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: Nadine Keleku-Lukwete, Mikiko Suzuki, Akihito Otsuki, Kouhei Tsuchida, Saori Katayama, Makiko Hayashi, Eriko Naganuma, Takashi Moriguchi, Osamu Tanabe, James Douglas Engel, Masue Imaizumi, Masayuki Yamamoto
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 39 Pg. 12169-74 (Sep 29 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 26371321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cytoskeletal Proteins
• DNA Primers
• Keap1 protein, mouse
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Luciferases

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Anemia, Sickle Cell (complications, therapy)
• Animals
• Cytoskeletal Proteins (genetics)
• DNA Primers (genetics)
• Flow Cytometry
• Gene Knockout Techniques
• Immunoblotting
• Inflammation (genetics, therapy)
• Kelch-Like ECH-Associated Protein 1
• Liver (pathology)
• Luciferases
• Mice
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oxidative Stress (genetics)
• Real-Time Polymerase Chain Reaction
• Transcriptional Activation (genetics)