β-catenin regulates innate and adaptive immunity in mouse liver ischemia-reperfusion injury

Liver ischemia and reperfusion injury (IRI), a local inflammatory response driven by innate and supported by adaptive immune responses, represents an important cause of organ dysfunction and failure in liver transplantation (1). Our group was one of the first to document the essential function of TLR4 in the mechanism of liver IRI by promoting local inflammation and hepatocellular damage via downstream IFN regulatory factor (IRF) 3 pathway (2). It soon became evident that IR-induced liver damage triggers TLR4 endogenous ligands, such as high-mobility group box 1 (HMGB1), to activate dendritic cells (DCs) and facilitate inflammatory cytokine programs that further enhance TLR4-mediated local inflammation (3-4). Although different cell types (hepatocytes, Kupffer cells, sinusoidal endothelial cells, and infiltrating T cells) contribute to IRI pathophysiology, hepatic DCs are well-suited to modulate local immune responses that can bridge innate and adaptive immunity in the liver (5). Indeed, immature DCs in peripheral tissues function to capture and process antigens (5-6). Upon exposure to pathogens and TLR ligands, however, DC rapidly acquire an activated phenotype and undergo maturation characterized by upregulated expression of MHC antigens, costimulatory CD80/CD86 molecules, and proinflammatory cytokines that stimulate naive T cell differentiation (5-6). Hence, controlling DC differentiation is important to prevent hepatic innate and adaptive inflammatory development. STAT3 is known to mediate many biological effects by regulating immune homeostasis and influencing cell proliferation/differentiation (7). Disruption of STAT3 during hematopoiesis activates innate immune response and promotes proinflammatory phenotype (8). STAT3 signaling may halt DC maturation in vitro (9), whereas STAT3 deficiency in IL-10-/- DCs was shown to increase NF-κB binding to the IL-12p40 promoter and to promote TLR-dependent IL-12 inflammation (10). As conditional deletion of STAT3 results in severe colitis and enhanced Th1-type activity (11), STAT3 may serve as an intrinsic negative regulator of DC function (12). The Wnt-β-catenin pathway is an important regulator of cell development, regeneration, and carcinogenesis (13-14). In response to Wnt signaling, β-catenin is rapidly phosphorylated and enters the nucleus, where it interacts with T cell factor/lymphoid enhancer factor (TCF/LEF) family members to regulate transcription of the target genes. Inhibition of STAT3 induces translocation of β-catenin from the nucleus to the cytoplasma leading to decreased β-catenin transcription activity (15), suggesting β-catenin function might be mediated by STAT3. Moreover, activation of β-catenin was shown to regulate the local immunity and tolerance balance in murine intestinal mucosa (16). Despite its essential immunomodulatory functions, however, little is known on the molecular mechanisms by which β-catenin may regulate DC function and/or local inflammation responses in the liver. Here, we report on the crucial regulatory function of STAT3-induced β-catenin on DC function and inflammatory responses in hepatic IRI. We demonstrate that β-catenin inhibits PTEN and promotes PI3K/Akt pathway, which in turn downregulates DC immune function and depresses TLR4-driven inflammation. Our data document β-catenin as a novel regulator of innate and adaptive immune responses in the mechanism of liver IRI.