GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection
Author(s)
Type
Journal Article
Abstract
Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis.
Date Issued
2022-09-07
Date Acceptance
2022-08-11
Citation
Journal of Experimental Medicine, 2022, 219 (11)
ISSN
0022-1007
Publisher
Rockefeller University Press
Journal / Book Title
Journal of Experimental Medicine
Volume
219
Issue
11
Copyright Statement
© 2022 Amaral et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
License URL
Sponsor
Wellcome Trust
Grant Number
104803/Z/14/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
Medicine, Research & Experimental
Research & Experimental Medicine
LIPID-PEROXIDATION
GLUTATHIONE-PEROXIDASE
IMMUNE-RESPONSES
FERROPTOSIS
HYDROPEROXIDE
PULMONARY
MICE
SUPPLEMENTATION
INFLAMMATION
MACROPHAGES
Animals
Ferroptosis
Glutathione
Glutathione Peroxidase
Lipid Peroxidation
Mice
Mice, Transgenic
Necrosis
Phospholipid Hydroperoxide Glutathione Peroxidase
Tuberculosis
Animals
Mice, Transgenic
Mice
Tuberculosis
Necrosis
Glutathione Peroxidase
Glutathione
Lipid Peroxidation
Ferroptosis
Phospholipid Hydroperoxide Glutathione Peroxidase
Immunology
11 Medical and Health Sciences
Publication Status
Published
Article Number
ARTN e20220504