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Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription
Open accessAbstract
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.
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“suggesting that Nrf2’s role in inflammation is not limited to just oxidative stress control [198].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [198]
In the citing paper
“Nrf2 has also been found to block the transcriptional upregulation of pro-inflammatory cytokine genes including interleukin 6 (IL-6) and interleukin 1 beta (IL-1β) in an ARE-independent manner through direct binding to the proximity of pro-inflammatory genes to inhibit RNA polymerase II recruitment”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [198]
In the citing paper
“the expression of pro-inflammatory cytokine genes in M1 macrophages is inhibited by Nrf2-ARE binding [198]”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [198]
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“it also appears to play a major role in embryo implantation in the womb, a process thought to require immunosuppression70–72.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [72]
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“Further, NRF2 possesses potent anti-inflammatory activity and alleviates a variety of inflammatory conditions, including autoimmune diseases.(8,9) In line with these protective roles of the KEAP1-NRF2 system, NRF2 activation effectively prevents chemical carcinogenesis by increasing antioxidant and detoxification capa…”
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“, interleukin [IL]‐6 and IL‐1β) due to NRF2 binding to the proximity of these genes.(28)”
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BackgroundNrf2: a dark horse in Alzheimer's disease treatment
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“Our recent description of a NOS2-dependent NRF2 gene signature in murine macrophages, together with NRF2′s known ability to attenuate inflammation [177], suggests that NO reprograms metabolism while supporting the antioxidant response, all at the expense of full inflammatory potential.”
BackgroundCan Activation of NRF2 Be a Strategy against COVID-19?
Cuadrado, A., Pajares, M., Benito, C., Jiménez-Villegas, J., Escoll, M., Fernández-Ginés, R., García‐Yagüe, Á. J., Lastra, D., Manda, G., Rojo, A. I., et al. (2020) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2020.07.003 · Cited by 240
“NRF2 also plays a role in both the execution and the resolution of inflammation [12] by repressing proinflammatory genes such as IL6 and IL1B [21].”
Targeting innate immunity-driven inflammation in CKD and cardiovascular disease
Speer, T., Dimmeler, S., Schunk, S. J., Fliser, D., & Ridker, P. M. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00621-9 · Cited by 251
Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease
Matoba, K., Takeda, Y., Nagai, Y., Kawanami, D., Utsunomiya, K., & Nishimura, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143393 · Cited by 223
“reported that Nrf2 binds to the regulatory regions of inflammatory genes and thereby induces their transcription in macrophages and alleviates RNA polymerase II recruitment [37].”
BackgroundThe Immunomodulatory Potential of the Metabolite Itaconate
Hooftman, A., & O'Neill, L. A. J. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.05.007 · Cited by 236
Oxidative Stress Is a Key Modulator in the Development of Nonalcoholic Fatty Liver Disease
Ma, Y., Lee, G., Heo, S.-Y., & Roh, Y. (2021) · Antioxidants · doi:10.3390/antiox11010091 · Cited by 233
Marchev, A. S., Dimitrova, P. A., Burns, A. J., Kostov, R. V., Dinkova‐Kostova, A. T., & Georgiev, M. I. (2017) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13407 · Cited by 225
Jiwaji, Z., Tiwari, S. S., Avilés-Reyes, R. X., Hooley, M., Hampton, D., Torvell, M., Johnson, D. A., McQueen, J., Baxter, P., Sabari-Sankar, K., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27702-w · Cited by 223
Transcriptional control of microglia phenotypes in health and disease
Holtman, I. R., Skola, D., & Glass, C. K. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90604 · Cited by 218
“In macrophages, NRF2 expression represses inflammation not only by regulating the antioxidative defense (98), but also by directly inhibiting the recruitment of RNA polymerase II to Il6 and Tnf (99).”
BackgroundSharma, A., Tate, M., Mathew, G., Vince, J. E., Ritchie, R. H., & de Haan, J. B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00114 · Cited by 221
“Equally intriguing, recent data by Kobayashi show an opposite effect where Nrf2 binds to a proximal region of the IL-1β and IL-18 gene to inhibit transcription (Kobayashi et al., 2016), whilst Nrf2 knockout mice on an LDL-R deficient background show increased atherogenesis (Barajas et al., 2011).”
