www.selleckchem.com/products/Decitabine.html correlation between RIP3 and liver HMGB1 (Fig. 7E) expression. Collectively, these data suggest that pathways that promote necrosis are preferentially up-regulated in steatohepatitis after a viral challenge, due at least in part to the regulatory involvement of RIP3. To validate our observations in
the mouse model of steatohepatitis, we next evaluated human livers. We found an increase of MAVS mRNA levels in livers of NASH patients compared with controls (Fig. 8A), mirroring MAVS RNA levels in the animal model of steatohepatitis (Fig. 2A). MAVS mRNA up-regulation was specific to NASH because we did not observe increased MAVS levels in hepatitis B virus infection (hepatitis B virus is
a DNA virus) or in liver tumors (no viral infection detected) (Fig. 8A). We also found higher expression of PSMA7 mRNA in human NASH livers (Fig. 8B) that mirrored findings in the mouse model (Fig. 3B). Finally, we detected highly increased RIP3 mRNA levels in NASH patients (Fig. 8C) compared with controls; this was parallel MLN0128 mw to the RIP3 mRNA increase in the mouse model of NASH (Fig. 7C). Steatosis and steatohepatitis are cofactors in the progression of liver diseases, including those of viral etiology, ischemia/reperfusion injury, and liver transplantation.2, 5 We report novel findings related to the impaired only capacity of the fatty liver to respond to dsRNA and related viral challenges. First, livers with steatohepatitis failed to activate antiviral innate immune pathways to produce type I IFNs in response to a dsRNA challenge.
Second, the MAVS adapter, which is required for type I IFN induction after recognition of dsRNA by the helicase receptors RIG-I and Mda5, was dissociated from the mitochondria to the cytosol and showed impaired oligomerization and function in steatohepatitis. Third, displacement of MAVS from mitochondria was associated with oxidative stress and instead of up-regulation of the apoptosis cascade, poly(I:C) promoted necrosis through increased expression of RIP3 in steatohepatitis. Fourth, dsRNA challenge resulted in increased liver damage in spite of decreased TNFα and proinflammatory cytokine induction in a diet-induced model of NASH. Viral-sensing receptors include Toll-like receptor (TLR) 3 and the cytoplasmic helicase receptors RIG-I and Mda5 for dsRNA recognition, TLR7/8 for single-stranded RNA and TLR9 for sensing viral DNA.14 Here we identified a selective defect in signaling from viral dsRNA in steatohepatitis that altered both proinflammatory cytokines and type I IFNs and was associated with increased liver damage. Although TLR3, Mda5, and RIG-I all sense poly(I:C), their signaling pathways are different. Mda5 plays a key role in poly(I:C)-induced IFNβ production even in the absence of TLR3 or RIG-I.