Thioredoxin-1 distinctly promotes NF-κB target DNA binding and NLRP3 inflammasome activation independently of Txnip

Elife. 2020 Feb 25:9:e53627. doi: 10.7554/eLife.53627.

Abstract

Antioxidant systems, such as the thioredoxin-1 (Trx1) pathway, ensure cellular redox homeostasis. However, how such systems regulate development and function of myeloid cells is barely understood. Here we show that in contrast to its critical role in T cells, the murine Trx1 system is dispensable for steady-state myeloid-cell hematopoiesis due to their capacity to tap the glutathione/glutaredoxin pathway for DNA biosynthesis. However, the Trx1 pathway instrumentally enables nuclear NF-κB DNA-binding and thereby pro-inflammatory responses in monocytes and dendritic cells. Moreover, independent of this activity, Trx1 is critical for NLRP3 inflammasome activation and IL-1β production in macrophages by detoxifying excessive ROS levels. Notably, we exclude the involvement of the Trx1 inhibitor Txnip as a redox-sensitive ligand of NLRP3 as previously proposed. Together, this study suggests that targeting Trx1 may be exploited to treat inflammatory diseases.

Keywords: NLRP3 inflammasome; glutaredoxin; immunology; inflammation; mouse; nf- kb; reactive oxygen species; thioredoxin-1; txnip.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • DNA / metabolism*
  • Female
  • Homeostasis
  • Inflammasomes / metabolism*
  • Male
  • Mice
  • Myeloid Cells / metabolism
  • NF-kappa B / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • T-Lymphocytes / metabolism
  • Thioredoxins / metabolism*

Substances

  • Carrier Proteins
  • Inflammasomes
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Txn1 protein, mouse
  • Txnip protein, mouse
  • Thioredoxins
  • DNA