10G). NASH is reversible in its early stages. However, the role of DCs in the recovery phase of disease is unknown. To investigate this, WT chimeric or CD11c-DTR chimeric mice fed an MCD diet for 6 weeks were abruptly transitioned to normal chow. In selected cohorts, DCs were depleted beginning at the time of cessation of the MCD diet. Consistent

with our data implicating a protective role for DCs in NASH, DC depletion delayed the resolution of NASH (Fig. 7A). In particular, absence of DCs on day 3 of normal diet resumption markedly delayed clearance of the intrahepatic CD45+ leukocytic infiltrate (Fig. 7B), neutrophilic infiltrate (Fig. 7C), and apoptotic bodies (Fig. 7D). Residual fibroplasia was also conspicuously find more more pronounced in mice depleted of DCs during the recovery period (Fig. 7E). Furthermore, DC depletion delayed resolution of the elevated cytokine and chemokine secretion by NASH NPC (Fig. 7F). Similar differences between control and DC-depleted mice were noted on day 7 of NASH recovery. However, by 14 days, there was complete resolution of NASH, even in mice depleted of DCs (not shown). Taken together, these

data imply that DCs facilitate recovery from NASH. This is the first investigation to report a significant role for hepatic DCs in NASH. We demonstrated that DCs are recruited to the liver soon after MCD diet initiation, plateau at 3-4 times normal levels by 2 weeks, and remain at an elevated level, unless there is disease resolution. NASH DCs exhibit an activated surface phenotype and increase their production of proinflammatory Torin 1 mw cytokines. Consistent with their mature phenotype, our in vitro experimentation shows that NASH DCs potently induce proliferation of both allogeneic T cells and antigen-restricted CD4+ T cells while reducing CD4+ T-cell expression of the CD25+FoxP3+ Treg phenotype. The finding of intrahepatic DC activation after hepatic insult is consistent with our previous reports showing immunogenic transformation of liver DCs in thioacetamide-induced liver fibrosis and acute hepatic injury induced

by acetaminophen overdose.[12, 21] However, despite their phenotypic and functional activation, ablation of DC in NASH results in increased hepatic inflammation, diminished numbers of Tregs, expansion of CD8+ T cells, enhanced viability check details and production of proinflammatory cytokines by immune effector cells, increased hepatocyte apoptosis, and, ultimately, accelerated liver fibrosis. These ostensibly paradoxical findings are not entirely unprecedented. Recent studies have shown that, despite adopting a proinflammatory phenotype, hepatic DCs can accelerate the regression of hepatic fibrosis and ameliorate hepatic ischemia-reperfusion (I/R) injury.[13, 28] For example, exogenous expansion of hepatic DC populations by Flt3 ligand administration accelerates the regression of CCl4-induced liver fibrosis, despite phenotypic activation of DCs.