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Review
, 2013, 529219

Roles nrf2 Plays in Myeloid Cells and Related Disorders

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Review

Roles nrf2 Plays in Myeloid Cells and Related Disorders

Eri Kobayashi et al. Oxid Med Cell Longev.

Abstract

The Keap1-Nrf2 system protects animals from oxidative and electrophilic stresses. Nrf2 is a transcription factor that induces the expression of genes essential for detoxifying reactive oxygen species (ROS) and cytotoxic electrophiles. Keap1 is a stress sensor protein that binds to and ubiquitinates Nrf2 under unstressed conditions, leading to the rapid proteasomal degradation of Nrf2. Upon exposure to stress, Keap1 is modified and inactivated, which allows Nrf2 to accumulate and activate the transcription of a battery of cytoprotective genes. Antioxidative and detoxification activities are important for many types of cells to avoid DNA damage and cell death. Accumulating lines of recent evidence suggest that Nrf2 is also required for the primary functions of myeloid cells, which include phagocytosis, inflammation regulation, and ROS generation for bactericidal activities. In fact, results from several mouse models have shown that Nrf2 expression in myeloid cells is required for the proper regulation of inflammation, antitumor immunity, and atherosclerosis. Moreover, several molecules generated upon inflammation activate Nrf2. Although ROS detoxification mediated by Nrf2 is assumed to be required for anti-inflammation, the entire picture of the Nrf2-mediated regulation of myeloid cell primary functions has yet to be elucidated. In this review, we describe the Nrf2 inducers characteristic of myeloid cells and the contributions of Nrf2 to diseases.

Figures

Figure 1
Figure 1
Keap1-Nrf2 stress response system. Stress-sensing system of Keap1 and Nrf2. Environmental stresses, including ROS and electrophiles, inactivate Keap1 and stall the ubiquitination and degradation of Nrf2. Nrf2 accumulates in the nucleus and forms a heterodimer with the sMaf protein. The binding of the Nrf2-sMaf heterodimer to the EpRE/ARE motif leads to the transactivation of Nrf2 target genes, which include a battery of antioxidant and detoxifying genes required for cellular protection.
Figure 2
Figure 2
Nrf2 activation by inflammation-related molecules. Inflammation stimulates the production/accumulation of Nrf2-inducing molecules. Nrf2 inducers modify target reactive cysteine residues of Keap1; blue arrows indicate the flow of various Nrf2 inducers toward the reactive cysteine residues of Keap1. Inflammation induces COX-2, which leads to the production of 15d-PGJ2 and PGA2. COX-2 also produces electrophilic derivatives from ω3-fatty acids. PGA2, 15d-PGJ2, and ω3-fatty acid derivatives inactivate Keap1, leading to Nrf2 activation. Inflammation also induces iNOS and causes NO production. NO and its derivatives 8-nitro-cGMP and OA-NO2 also modify Keap1 and activate Nrf2. PGA2, 15d-PGJ2, ω3-fatty acid derivatives, and OA-NO2 preferentially modify Cys273/288 of Keap1, whereas NO preferentially modifies Cys151, and 8-nitro-cGMP preferentially modifies Cys434.
Figure 3
Figure 3
Suppression of acute inflammation by Nrf2. Nrf2 function related to acute inflammation in myeloid cells. The blue line represents the consequence of Nrf2 activation, that is, the loss of ROS, while the consequences of ROS hyperaccumulation are shown with orange arrows. Although ROS exacerbate inflammation, Nrf2 exerts anti-inflammatory effects through the suppression of ROS accumulation. In macrophages, ROS is primarily generated by the NADPH oxidase complex for bacterial killing.
Figure 4
Figure 4
Physiological roles of Nrf2 in myeloid cells. The roles of Nrf2 in myeloid cells have been clarified in disease models. In tumor development models, Nrf2 suppresses ROS in MDSCs, in which ROS is required for the suppression of T cells. Thus, Nrf2 supports antitumor immunity and reduces tumor metastasis. In an ApoE-deficient atherosclerotic mouse model, Nrf2 upregulates the scavenger receptor CD36 and promotes atherogenesis.

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