Abstract
Abstract Although an essential component to clear invading bacteria in innate immunity, reactive oxygen species (ROS) can adversely affect tissue. However, ROS activate Nrf2 and induce the expression of anti-oxidant enzymes including NQO1, HO-1 and GCLC, which in turn reduce the adverse effects of ROS. Given a high reactivity of ROS, we postulate that NADPH oxidase, a major producer of ROS in macrophages, exists proximal to Nrf2-Keap1 complex to effectively activate Nrf2. Here, we show that p47phox, a cytosolic subunit of NADPH oxidase, physically interacted with Nrf2 and facilitated the protective function of Nrf2 in inflammation. Biochemical and functional analyses show that p47phox bound to Nrf2 and enhanced the expression of Nrf2-dependent genes such as NQO1, HO-1 and GCLC. Immunoprecipitation assays indicate that p47phox did not interfere with the binding between Nrf2 and Keap1 but suppressed the ubiquitination of Nrf2, suggesting that p47phox enhances Nrf2 transcriptional activity by disturbing the ubiquitination of Nrf2 by Keap1. Consistent with these results, bone marrow-derived macrophage (BMDM) from p47phox -/- mice showed reduced expression levels of Nrf2-dependent genes, compared with BMDM from wild type littermates. In addition, overexpression of p47phox in the mouse lung was sufficient to suppress LPS-induced neutrophilic lung inflammation. Together, our results suggest that p47phox binds to Nrf2, enhancing the protective function of Nrf2 in inflammation.
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