LPS protects macrophages from AIF-independent parthanatos by downregulation of PARP1 expression, induction of SOD2 expression, and a metabolic shift to aerobic glycolysis
Open accessAbstract
In inflamed tissues or during ischemia-reperfusion episodes, activated macrophages produce large amounts of reactive species and are, thus, exposed to the damaging effects of reactive species. Here, our goal was to investigate the mechanism whereby activated macrophages protect themselves from oxidant stress-induced cell death. Hydrogen peroxide-treated mouse bone marrow-derived macrophages (BMDM) and THP-1 human monocyte-derived cells were chosen as models. We found a gradual development of resistance: first in monocyte-to-macrophage differentiation, and subsequently after lipopolysaccharide (LPS) exposure. Investigating the mechanism of the latter, we found that exposure to intense hydrogen peroxide stress causes poly(ADP-ribose) polymerase-1 (PARP-1) dependent programmed necrotic cell death, also known as parthanatos, as indicated by the protected status of PARP-1 knockout BMDMs and the protective effect of the PARP inhibitor PJ-34. In hydrogen peroxide-treated macrophages, however, apoptosis inducing factor (AIF) proved dispensable for parthanatos; nuclear translocation of AIF was not observed. A key event in LPS-mediated protection against the hydrogen peroxide-induced AIF independent parthanatos was downregulation of PARP1 mRNA and protein. The importance of this event was confirmed by overexpression of PARP1 in THP1 cells using a viral promoter, which lead to stable PARP1 levels even after LPS treatment and unresponsiveness to LPS-induced cytoprotection. In BMDMs, LPS-induced PARP1 suppression lead to prevention of NAD+ depletion. Moreover, LPS also induced expression of antioxidant proteins (superoxide dismutase-2, thioredoxin reductase 1 and peroxiredoxin) and triggered a metabolic shift to aerobic glycolysis, also known as the Warburg effect. In summary, we provide evidence that in macrophages intense hydrogen peroxide stress causes AIF-independent parthanatos from which LPS provides protection. The mechanism of LPS-mediated cytoprotection involves downregulation of PARP1, spared NAD+ and ATP pools, upregulation of antioxidant proteins, and a metabolic shift from mitochondrial respiration to aerobic glycolysis.
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M1 macrophages are protected from reactive oxygen species-induced DNA damage as a result of increased transcription of antioxidant defence genes such as SOD2.
“M1 macrophages are protected from reactive oxygen species-induced DNA damage as a result of increased transcription of genes involved in antioxidant defence, such as SOD2 (REFS102–104).”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [103]
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- Authors
- Regdon, Z., Robaszkiewicz, A., Kovács, K., Rygielska, Ż., Hegedűs, C., Bodoor, K., Szabó, É., & Virág, L.
- Affiliations
- University of Debrecen (HU)
- Corresponding author
- Virág, László
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 131
- Pages
- 184-196
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W2903413848
- Cited by
- 59
- References
- 47
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 8 · 2023: 5 · 2022: 11 · 2021: 9 · 2020: 10 · 2019: 4 · 2018: 1
- FWCI
- 2.14
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
- Funders
- National Research, Development and Innovation Office (GINOP-2.3.2-15-2016-00020 TUMORDNS, GINOP-2.3.2-15-2016-00048-STAYALIVE, OTKA K112336, OTKA PD 116845)
- Polish National Science Centre (DEC-2013/11/D/NZ2/00033)
- Ministry of Science and Higher Education (5811/E-345/M/2016, 776/STYP/11/2016)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- lipopolysaccharide, macrophages, parthanatos, PARP1, hydrogen peroxide, oxidative stress, NAD+ depletion, manganese superoxide dismutase, thioredoxin reductase 1, peroxiredoxin, aerobic glycolysis, Warburg effect, cytoprotection, monocyte-to-macrophage differentiation, reactive oxygen species
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, THP-1 Cells, Parthanatos, Superoxide Dismutase 2, Animals, Gene Expression Regulation, Glycolysis, Humans, Hydrogen Peroxide, Lipopolysaccharides, Macrophage Activation, Macrophages, Mitochondria, NAD, Oxidative Phosphorylation, Phenanthrenes, Promoter Regions, Genetic, RNA, Messenger, Superoxide Dismutase, Signal Transduction, Apoptosis Inducing Factor, Mice, Peroxiredoxins, Thioredoxin Reductase 1, Primary Cell Culture
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