Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis.

Piattini, Federica; Matsushita, Mai; Muri, Jonathan; Bretscher, Peter; Feng, Xiaogang; Freigang, Stefan; Dalli, Jesmond; Schneider, Christoph; Kopf, Manfred (2021). Differential sensitivity of inflammatory macrophages and alternatively activated macrophages to ferroptosis. European journal of immunology, 51(10), pp. 2417-2429. Wiley 10.1002/eji.202049114

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Acumulation of oxidized membrane lipids ultimately results in ferroptotic cell death, which can be prevented by the selenoenzyme glutathione peroxidase 4 (Gpx4). In vivo conditions promoting ferroptosis and susceptible cell types are still poorly defined. In this study, we analyzed the conditional deletion of Gpx4 in mice specifically in the myeloid cell lineages. Surprisingly, development and maintenance of LysM+ macrophages and neutrophils, as well as CD11c+ monocyte-derived macrophages and dendritic cells were unaffected in the absence of Gpx4. Gpx4-deficient macrophages mounted an unaltered proinflammatory cytokine response including IL-1β production following stimulation with TLR ligands and activation of several inflammasomes. Accordingly, Gpx4fl/fl LysM-cre mice were protected from bacterial and protozoan infections. Despite having the capacity to differentiate to alternatively activated macrophages (AAM), these cells lacking Gpx4 triggered ferroptosis both in vitro and in vivo following IL-4 overexpression and nematode infection. Exposure to nitric oxide restored viability of Gpx4-deficient AAM, while inhibition of iNOS in proinflammatory macrophages had no effect. These data together suggest that activation cues of tissue macrophages determine sensitivity to lipid peroxidation and ferroptotic cell death.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Freigang, Stefan Bernd

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1521-4141

Publisher:

Wiley

Language:

English

Submitter:

Cornelia Mileto

Date Deposited:

21 Dec 2021 10:22

Last Modified:

21 Sep 2022 03:29

Publisher DOI:

10.1002/eji.202049114

PubMed ID:

34272880

Uncontrolled Keywords:

Alternatively activated macrophages ferroptosis glutathione glutathione peroxidase 4 inflammation

BORIS DOI:

10.48350/161805

URI:

https://boris.unibe.ch/id/eprint/161805

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