BackgroundTime-resolved single-cell transcriptomics defines immune trajectories in glioblastoma
Kirschenbaum, D. S., Xie, K., Ingelfinger, F., Katzenelenbogen, Y., Abadie, K., Look, T., Sheban, F., Phan, T. S., Li, B., Zwicky, P., et al. (2023) · Cell · doi:10.1016/j.cell.2023.11.032 · Cited by 224
Sharma, R. S., Harrison, D. J., Kisielewski, D., Cassidy, D. M., McNeilly, A. D., Gallagher, J. R., Walsh, S. V., Honda, T., McCrimmon, R. J., Dinkova‐Kostova, A. T., et al. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.11.016 · Cited by 214
“TBE-31 decreased Il-1bmRNA levels, in line with the proposal that Nrf2 inhibits transcription of the Il-1b gene by binding to the promoter and preventing recruitment of RNA pol II.61 Therefore, it is likely TBE-31 increases the effectiveness of this mode of repression of inflammation.”
BackgroundBahn, G., Park, J.-S., Yun, U. J., Lee, Y. J., Choi, Y., Park, J. S., Baek, S. H., Choi, B. Y., Cho, Y. S., Kim, H. K., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819541116 · Cited by 210
“However, there are several reports suggesting that NRF2 negatively regulates the expression of certain genes (49, 50).”
BackgroundCui, Y., Zhang, Z., Zhou, X., Zhao, Z., Zhao, R., Xu, X., Kong, X., Ren, J., Yao, X., Wen, Q., et al. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02231-x · Cited by 208
“Notably, one previous study showed that Nrf2 can inhibit LPS-induced inflammation by blocking proinflammatory cytokine transcription, which is independent of their ROS elimination effect [37].”
BackgroundNrf2 and oxidative stress in liver ischemia/reperfusion injury
Bardallo, R. G., Rosello, A. P., Sánchez-Nuño, S., Alva, N., Roselló‐Catafau, J., & Carbonell, T. (2021) · FEBS Journal · doi:10.1111/febs.16336 · Cited by 208
Role of Nrf2 in aging, Alzheimer’s and other neurodegenerative diseases
George, M., Tharakan, M., Culberson, J. W., Reddy, A. P., & Reddy, P. H. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101756 · Cited by 216
Saha, S., Buttari, B., Profumo, E., Tucci, P., & Saso, L. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.787258 · Cited by 185
“…candidate ALGERNON2 (altered generation of neurons 2) reduced the proinflammatory cytokines secretion and stabilized cyclinD1/p21 complex by inhibiting Dyrk1A activity, leading to Nrf2-dependent antioxidant and anti-inflammatory responses in a MPTP-induced PD model (Kobayashi et al., 2016).”
BackgroundInfluentialActivation of Nrf2 signaling by natural products-can it alleviate diabetes?
Matzinger, M., Fischhuber, K., & Heiß, E. H. (2017) · Biotechnology Advances · doi:10.1016/j.biotechadv.2017.12.015 · Cited by 208
Li, S.-T., Dai, Q., Zhang, S., Liu, Y., Yu, Q.-Q., Tan, F., Lu, S.-H., Wang, Q., Chen, J., Huang, H., et al. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.143 · Cited by 203
Fetoni, A. R., Paciello, F., Rolesi, R., Paludetti, G., & Troiani, D. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.02.022 · Cited by 210
Nrf2: Molecular and epigenetic regulation during aging
Silva‐Palacios, A., Ostolga-Chavarría, M., Zazueta, C., & Königsberg, M. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.06.003 · Cited by 199
The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment
Taguchi, K., & Yamamoto, M. (2020) · Cancers · doi:10.3390/cancers13010046 · Cited by 195
“In contrast, NRF2 downregulates genes encoding proinflammatory factors such as interleukin-6 (IL6) and interleukin 1β (IL1β) [15].”
BackgroundSelf-citationCrosstalk of toll-like receptors signaling and Nrf2 pathway for regulation of inflammation
Mohan, S. V., & Gupta, D. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.10.019 · Cited by 221
Feng, R., Morine, Y., Ikemoto, T., Imura, S., Iwahashi, S., Saito, Y., & Shimada, M. (2018) · Cell Communication and Signaling · doi:10.1186/s12964-018-0262-x · Cited by 197
NRF2: KEAPing Tumors Protected
Pillai, R., Hayashi, M., Zavitsanou, A.-M., & Papagiannakopoulos, T. Y. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0922 · Cited by 196
Self-citationTargeting Mechanosensitive Transcription Factors in Atherosclerosis
Niu, N., Xu, S., Xu, Y., Little, P. J., & Jin, Z. (2019) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2019.02.004 · Cited by 194
Hoffmann, M. H., & Griffiths, H. R. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.03.016 · Cited by 193
Horowitz, R. I., Freeman, P. R., & Bruzzese, J. (2020) · Respiratory Medicine Case Reports · doi:10.1016/j.rmcr.2020.101063 · Cited by 184
“Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription [72], and both curcumin and sulforaphane are potent Nrf2 activators that have been shown to decrease a broad range of inflammatory cytokines including IL-6 [73], helping to lower inflammation [74,75].”
