The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis
Open accessAbstract
Rationale: NR4A1 (Nur77) is a nuclear receptor that is expressed in macrophages and within atherosclerotic lesions, yet its function in atherosclerosis is unknown. Objective: Nur77 regulates the development of monocytes, particularly patrolling Ly6C − monocytes that may be involved in resolution of inflammation. We sought to determine how absence of nuclear receptor subfamily 4, group A, member 1 (NR4A1) in hematopoietic cells affected atherosclerosis development. Methods and Results: Nur77 −/− chimeric mice on a Ldlr −/− background showed a 3-fold increase in atherosclerosis development when fed a Western diet for 20 weeks, despite having a drastic reduction in Ly6C − patrolling monocytes. In a second model, mice deficient in both Nur77 and ApoE (ApoE −/− Nur77 −/− ) also showed increased atherosclerosis after 11 weeks of Western diet. Atherosclerosis was associated with a significant change in macrophage polarization toward a proinflammatory phenotype, with high expression of tumor necrosis factor-α and nitric oxide and low expression of Arginase-I. Moreover, we found increased expression of toll-like receptor 4 mRNA and protein in Nur77 −/− macrophages as well as increased phosphorylation of the p65 subunit of NFκB. Inhibition of NFκB activity blocked excess activation of Nur77 −/− macrophages. Conclusions: We conclude that the absence of Nur77 in monocytes and macrophages results in enhanced toll-like receptor signaling and polarization of macrophages toward a proinflammatory M1 phenotype. Despite having fewer monocytes, Nur77 −/− mice developed significant atherosclerosis when fed a Western diet. These studies indicate that Nur77 is a novel target for modulating the inflammatory phenotype of monocytes and macrophages and may be important for regulation of atherogenesis.
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Cites
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The Macrophage Cholesterol Exporter ABCA1 Functions as an Anti-inflammatory Receptor
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Cited by
Macrophages in atherosclerosis: a dynamic balance
Moore, K. J., Sheedy, F. J., & Fisher, E. A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3520 · Cited by 2,559
Monocytes and macrophages: developmental pathways and tissue homeostasis
Ginhoux, F., & Jung, S. (2014) · Nature Reviews Immunology · doi:10.1038/nri3671 · Cited by 1,840
Developmental and Functional Heterogeneity of Monocytes
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The role of macrophages in the resolution of inflammation
Watanabe, S., Alexander, M., Misharin, A. V., & Budinger, G. R. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124615 · Cited by 925
Cochain, C., Vafadarnejad, E., Arampatzi, P., Pelisek, J., Winkels, H., Ley, K., Wolf, D., Saliba, A.-E., & Zernecke, A. (2018) · Circulation Research · doi:10.1161/circresaha.117.312509 · Cited by 894
Self-citation
Metadata
- Authors
- Hanna, R. N., Shaked, I., Hubbeling, H. G., Punt, J. A., Wu, R., Herrley, E., Zaugg, C., Pei, H., Geissmann, F., Ley, K., & Hedrick, C. C.
- Venue
- Circulation Research
- Published
- 2012-02-03
- Volume
- 110
- Issue
- 3
- Pages
- 416-427
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2171029424
- Cited by
- 450
- References
- 11
- FWCI
- 9.08
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Hanna, R. N., Shaked, I., Hubbeling, H. G., Punt, J. A., Wu, R., Herrley, E., Zaugg, C., Pei, H., Geissmann, F., Ley, K., & Hedrick, C. C. (2012). NR4A1 (Nur77) Deletion Polarizes Macrophages Toward an Inflammatory Phenotype and Increases Atherosclerosis. Circulation Research. https://doi.org/10.1161/circresaha.111.253377
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