Brucella Melitensis 16M Regulates the Effect of AIR Domain on Inflammatory Factors, Autophagy, and Apoptosis in Mouse Macrophage through the ROS Signaling Pathway

PLoS One. 2016 Dec 1;11(12):e0167486. doi: 10.1371/journal.pone.0167486. eCollection 2016.

Abstract

Brucellosis is a highly contagious zoonosis caused by Brucella. Brucella can invade and persist inside host cells, which results in chronic infection. We constructed AIR interference and overexpression lentiviruses to acquire AIR interference, overexpression, and rescue stable expression cell lines. We also established a Brucella melitensis 16M-infected macrophage model, which was treated with either the vehicle control or NAC (ROS scavenger N-acetylcysteine (NAC) for 0, 3, 6, 12, and 24 h. Confocal laser microscopy, transmission electron microscopy, fluorescence quantitative PCR, flow cytometry, ELISA, and Western blot were used to detect inflammation, cell autophagy and apoptosis-related protein expression levels, ROS levels, and the distribution of mitochondria. It was found that after interference and overexpression of AIR, ROS release was significantly changed, and mitochondria became abnormally aggregated. B. melitensis 16M activated the NLRP3/AIM2 inflammatory complex, and induced RAW264.7 cells to secrete IL-1β and IL-18 through the ROS pathway. B. melitensis 16M also altered autophagy-related gene expression, increased autophagy activity, and induced cell apoptosis through the ROS pathway. The results showed that after B. melitensis 16M infection, ROS induced apoptosis, inflammation, and autophagy while AIR inhibited autophagosome maturation and autophagy initiation. Autophagy negatively regulated the activation of inflammasomes and prevented inflammation from occurring. In addition, mitophagy could promote cell apoptosis.

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis* / genetics
  • Autophagy* / genetics
  • Biomarkers
  • Brucella melitensis / physiology*
  • Brucellosis / genetics
  • Brucellosis / metabolism
  • Brucellosis / microbiology
  • Cell Line
  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Inflammasomes / metabolism
  • Inflammation Mediators / chemistry
  • Inflammation Mediators / metabolism*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • Mitochondria / metabolism
  • Protein Binding
  • Protein Domains*
  • Protein Transport
  • Reactive Oxygen Species / metabolism*
  • Signal Transduction*

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Cytokines
  • Inflammasomes
  • Inflammation Mediators
  • Reactive Oxygen Species

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (31460650,31572491,31360610,31201863,81360239). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.