Atg7 knockdown augments concanavalin A-induced acute hepatitis through an ROS-mediated p38/MAPK pathway

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Abstract

© 2016 Zhuang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Concanavalin A (ConA), a T-cell mitogen that induces acute autoimmune hepatitis, is widely used to model pathophysiological processes of human acute autoimmune liver disease. Although autophagy has been extensively studied in the past decade, little is known about its molecular mechanism underlying the regulation of ConA-induced acute hepatitis. In this study, we used a Cre-conditional atg7 KO mouse to investigate the effects of Atg7-associ-ated autophagy on ConA-induced murine hepatitis. Our results demonstrated that atg7 deficiency in mice enhanced macrophage activation and increased pro-inflammatory cytokines upon ConA stimulation. Atg7 silencing resulted in accumulation of dysfunctional mitochondria, disruption of reactive oxygen species (ROS) degradation, and increase in pro-inflammatory cytokines in Raw264.7 cells. p38/MAPK and NF-KB levels were increased upon ConA induction due to Atg7 deficiency. Blocking ROS production inhibited ConA-induced p38/kB phosphorylation and subsequent intracellular inflammatory responses. Hence, this study demonstrated that atg7 knockout in mice or Atg7 knockdown in cell culture augmented ConA-induced acute hepatitis and related cellular malfunction, indicating protective effects of Atg7 on regulating mitochondrial ROS via a p38/MAPK-mediated pathway. Collectively, our findings reveal that autophagy may attenuate macrophage-mediated inflammatory response to ConA and may be the potential therapeutic targets for acute liver injury.

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Zhuang, Y., Li, Y., Li, X., Xie, Q., & Wu, M. (2016). Atg7 knockdown augments concanavalin A-induced acute hepatitis through an ROS-mediated p38/MAPK pathway. PLoS ONE, 11(3). https://doi.org/10.1371/journal.pone.0149754

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