Mycotoxin Patulin Suppresses Innate Immune Responses by Mitochondrial Dysfunction and p62/Sequestosome-1-dependent Mitophagy

Abstract

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...

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets

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Mycotoxin‐assisted mitochondrial dysfunction and cytotoxicity: Unexploited tools against proliferative disorders

“…Immune modulation resulting from pattern recognition receptor‐induced responses were a potential strategy for controlling immunopathology and related diseases. In an investigation by Tsai and colleagues, patulin was found to suppress mitochondrial dysfunction, Toll‐ like receptor‐ and RIG‐I/MAVS‐dependent cytokine production through reduced glutathione (GSH) depletion, activation of p62‐associated mitophagy, and p62‐TRAF6 interaction . Furthermore, patulin at 8 μM was found to decrease expression of ATP synthase, destabilize mitochondrial membrane potential, and reduce intracellular ATP level.…”

Lung Cancer Chemopreventive Activity of Patulin Isolated from Penicillium vulpinum

“…To our knowledge, this work presents the first report of the inhibitory activity of patulin against TNF-α-induced NF-κB activity. Interestingly, Tsai et al recently described NF-κB inhibitory properties of patulin that seemed specific to LPS induction [ 15 ]. Consistent with the present work, they observed no effect on TNF-α-induced IκBα degradation after patulin treatment.…”