title: Amelioration of inflammation and tissue damage in sickle cell model mice by Nrf2 activation.
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.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai 989-3126, Japan;
authors.forename: Nadine
authors.initials: N
authors.lastname: Keleku-Lukwete
authors.affiliation: Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; suzukimikiko@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Akihito
authors.initials: A
authors.lastname: Otsuki
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsuchida
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Saori
authors.initials: S
authors.lastname: Katayama
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Makiko
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Eriko
authors.initials: E
authors.lastname: Naganuma
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Moriguchi
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan;
authors.forename: Osamu
authors.initials: O
authors.lastname: Tanabe
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai 989-3126, Japan;
authors.forename: Masue
authors.initials: M
authors.lastname: Imaizumi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan; Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai 980-8573, Japan; suzukimikiko@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000628:therapy; D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D055786:Gene Knockout Techniques; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics* / Q000628:therapy*; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000473:pathology*; D008156:Luciferases; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D017931:DNA Primers; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D008156:Luciferases
keywords: Keap1; Nrf2; sickle cell disease