Ferroptosis in infection, inflammation, and immunity

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Abstract

In this review, the authors focus on ferroptosis in innate and adaptive immunity. They also discuss and highlight the impact of ferroptotic death in infection, inflammation, and immune diseases.

Abstract

Ferroptosis is a type of regulated necrosis that is triggered by a combination of iron toxicity, lipid peroxidation, and plasma membrane damage. The upstream inducers of ferroptosis can be divided into two categories (biological versus chemical) and activate two major pathways (the extrinsic/transporter versus the intrinsic/enzymatic pathways). Excessive or deficient ferroptotic cell death is implicated in a growing list of physiological and pathophysiological processes, coupled to a dysregulated immune response. This review focuses on new discoveries related to how ferroptotic cells and their spilled contents shape innate and adaptive immunity in health and disease. Understanding the immunological characteristics and activity of ferroptotic death not only illuminates an intersection between cell death and immunity but may also lead to the development of novel treatment approaches for immunopathological diseases.

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Lorenzo Galluzzi, Ilio Vitale, Stuart A. Aaronson … (2018)

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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Author and article information

Contributors

Xin Chen:

ORCID: https://orcid.org/0000-0003-3668-4830

Role: Writing - original draftRole: Writing - review & editing

Rui Kang:

ORCID: https://orcid.org/0000-0003-2725-1574

Role: ConceptualizationRole: Writing - review & editing

Guido Kroemer:

ORCID: https://orcid.org/0000-0002-9334-4405

Role: ConceptualizationRole: Writing - original draft

Daolin Tang:

ORCID: https://orcid.org/0000-0002-1903-6180

Role: ConceptualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J Exp Med

Journal ID (publisher-id): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 07 June 2021

Publication date (Electronic): 12 May 2021

Volume: 218

Issue: 6

Electronic Location Identifier: e20210518

Affiliations

[1 ]Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, The Third Affiliated Hospital, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China

[2 ]Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China

[3 ]Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA

[4 ]Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Institut national de la santé et de la recherche médicale U1138, Institut Universitaire de France, Paris, France

[5 ]Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

[6 ]Pôle de Biologie, Hôpital Européen Georges Pompidou, Assistance Publique–Hôpitaux de Paris, Paris, France

[7 ]Suzhou Institute for Systems Biology, Chinese Academy of Sciences, Suzhou, China

[8 ]Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden

Author notes

Correspondence to Daolin Tang: daolin.tang@ 123456utsouthwestern.edu

Guido Kroemer: kroemer@ 123456orange.fr

Disclosures: G. Kroemer reported grants from Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Samsara, Sanofi, Vascage, and Vasculox outside the submitted work; additionally, G. Kroemer is on the Board of Directors of the Bristol Myers Squibb Foundation France and is a scientific co-founder of everImmune, Samsara Therapeutics, and Therafast Bio. No other disclosures were reported.

Author information

Xin Chen https://orcid.org/0000-0003-3668-4830

Rui Kang https://orcid.org/0000-0003-2725-1574

Guido Kroemer https://orcid.org/0000-0002-9334-4405

Daolin Tang https://orcid.org/0000-0002-1903-6180

Article

Publisher ID: jem.20210518

DOI: 10.1084/jem.20210518

PMC ID: 8126980

PubMed ID: 33978684

SO-VID: 5a54d203-d24b-414e-941d-91b9b65b8a9d

License:

This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 08 March 2021

Date revision received : 08 April 2021

Date accepted : 20 April 2021

Page count

Pages: 15

Funding

Funded by: Agence Nationale de la Recherche, DOI http://dx.doi.org/10.13039/501100001665;

Funded by: Association pour la Recherche sur le Cancer, DOI http://dx.doi.org/10.13039/100007391;

Funded by: Cancéropôle Ile de France, DOI http://dx.doi.org/10.13039/501100006431;

Funded by: Chancellerie des Universités de Paris, DOI http://dx.doi.org/10.13039/501100010466;

Funded by: Elior;

Funded by: European Research Area Network on Cardiovascular Diseases;

Funded by: Fondation Carrefour;

Funded by: Fondation pour la Recherche Médicale, DOI http://dx.doi.org/10.13039/501100002915;

Funded by: Gustave Roussy Odyssea;

Funded by: Horizon 2020 Framework Programme, DOI http://dx.doi.org/10.13039/100010661;

Funded by: High-end Foreign Expert Program in China;

Award ID: GDW20171100085

Award ID: GDW20181100051

Funded by: Institut national de la santé et de la recherche médicale, DOI http://dx.doi.org/10.13039/501100001677;

Funded by: Institut National du Cancer, DOI http://dx.doi.org/10.13039/501100006364;

Funded by: Institut Universitaire de France, DOI http://dx.doi.org/10.13039/501100004795;

Funded by: LabEx Immuno-Oncology;

Funded by: LeDucq Foundation;

Funded by: Ligue Contre le Cancer, DOI http://dx.doi.org/10.13039/501100004099;

Funded by: Recherche Hospitalo-Universitaire Torino Lumière;

Funded by: Seerave Foundation, DOI http://dx.doi.org/10.13039/100015545;

Funded by: SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination;

Funded by: SIRIC Cancer Research and Personalized Medicine;

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Ferroptosis in infection, inflammation, and immunity

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Most cited references 154

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Ferroptosis: mechanisms, biology and role in disease

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