Innate immune responses are important for pathogen elimination and adaptive immune response activation. However, excess inflammation may contribute to immunopathology and disease progression (e.g. inflammation-associated hepatocellular carcinoma). Immune modulation resulting from pattern recognition receptor-induced responses is a potential strategy for controlling immunopathology and related diseases. This study demonstrates that the mycotoxin patulin suppresses Toll-like receptor-and RIG-I/MAVS-dependent cytokine production through GSH depletion, mitochondrial dysfunction, the activation of p62-associated mitophagy, and p62-TRAF6 interaction. Blockade of autophagy restored the immunosuppressive activity of patulin, and pharmacological activation of p62-dependent mitophagy directly reduced RIG-I-like receptor-dependent inflammatory cytokine production. These results demonstrated that p62-dependent mitophagy has an immunosuppressive role to innate immune response and might serve as a potential immunomodulatory target for inflammation-associated diseases. Although innate immune responses are critical to pathogen elimination and immune response activation, the pro-inflammatory responses elicited as a result of pattern recognition receptor signaling can lead to excess inflammation if not controlled and may contribute to disease progression (e.g. Helicobacter pylori-associated gastric cancer (3) and chronic hepatitis virus infection-associated hepatocellular carcinoma (4, 5)). Therefore, controlling immunopathology and related diseases caused by inflammation resulting from pattern recognition receptor-dependent signaling represents a potential treatment strategy (6 -8). How to fine tune unwanted inflammation while maintaining protective immune responses intact will be a critical hurdle to overcome.Hepatic diseases, such as cirrhosis and hepatocellular carcinoma are typically associated with chronic inflammation that can take decades to develop. Activation of proinflammatory cytokines in the liver, such as IL-6/gp130/STAT3, is a critical step in the development of hepatic disease, including hepatocellular carcinoma (9 -11). In addition, serum proinflammatory cytokine levels were higher in hepatitis C virus (HCV)-associated hepatocellular carcinoma patients (12). Modulation of these immune responses represents a potential strategy for ameliorating disease progression (7). Therefore, we aimed to identify new targets for immune modulation as a means of reducing proinflammatory cytokine production by screening a library of natural compounds for the treatment of inflammation-related liver diseases. An in vitro screening platform was developed to evaluate natural compounds collected by Microsource Discovery Systems that was composed of two screens: one to evaluate cytokine production activated by LPS/TLR4 pathway signaling and the other to analyze the cytokines triggered by HCV-NS5B-dependent RIG-I/MAVS activation (13). IL-6 production was measured as a readout to evaluate the immune modulatory activity of candidate compou...

BackgroundThe role of interleukin (IL) 17A in chronic liver diseases had been extensively studied, but the function of IL-17F, which shares a high degree of homology with IL-17A, in the progression of chronic hepatic diseases is poorly understood. The aim of the study was to evaluate the association between IL-17F and liver diseases including, fibrosis and hepatocellular carcinoma (HCC).MethodsHepatic tumor samples from both hepatitis C virus (HCV) positive and negative patients (without HBV and HCV, NBNC) were examined with quantitative PCR and immunohistochemistry staining for inflammatory cytokine genes expression. In addition, 250 HCV patients naïve for interferon treatment were also subjected to enzyme-linked immunosorbent Assay (ELISA) for their serum cytokine concentrations.ResultsSerum IL-17F concentrations were significantly elevated in HCV patients with severe fibrosis stages. In accordance with serum data, IL-17F expression was also found higher in HCV-associated HCC tissues compared with NBNC HCC tissues at both the mRNA and protein levels.ConclusionsOur data suggest that IL-17F might be used as a valuable biological marker than IL-17A during chronic fibrosis progression and HCC development in HCV patients.

Type I interferon (IFN-I) has a well-known function in controlling viral infections, but its contribution in hepatocyte proliferation and hepatocellular carcinoma (HCC) formation remains unclear. Mice deficient in IFN-a receptor expression in whole mice or only in hepatocytes (Ifnar À/À and Ifnar Dliver) were used to investigate the role of IFN-I signaling in cell proliferation and cancer formation in the liver. We found that Ifnar À/À mice were resistant to chemical-induced HCC formation in the absence of infection. Our results showed that low grade of IFN-I and interferon-stimulated gene were expressed substantially in naïve mouse liver. The low level of IFN-I activation is constantly present in mouse liver after weaning and negatively modulates forkhead box O hepatic expression. The IFN-I signaling can be partially blocked by the clearance of lipopolysaccharide. Mice lacking IFN-I signaling have lower basal proliferation activity and delayed liver regeneration processes after two-thirds partial hepatectomy. The activation of IFN-I signaling on hepatocyte controls glucose homeostasis and lipid metabolism to support proliferation potency and long-term tumorigenesis. Our results reveal a positive role of low-grade IFN-I singling Q3 to hepatocyte proliferation and HCC formation by modulating glucose homeostasis and lipid metabolism.

Pattern-recognition receptors detect pathogen-associated molecular patterns to trigger downstream pathways leading to type I IFN and inflammatory cytokines production to defend pathogen infection. RIG-I-like receptors (RLRs) are key cytosolic sensors for recognizing viral RNA to trigger antiviral immunity. The underlying mechanisms linking RLR-mediated viral recognition to antiviral immunity remain to be further explored. Through our previous work, we uncovered an innate immune regulator termed TAPE (TBK1-Associated Protein in Endolysosomes), also known as CC2D1A, which is implicated in the viral RNA senor TLR3 and RLR pathways. Yet, the in vivo role of TAPE in antiviral defenses and the mechanistic mechanisms of how TAPE regulates cytosolic RIG-I signaling still remain to be established. TAPE conditional knockout mice were generated for our study. Results from in vivo studies showed that TAPEf/f CD11c-Cre mice exhibited a more severe mortality than WT mice upon influenza A virus (IAV) infection. Ex vivo studies also showed that TAPE-deficient mouse embryonic fibroblasts and macrophages were defective in type-I interferon induction upon RLR ligand stimulation. In addition, our biochemical analyses showed that the N-terminal region of TAPE was critical for interacting with the CARD domain of RIG-I while the C-terminal region of TAPE contributed most to the interaction with MAVS/IPS-1, a RLR downstream mediator. Together, our results suggest a crucial role for TAPE in linking RIG-I to type I IFN-mediated antiviral responses. Future work will further determine the in vivo role of TAPE in IAV and other RNA virus infection, and explore the mechanistic mechanisms of how TAPE regulates RIG-I signaling.