Abstract
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-associated 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-κB levels were increased upon ConA induction due to Atg7 deficiency. Blocking ROS production inhibited ConA-induced p38/IκB 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.
Highlights
Concanavalin A (ConA), the most widely used Jack bean seed lectin, is a T-cell mitogen that can induce acute autoimmune hepatitis [1,2]
In this study, using a tamoxifen-induced conditional atg7-/- mice, we investigated the role of Atg7 in the pathogenesis of ConA-induced autoimmune hepatitis
It is well established that ConA-induced liver injury is initiated by specific activation of CD4+ lymphocytes, which is followed by activation of macrophage function and release of inflammatory cytokines, resulting in necrosis and apoptosis of hepatocytes [5,40,41]
Summary
Concanavalin A (ConA), the most widely used Jack bean seed lectin, is a T-cell mitogen that can induce acute autoimmune hepatitis [1,2]. ConA-induced hepatitis, which exhibits pathological changes of acute hepatic inflammation, has long been regarded as an appropriate model for studying the pathogenic mechanisms of human acute autoimmune liver disease [3,4]. During this process, CD4+ T lymphocyte-mediated activation of macrophage function serves as an crucial pathogenic parameter [5]. Autophagy is an evolutionarily conserved lysosomal pathway critical to cytoplasmic homeostasis to control the turnover of long-lived proteins and excess or dysfunctional organelles [9,10]. It occurs at basal levels, but can be induced by nutritional cues and stress signals. We utilized a Cre-conditional atg KO mouse model to investigate the effect of autophagy in ConA-induced murine autoimmune hepatitis, explored the mechanisms and indicated possible ways to prevent or treat ConA-induced liver injury
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