Inflammation is a complex process that occurs when tissues become infected or otherwise injured by physical damage or exposure to irritants. The first goal of inflammation is to limit the extent of damage and, in the case of infection, eliminate the cause of injury. Infected and injured tissues send signals to recruit immune cells, such as macrophages, to the sites of injury. Once the immune cells arrive, they produce reactive oxygen species (ROS), which help proinflammatory transcription factors, such as NF-κB, to turn on proinflammatory cytokine genes. The ROS and proinflammatory cytokines are then able to coordinate the attack on infectious agents and irritants to prevent further injury.
After the battle is over, it is essential that the inflammatory response is turned off and tissues are repaired. In fact, the resolution of inflammation is equally as important as the initiation of inflammation. In many chronic diseases, failure to resolve inflammation leads to the persistent production of cytokines and ROS, which causes chronic (long-term) inflammation and ultimately leads to permanent tissue damage and loss of organ function.
Nrf2 – Master Regulator of the Antioxidant Response
Nuclear factor erythroid 2-related factor (Nrf2) plays an important role in the resolution of inflammation. Nrf2 is a transcription factor that is often thought of as the “master” regulator of the antioxidant response as it turns on genes that protect the cell during periods of oxidative stress. Oxidative stress is an imbalance that occurs when the levels of oxidants, such as ROS, are too high or the ability of the natural antioxidant defense system to remove excess ROS is impaired. High levels of ROS and oxidative stress damage the cell and increase inflammation, which can lead to cell death and damage neighboring tissues.
It has been widely accepted that Nrf2 suppresses inflammation indirectly by turning on antioxidant genes, which eliminate ROS and subsequently reduce inflammation. However, some studies have hinted that Nrf2 may also directly affect genes involved in inflammation.1,2 To better understand the role of Nrf2 in inflammation, Dr. Masayuki Yamamoto, the scientist who first discovered the Nrf2 regulatory system3,4, and researchers in his lab, conducted a study to examine whether Nrf2 directly turns off proinflammatory cytokines, or if its effects on inflammation are merely a consequence of an increased antioxidant response.5
Nrf2 – Suppressor of Inflammation
In this study, published by Kobayashi, et al., in Nature Communications, researchers found that exposing macrophages to an inflammatory irritant turned on many genes that make proinflammatory cytokines. However, when Nrf2 was activated in macrophages, the irritant was no longer able to turn on these genes.
In contrast to the accepted theory that Nrf2 turns off proinflammatory genes by first turning on antioxidant genes that reduce ROS levels, researchers in the Yamamoto lab showed that Nrf2 turns off proinflammatory genes and turns on antioxidant genes at the same time. These findings support the idea that Nrf2 could influence proinflammatory genes outside of its role in the antioxidant response.
Since Nrf2 is a transcription factor that binds to DNA to turn genes on and off, the researchers went on to ask whether Nrf2 binds to DNA near these proinflammatory genes. They found that this was indeed the case—Nrf2 directly associated with proinflammatory genes. Previous studies have shown that when Nrf2 turns on antioxidant genes, it does so by binding to a specific DNA sequence called the antioxidant response element (ARE). However, researchers in the Yamamoto lab discovered that Nrf2 appears to turn off proinflammatory genes in a completely different way. They found that Nrf2 turned off the expression of two proinflammatory cytokines, IL-6 and IL-1β, by blocking the recruitment of the transcriptional machinery that is required for genes to be turned on. They also showed that Nrf2 may block proinflammatory gene expression by associating with proinflammatory transcription factors, such as NF-κB, and interfering with their activity.
Nrf2 – Potential Target for the Treatment of Chronic Diseases
Not only were the researchers in the Yamamoto lab the first to show that Nrf2 directly blocks proinflammatory genes, they also demonstrated that the Nrf2 pathway may be a target for the development of new treatments for chronic inflammatory diseases. IL-6 is a key player in the development of multiple sclerosis and other inflammatory diseases. The Yamamoto lab found that Nrf2 activation turned off IL-6 gene expression in a nonclinical model of multiple sclerosis. Importantly, they also found that Nrf2 activation reduced the symptoms of multiple sclerosis in this model.
In many chronic diseases, the activity of Nrf2 is often inadequate, which may render the cell unable to turn off the processes that lead to chronic inflammation. The results from this study suggest that activation of Nrf2 may be a potential approach for the treatment of acute and chronic diseases that have an inflammatory component.
- Harvey, et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3(78):78ra32.
- Ishii, et al. Role of Nrf2 in the regulation of CD36 and stress protein expression in murine macrophages: activation by oxidatively modified LDL and 4-hydroxynonenal. Circ Res. 2004;94(5):609-616.
- Itoh K, et al. Cloning and characterization of a novel erythroid cell-derived CNC family transcription factor heterodimerizing with the small Maf family proteins. Mol Cell Biol. 1995;15: 4184–4193.
- Itoh K, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13:76–86.
- Kobayashi, et al. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun. 2016;7:11624.