TXNIP deficiency exacerbates endotoxic shock via the induction of excessive nitric oxide synthesis

PLoS Pathog. 2013;9(10):e1003646. doi: 10.1371/journal.ppat.1003646. Epub 2013 Oct 3.

Abstract

Thioredoxin-interacting protein (TXNIP) has multiple functions, including tumor suppression and involvement in cell proliferation and apoptosis. However, its role in the inflammatory process remains unclear. In this report, we demonstrate that Txnip⁻/⁻ mice are significantly more susceptible to lipopolysaccharide (LPS)-induced endotoxic shock. In response to LPS, Txnip⁻/⁻ macrophages produced significantly higher levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS), and an iNOS inhibitor rescued Txnip⁻/⁻ mice from endotoxic shock-induced death, demonstrating that NO is a major factor in TXNIP-mediated endotoxic shock. This susceptibility phenotype of Txnip⁻/⁻ mice occurred despite reduced IL-1β secretion due to increased S-nitrosylation of NLRP3 compared to wild-type controls. Taken together, these data demonstrate that TXNIP is a novel molecule that links NO synthesis and NLRP3 inflammasome activation during endotoxic shock.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nitric Oxide / genetics
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism*
  • Shock, Septic / chemically induced
  • Shock, Septic / genetics
  • Shock, Septic / metabolism*
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Txnip protein, mouse
  • Nitric Oxide
  • Thioredoxins
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse

Grants and funding

This work was supported in part by grants from the GRL project, New Drug Target Discovery Project (M10848000352-08N4800-35210), Basic Science Research Program (RBM0221211) through the National Research Foundation of Korea (NRF), the Ministry of Education, Science & Technology, and KRIBB Research Initiative Program, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.