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

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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.

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

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Jonathan Muri

Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Helen Thut

Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Qian Feng

Institute of Biochemistry, ETH Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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).

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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.