Amelioration of trichloroethene‐mediated autophagy, inflammasome activation, and hepatic immune dysregulation by N‐acetylcysteine

Abstract

Listen

Translate article

Trichloroethene (TCE) exposure can cause induction of autoimmune diseases (i.e., autoimmune hepatitis and systemic lupus erythematosus) potentially through increased oxidative stress (OS). Activation of autophagy has emerged as a pivotal pathogenic factor in various autoimmune diseases. However, role of OS in the regulation of autophagy leading to autoimmune diseases is largely unknown. Here, we tested the hypothesis that OS‐induced activation of autophagy and inflammasome contribute to induction and pathogenesis of TCE‐mediated autoimmune diseases. Female MRL +/+ mice were treated with TCE along with or without antioxidant N‐acetylcysteine (NAC) for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, 250 mg/kg/day via drinking water). TCE‐treated mice had elevated anti‐nuclear antibodies (ANA) and anti‐4‐hydroxynonenal (HNE)‐specific circulating immune complexes, suggesting the association of TCE‐induced OS with autoimmune response. Moreover, TCE exposure led to hepatic autophagy activation as evident from increased beclin‐1 and autophagic light chain 3 conversation (LC3‐II/LC3‐I). The TCE‐mediated autophagy activation was associated with activation of hepatic inflammasome (NLRP3 and caspase‐1) and up‐regulated pro‐inflammatory cytokine IL‐1β. TCE exposure led to hepatic morphological changes, including sinusoid dilation, increased sinusoidal cellularity and proliferating cell nuclear antigen (PCNA) intensity. In addition, dysregulation of hepatic immune response was also observed as evident from markedly increased hepatic lymphocyte infiltration and imbalance between Tregs (decreased) and Th17 cells (increased). Remarkably, TCE‐mediated increased autoantibody formation, hepatic activation of autophagy and inflammasome, and immune dysregulation were effectively attenuated by NAC. Taken together, these results suggest that TCE mediated the hepatic immune dysregulation via OS and activating autophagy and inflammasome. Amelioration of these responses by NAC further supports the role of OS in TCE‐mediated autoimmunity. These novel findings could help in designing therapeutic strategies for such autoimmune diseases.Support or Funding InformationSupported by NIH R01 grants ES026887 and ES016302.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.