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

  1. Jonathan Muri
  2. Helen Thut
  3. Qian Feng
  4. Manfred Kopf  Is a corresponding author
  1. ETH Zürich, Switzerland

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-kB 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-1b 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Jonathan Muri

    Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Helen Thut

    Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Qian Feng

    Institute of Biochemistry, ETH Zürich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Manfred Kopf

    Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
    For correspondence
    manfred.kopf@biol.ethz.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0628-7140

Funding

ETH Zurich (ETH-23-16-2)

  • Manfred Kopf

Swiss National Science Foundation (310030B_182829)

  • Manfred Kopf

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Tiffany Horng, ShanghaiTech University, China

Ethics

Animal experimentation: All animal experiments were approved by the local animal ethics committee (Kantonales Veterinärsamt Zürich, licenses 25/2014, ZH054/18, ZH054/19 and ZH134/18), and per- formed according to local guidelines (TschV, Zurich) and the Swiss animal pro- tection law (TschG).

Version history

  1. Received: November 14, 2019
  2. Accepted: February 24, 2020
  3. Accepted Manuscript published: February 25, 2020 (version 1)
  4. Version of Record published: March 9, 2020 (version 2)

Copyright

© 2020, Muri et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jonathan Muri
  2. Helen Thut
  3. Qian Feng
  4. Manfred Kopf
(2020)
Thioredoxin-1 distinctly promotes NF-κB target DNA binding and NLRP3 inflammasome activation independently of Txnip
eLife 9:e53627.
https://doi.org/10.7554/eLife.53627

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https://doi.org/10.7554/eLife.53627

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