GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

• Published in: The Journal of experimental medicine Vol. 219; no. 11
• Main Authors: Amaral, Eduardo P, Foreman, Taylor W, Namasivayam, Sivaranjani, Hilligan, Kerry L, Kauffman, Keith D, Barbosa Bomfim, Caio Cesar, Costa, Diego L, Barreto-Duarte, Beatriz, Gurgel-Rocha, Clarissa, Santana, Monique Freire, Cordeiro-Santos, Marcelo, Du Bruyn, Elsa, Riou, Catherine, Aberman, Kate, Wilkinson, Robert John, Barber, Daniel L, Mayer-Barber, Katrin D, Andrade, Bruno B, Sher, Alan
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 07.11.2022
• Subjects: Animals; Ferroptosis; Glutathione - metabolism; Glutathione Peroxidase - metabolism; Infectious Disease and Host Defense; Innate Immunity and Inflammation; Lipid Peroxidation; Metabolism; Mice; Mice, Transgenic; Necrosis; Phospholipid Hydroperoxide Glutathione Peroxidase; Tuberculosis - immunology; Tuberculosis - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20220504

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.