Inflammation and Oxidative Stress in Chronic Kidney Disease and Dialysis Patients
Ebert, T., Neytchev, O., Witasp, A., Kublickiene, K. R., Stenvinkel, P., & Shiels, P. G. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8184 · Cited by 197
Luo, J.-F., Shen, X., Lio, C.-K., Dai, Y., Cheng, C., Liu, J.-X., Yao, Y.-D., Yu, Y., Xie, Y., Luo, P., et al. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00911 · Cited by 181
Baardman, J., Verberk, S. G. S., Prange, K. H. M., van Weeghel, M., van der Velden, S., Ryan, D. G., Wüst, R. C. I., Neele, A. E., Speijer, D., Denis, S. W., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.10.092 · Cited by 175
“Nrf2 emerged as a crucial regulator of the inflammatory responses in macrophages (Kobayashi et al., 2016; Mills et al., 2018).”
BackgroundResultLiu, W., Zhao, Y., Wang, G., Feng, S., Ge, X., Ye, W., Wang, Z., Zhu, Y., Cai, W., Bai, J., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102344 · Cited by 174
Widhalm, J. R., & Rhodes, D. (2016) · Horticulture Research · doi:10.1038/hortres.2016.46 · Cited by 183
Rothchild, A. C., Olson, G. S., Nemeth, J., Amon, L. M., Mai, D., Gold, E. S., Diercks, A. H., & Aderem, A. A. (2019) · Science Immunology · doi:10.1126/sciimmunol.aaw6693 · Cited by 171
Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer’s Disease Model Mice
Uruno, A., Matsumaru, D., Ryoke, R., Saito, R., Kadoguchi, S., Saigusa, D., Saito, T., Saido, T. C., Kawashima, R., & Yamamoto, M. P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00467-19 · Cited by 168
“ELISA showed that the soluble A (1-40) (F) and A (1-42) levels were comparable among cerebral cortices and hippocampi in AppNLGF and AppNLGF::Keap1FA/FA mouse”
BackgroundMethodInfluentialSelf-citationCellular Defensive Mechanisms of Tea Polyphenols: Structure-Activity Relationship
Truong, V., & Jeong, W. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179109 · Cited by 189
Marrocco, A., & Ortiz, L. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.936167 · Cited by 173
Piotrowska, M., Świerczyński, M., Fichna, J., & Piechota-Polańczyk, A. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105243 · Cited by 162
Metadata
- Authors
- Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., Tanaka, N., Moriguchi, T., Motohashi, H., Nakayama, K., & Yamamoto, M.
- Affiliations
- Tohoku University (JP)
- Miyagi Prefectural Hospital Organization (JP)
- Institute of Development, Aging and Cancer, Tohoku University (JP)
- Corresponding author
- Kobayashi, Eri H.
- Yamamoto, Masayuki
- ORCID
- Venue
- Nature Communications
- Published
- 2016-05-23
- Volume
- 7
- Issue
- 1
- Pages
- 11624-11624
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4879264
- OpenAlex
- W2400239628
- Cited by
- 1,878
- References
- 58
- Citations by year
- 2026: 188 · 2025: 244 · 2024: 245 · 2023: 214 · 2022: 243 · 2021: 209 · 2020: 236 · 2019: 115 · 2018: 109 · 2017: 61 · 2016: 13
- FWCI
- 51.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- The Japanese Biochemical Society
- Funders
- Japan Agency for Medical Research and Development (CREST)
- Ministry of Education, Culture, Sports, Science and Technology (23116002, 22118002, 24249015, CREST)
- Japan Society for the Promotion of Science (15K14414, 15H04692, 16H05147, 26111002, 24249015, 25840001, CREST, 15K08257, 16K15228)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Nrf2, macrophages, inflammation, inflammatory cytokines, interleukin-6, IL-1β, transcriptional repression, RNA polymerase II recruitment, lipopolysaccharide, anti-inflammatory mechanism, oxidative stress response
- MeSH terms
- Animals, Gene Expression Regulation, Inflammation, Macrophages, Mice, Inbred C57BL, Mice, Inbred ICR, RNA Polymerase II, Cytokines, Mice, Knockout, Oxidative Stress, NF-E2-Related Factor 2
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