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ORIGINAL RESEARCH ARTICLE

Antioxidants and Phase 2 Enzymes in Macrophages: Regulation by Nrf2 Signaling and Protection Against Oxidative and Electrophilic Stress

Hong Zhu^*, Zhenquan Jia^*, Li Zhang, Masayuki Yamamoto, Hara P. Misra^*,, Michael A. Trush^|| and Yunbo Li^*,,1

^* Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center, Blacksburg, Virginia 24060; Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, Ohio 43210; Center for TARA and Institute for Basic Medical Sciences, University of Tsukuba, Tsukuba 305-8577, Japan; Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia 24061; and ^|| Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205

To whom requests for reprints should be addressed at ¹ Division of Biomedical Sciences, Edward Via Virginia College of Osteopathic Medicine, Virginia Tech Corporate Research Center Research Building II, 1861 Pratt Drive, Blacksburg, VA 24060. E-mail: yli{at}vcom.vt.edu

Macrophages play important roles in immunity and other physiological processes. They are also target cells of various toxic agents, including oxidants and electrophiles. However, little is known regarding the molecular regulation and chemical inducibility of a spectrum of endogenous antioxidants and phase 2 enzymes in normal macrophages. Understanding the molecular pathway(s) controlling the coordinated expression of various macrophage antioxidants and phase 2 defenses is of importance for developing strategies to protect against macrophage injury induced by oxidants and electrophiles. Accordingly, this study was undertaken to determine the role of the nuclear factor E2-related factor 2 (Nrf2) in regulating both constitutive and chemoprotectant-inducible expression of various antioxidants and phase 2 enzymes in mouse macrophages. The constitutive expression of a series of antioxidants and phase 2 enzymes was significantly lower in macrophages derived from Nrf2-null (Nrf2^–/–) mice than those from wild-type (Nrf2^+/+) littermates. Incubation of wild-type macrophages with 3H-1,2-dithiole-3-thione (D3T) led to significant induction of various antioxidants and phase 2 enzymes, including catalase, glutathione, glutathione peroxidase (GPx), glutathione reductase, glutathione S-transferase, and NAD(P)H:quinone oxidoreductase 1. The inducibility of the above cellular defenses except for GPx by D3T was completely abolished in Nrf2^–/– macrophages. As compared with wild-type cells, Nrf2^{– /–} macrophages were much more susceptible to cell injury induced by reactive oxygen/nitrogen species, as well as two known macrophage toxins, acrolein and cadmium. Up-regulation of the antioxidants and phase 2 enzymes by D3T in wild-type macrophages resulted in increased resistance to the above oxidant-and electrophile-induced cell injury, whereas D3T treatment of Nrf2^{– /–} macrophages provided only marginal or no cytoprotec-tion. This study demonstrates that Nrf2 is an indispensable factor in controlling both constitutive and inducible expression of a wide spectrum of antioxidants and phase 2 enzymes in macrophages as well as the susceptibility of these cells to oxidative and electrophilic stress.

Key Words: Nrf2 • macrophages • phase 2 enzymes • cytotoxicity • oxidants • electrophiles