Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

By E. Kobayashi, Takafumi Suzuki, R. Funayama, Takeshi Nagashima, M. Hayashi, Hiroki Sekine, N. Tanaka, Takashi Moriguchi, Hozumi Motohashi, Keiko Nakayama and 1 more. Nature Communications, 2016

1,683 citations recorded by the source corpus.

Nrf2 (NF-E2-related factor-2) transcription factor regulates oxidative/xenobiotic stress response and also represses inflammation. However, the mechanisms how Nrf2 alleviates inflammation are still unclear. Here, we demonstrate that Nrf2 interferes with lipopolysaccharide-induced transcriptional upregulation of proinflammatory cytokines, including IL-6 and IL-1β. Chromatin immunoprecipitation (ChIP)-seq and ChIP-qPCR analyses revealed that Nrf2 binds to the proximity of these genes in macrophages and inhibits RNA Pol II recruitment. Further, we found that Nrf2-mediated inhibition is independent of the Nrf2-binding motif and reactive oxygen species level. Murine inflammatory models further demonstrated that Nrf2 interferes with IL6 induction and inflammatory phenotypes in vivo. Thus, contrary to the widely accepted view that Nrf2 suppresses inflammation through redox control, we demonstrate here that Nrf2 opposes transcriptional upregulation of proinflammatory cytokine genes. This study identifies Nrf2 as the upstream regulator of cytokine production and establishes a molecular basis for an Nrf2-mediated anti-inflammation approach. Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c124889111063dc91058d620551ec6af6d2c5c70

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Citations in the corpus

Transcriptional Regulation by Nrf2 (2017, background): “Together with the ‘‘default Nrf2 program,’’ Nrf2 selectively activates other genes that are specific to the cell type and the nature of the inducing agent (2, 13, 82, 89, 107, 164, 182, 188).”
An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation (2020, background): “This connection was further corroborated by the observation that Nrf2 negatively regulates the NF-κB-mediated transcription of pro-inflammatory cytokine genes [142].”
NRF2, a Transcription Factor for Stress Response and Beyond (2020, background): “ChIP-seq analysis revealed that NRF2 directly binds to the promoter proximal regions of IL-6 and IL-1β genes to disrupt RNA polymerase II recruitment and blocks gene induction in macrophages [127].”
Nrf2, the Master Regulator of Anti-Oxidative Responses (2017, background): “In contrast, after alternative activation with IL-4, IL-13, or glucocorticoid treatment, an anti-inflammatory, wound-healing promoting, M2-like macrophage phenotype is observed [37].”
Oxidative Stress in Cancer (2020, background): “It is not clear whether NRF2 can repress prooxidant genes, but it has been reported to downregulate NOX4 and, through its ability to repress the expression of genes encoding interleukin-1β (IL-1β) and IL-6, along with induction of the gene encoding peroxisome proliferator-activated receptor gamma (P”
The Metabolic Signature of Macrophage Responses (2019, background): “Finally, M2d macrophages, also known as tumor-associated macrophages (TAMs), are induced by TLR ligands and A2 adenosine receptor (A2R) agonists, or by IL-6; they secrete high levels of IL-10, TGF-β, and VEGF and low IL12, TNF-α, and IL-1β, and contribute to tumor angiogenesis, growth and metastasis”