Cutting Edge: Essential Role of Hypoxia Inducible Factor-1α in Development of Lipopolysaccharide-Induced Sepsis
Open accessAbstract
Sepsis, the leading cause of death in intensive care units, reflects a detrimental host response to infection in which bacteria or LPS act as potent activators of immune cells, including monocytes and macrophages. In this report, we show that LPS raises the level of the transcriptional regulator hypoxia-inducible factor-1α (HIF-1α) in macrophages, increasing HIF-1α and decreasing prolyl hydroxylase mRNA production in a TLR4-dependent fashion. Using murine conditional gene targeting of HIF-1α in the myeloid lineage, we demonstrate that HIF-1α is a critical determinant of the sepsis phenotype. HIF-1α promotes the production of inflammatory cytokines, including TNF-α, IL-1, IL-4, IL-6, and IL-12, that reach harmful levels in the host during early sepsis. HIF-1α deletion in macrophages is protective against LPS-induced mortality and blocks the development of clinical markers including hypotension and hypothermia. Inhibition of HIF-1α activity may thus represent a novel therapeutic target for LPS-induced sepsis.
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Iron depletion of macrophages could mimic hypoxia by stabilizing HIF1α and promoting transcription and synthesis of IL-1β and perhaps other cytokines.
“Iron depletion of macrophages could therefore mimic the effects of hypoxia, stabilizing HIF1α and promoting the transcription and synthesis of IL-1β68 and perhaps other cytokines.”
From Iron homeostasis in host defence and inflammation (2015) · cites this paper as [68]
HIF effects (via hepcidin) mobilisation of iron and can cause expression of inflammatory cytokines such as IL-1, IL-6 and TNF-α under hypoxia, and consequently increases sepsis (HIF-knockout mice are resistant to LPS-induced sepsis).
“In particular, HIF effects (via hepcidin) the mobilisation or iron and can cause the expression of inflammatory cytokines such as IL-1, IL-6 and TNF-α [2254-2256] under conditions (hypoxia) where superoxide and peroxide production are likely to be increased, and consequently increases sepsis (in that HIF-knockout mice are resistant to LPS-induced sepsis [2254,2255]).”
From Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases (2009) · cites this paper as [2255]
IL-1β is a direct target of HIF-1α.
“Therefore IL-1β is a direct target of HIF-1α supporting previous data6,7.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [7]
HIF-1α deficiency rescues mice from LPS-induced sepsis.
“HIF-1α deficiency also rescues mice from LPS-induced sepsis7 but how HIF-1α protein is regulated by LPS is still unknown.”
From Succinate is an inflammatory signal that induces IL-1β through HIF-1α (2013) · cites this paper as [7]
Innate immune training involves epigenetic modifications leading to stronger gene transcription upon re-stimulation.
“At a molecular level this involves epigenetic modifications, leading to stronger gene transcription upon re-stimulation, as opposed to gene recombination that occurs in the adaptive memory response.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [35]
Activation of PKM2 impairs the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of IL-1β, thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β in response to LPS.
“This impairs the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of the known Hif-1α target gene IL-1β (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β”
From Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages (2015) · cites this paper as Peyssonnaux et al., 2007
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- Authors
- Peyssonnaux, C., Cejudo-Martin, P., Doedens, A., Zinkernagel, A. S., Johnson, R. S., & Nizet, V.
- Affiliations
- University of California San Diego (US)
- Division of Biological Sciences, University of California San Diego , La Jolla, CA 92093
- Corresponding author
- Peyssonnaux, Carole
- Doedens, Andrew
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06
- Volume
- 178
- Issue
- 12
- Pages
- 7516-7519
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1906027219
- Cited by
- 480
- References
- 4
- Citations by year
- 2026: 17 · 2025: 22 · 2024: 24 · 2023: 25 · 2022: 18 · 2021: 35 · 2020: 33 · 2019: 29 · 2018: 28 · 2017: 28 · 2016: 24 · 2015: 28 · 2014: 20 · 2013: 22 · 2012: 19
- FWCI
- 17.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Cancer Institute (R01CA082515, CA82515)
- National Institute of Allergy and Infectious Diseases (R01AI048694, AI48694)
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- hypoxia-inducible factor-1α, lipopolysaccharide, sepsis, macrophages, prolyl hydroxylase, TLR4, inflammatory cytokines, HIF-1α inhibition, therapeutic target, hypotension, hypothermia
- MeSH terms
- Animals, Lipopolysaccharides, Macrophages, Mice, Transgenic, RNA, Messenger, Cytokines, Gene Deletion, Sepsis, Toll-Like Receptor 4, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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