ArticleProceedings of the National Academy of Sciences of the United States of America2015
Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 110 citations in OpenAlex.
- Trial
- The oxidative stress-inflammation self-perpetuating cycle in multiple sclerosis: from mechanisms to emerging antioxidant strategies.Frontiers in pharmacology · 2026Review
- Selective AMPKβ1 activation induces fetal hemoglobin in human erythroid cells and sickle cell mice via the noncanonical NRF2 pathway.Science advances · 2025Article
- The Nrf2 Activator CDDO-Imidazole Suppresses Inflammation-Induced Red Blood Cell Alloimmunization.Antioxidants (Basel, Switzerland) · 2025Article
- Metabolic gatekeeping in murine stress erythropoiesis.Blood. Red cells & iron · 2025Article
- Reduced GATA1 levels are associated with ineffective erythropoiesis in sickle cell anemia.Haematologica · 2025Article
- Innovations in Drug Discovery for Sickle Cell Disease Targeting Oxidative Stress and NRF2 Activation-A Short Review.International journal of molecular sciences · 2025Review
- CDDO-Imidazole regulates RBC alloimmunization to the KEL antigen by activating Nrf2.bioRxiv : the preprint server for biology · 2025Article
- MFSD7C protects hemolysis-induced lung impairments by inhibiting ferroptosis.Nature communications · 2024Article
- Anti-Inflammatory Therapeutic Mechanisms of Isothiocyanates: Insights from Sulforaphane.Biomedicines · 2024Review
- Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease.Antioxidants (Basel, Switzerland) · 2024Article
- Mouse models of sickle cell disease: Imperfect and yet very informative.Blood cells, molecules & diseases · 2024Review
- Flurbiprofen inhibits heme induced NLRP3 inflammasome in Berkeley sickle cell disease mice.Frontiers in pharmacology · 2023Article
- Higher Levels of Plasma Fetuin-A, Nrf2, and Cytokeratin 18 in Patients with Hashimoto's Disease.Sisli Etfal Hastanesi tip bulteni · 2023Article
- Genetic Ablation of Nrf2 Exacerbates Neuroinflammation in Ocular Autoimmunity.International journal of molecular sciences · 2022Article
- The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 DegradationMolecular and cellular biology · 2022Article
- Immunomodulatory actions of a kynurenine-derived endogenous electrophile.Science advances · 2022Article
- Pharmacological Induction of Fetal Hemoglobin in β-Thalassemia and Sickle Cell Disease: An Updated Perspective.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Limitations of mouse models for sickle cell disease conferred by their human globin transgene configurations.Disease models & mechanisms · 2022Article
- Multifaceted Roles of the KEAP1-NRF2 System in Cancer and Inflammatory Disease Milieu.Antioxidants (Basel, Switzerland) · 2022Review
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
Sickle cell disease (SCD) is an inherited disorder caused by a point mutation in the β-globin gene, leading to the production of abnormally shaped red blood cells. Sickle cells are prone to hemolysis and thereby release free heme into plasma, causing oxidative stress and inflammation that in turn result in damage to multiple organs. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a master regulator of the antioxidant cell-defense system. Here we show that constitutive Nrf2 activation by ablation of its negative regulator Keap1 (kelch-like ECH-associated protein 1) significantly improves symptoms in SCD model mice. SCD mice exhibit severe liver damage and lung inflammation associated with high expression levels of proinflammatory cytokines and adhesion molecules compared with normal mice. Importantly, these symptoms subsided after Nrf2 activation. Although hemolysis and stress erythropoiesis did not change substantially in the Nrf2-activated SCD mice, Nrf2 promoted the elimination of plasma heme released by sickle cells' hemolysis and thereby reduced oxidative stress and inflammation, demonstrating that Nrf2 activation reduces organ damage and segregates inflammation from prevention of hemolysis in SCD mice. Furthermore, administration of the Nrf2 inducer CDDO-Im (2-cyano-3, 12 dioxooleana-1, 9 diene-28-imidazolide) also relieved inflammation and organ failure in SCD mice. These results support the contention that Nrf2 induction may be an important means to protect organs from the pathophysiology of sickle cell-induced damage.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.