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The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytes

Nature Immunology volume 12, pages 778–785 (2011)Cite this article

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Abstract

The transcription factors that regulate differentiation into the monocyte subset in bone marrow have not yet been identified. Here we found that the orphan nuclear receptor NR4A1 controlled the differentiation of Ly6C− monocytes. Ly6C− monocytes, which function in a surveillance role in circulation, were absent from Nr4a1−/− mice. Normal numbers of myeloid progenitor cells were present in Nr4a1−/− mice, which indicated that the defect occurred during later stages of monocyte development. The defect was cell intrinsic, as wild-type mice that received bone marrow from Nr4a1−/− mice developed fewer patrolling monocytes than did recipients of wild-type bone marrow. The Ly6C− monocytes remaining in the bone marrow of Nr4a1−/− mice were arrested in S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of the differentiation and survival of 'patrolling' Ly6C− monocytes.

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Figure 1: Expression of NR4A1 by Ly6C− monocytes.
Figure 2: Absence of Ly6C− monocytes in Nr4a1−/− mice.
Figure 3: Cell-intrinsic defect in monocyte development and lack of patrolling ability of monocytes from Nr4a1−/− bone marrow.
Figure 4: Normal stem cell populations and abnormal Ly6C− monocytes in Nr4a1−/− mice.
Figure 5: Specific defect in the differentiation of Nr4a1−/− Ly6C− monocytes from MDPs in the bone marrow.
Figure 6: Abnormal cell cycle and DNA damage in Ly6C− monocytes from Nr4a1−/− mice.
Figure 7: Greater apoptosis exclusively of Ly6C− bone marrow monocytes from Nr4a1−/− mice.
Figure 8: Lower expression of chemokine receptors, adhesion molecules and differentiation factors in Nr4a1−/− Ly6C− monocytes.

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References

  1. Martínez-González, J. & Badimon, L. The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells. Cardiovasc. Res. 65, 609–618 (2005).

    Article  Google Scholar 

  2. Lim, R.W., Varnum, B.C. & Herschman, H.R. Cloning of tetradecanoyl phorbol ester-induced 'primary response' sequences and their expression in density-arrested Swiss 3T3 cells and a TPA non-proliferative variant. Oncogene 1, 263–270 (1987).

    CAS  PubMed  Google Scholar 

  3. Hazel, T.G., Nathans, D. & Lau, L.F. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc. Natl. Acad. Sci. USA 85, 8444–8448 (1988).

    Article  CAS  Google Scholar 

  4. Moll, U.M., Marchenko, N. & Zhang, X.K. p53 and Nur77/TR3—transcription factors that directly target mitochondria for cell death induction. Oncogene 25, 4725–4743 (2006).

    Article  CAS  Google Scholar 

  5. Li, Q.X., Ke, N., Sundaram, R. & Wong-Staal, F. NR4A1, 2, 3—an orphan nuclear hormone receptor family involved in cell apoptosis and carcinogenesis. Histol. Histopathol. 21, 533–540 (2006).

    CAS  PubMed  Google Scholar 

  6. Rajpal, A. et al. Transcriptional activation of known and novel apoptotic pathways by Nur77 orphan steroid receptor. EMBO J. 22, 6526–6536 (2003).

    Article  CAS  Google Scholar 

  7. Lee, J.M., Lee, K.H., Weidner, M., Osborne, B.A. & Hayward, S.D. Epstein-Barr virus EBNA2 blocks Nur77-mediated apoptosis. Proc. Natl. Acad. Sci. USA 99, 11878–11883 (2002).

    Article  CAS  Google Scholar 

  8. Zhou, T. et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J. Exp. Med. 183, 1879–1892 (1996).

    Article  CAS  Google Scholar 

  9. Woronicz, J.D., Calnan, B., Ngo, V. & Winoto, A. Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367, 277–281 (1994).

    Article  CAS  Google Scholar 

  10. Cho, H.J. et al. Cutting edge: identification of the targets of clonal deletion in an unmanipulated thymus. J. Immunol. 170, 10–13 (2003).

    Article  CAS  Google Scholar 

  11. Pei, L., Castrillo, A., Chen, M., Hoffmann, A. & Tontonoz, P. Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli. J. Biol. Chem. 280, 29256–29262 (2005).

    Article  CAS  Google Scholar 

  12. Baker, K.D. et al. The Drosophila orphan nuclear receptor DHR38 mediates an atypical ecdysteroid signaling pathway. Cell 113, 731–742 (2003).

    Article  CAS  Google Scholar 

  13. Wang, Z. et al. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423, 555–560 (2003).

    Article  CAS  Google Scholar 

  14. Fahrner, T.J., Carroll, S.L. & Milbrandt, J. The NGFI-B protein, an inducible member of the thyroid/steroid receptor family, is rapidly modified posttranslationally. Mol. Cell. Biol. 10, 6454–6459 (1990).

    Article  CAS  Google Scholar 

  15. Wilson, T.E., Fahrner, T.J., Johnston, M. & Milbrandt, J. Identification of the DNA binding site for NGFI-B by genetic selection in yeast. Science 252, 1296–1300 (1991).

    Article  CAS  Google Scholar 

  16. Wallen-Mackenzie, A. et al. Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells. Genes Dev. 17, 3036–3047 (2003).

    Article  CAS  Google Scholar 

  17. Li, H. et al. Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3. Science 289, 1159–1164 (2000).

    Article  CAS  Google Scholar 

  18. Lin, B. et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 116, 527–540 (2004).

    Article  CAS  Google Scholar 

  19. Thompson, J. & Winoto, A. During negative selection, Nur77 family proteins translocate to mitochondria where they associate with Bcl-2 and expose its proapoptotic BH3 domain. J. Exp. Med. 205, 1029–1036 (2008).

    Article  CAS  Google Scholar 

  20. Bonta, P.I. et al. Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses. Arterioscler. Thromb. Vasc. Biol. 26, 2288–2294 (2006).

    Article  CAS  Google Scholar 

  21. Arkenbout, E.K. et al. Protective function of transcription factor TR3 orphan receptor in atherogenesis: decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation 106, 1530–1535 (2002).

    Article  CAS  Google Scholar 

  22. Bonta, P.I. et al. Nuclear receptor Nur77 inhibits vascular outward remodelling and reduces macrophage accumulation and matrix metalloproteinase levels. Cardiovasc. Res. 87, 561–568 (2010).

    Article  CAS  Google Scholar 

  23. Mullican, S.E. et al. Abrogation of nuclear receptors Nr4a3 and Nr4a1 leads to development of acute myeloid leukemia. Nat. Med. 13, 730–735 (2007).

    Article  CAS  Google Scholar 

  24. Ramirez-Herrick, A.M., Mullican, S.E., Sheehan, A.M. & Conneely, O.M. Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Blood 117, 2681–2690 (2011).

    Article  CAS  Google Scholar 

  25. Lee, S.L. et al. Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77). Science 269, 532–535 (1995).

    Article  CAS  Google Scholar 

  26. Sirin, O., Lukov, G.L., Mao, R., Conneely, O.M. & Goodell, M.A. The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat. Cell Biol. 12, 1213–1219 (2010).

    Article  CAS  Google Scholar 

  27. Randolph, G.J. Emigration of monocyte-derived cells to lymph nodes during resolution of inflammation and its failure in atherosclerosis. Curr. Opin. Lipidol. 19, 462–468 (2008).

    Article  CAS  Google Scholar 

  28. Geissmann, F., Jung, S. & Littman, D. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  29. Palframan, R.T. et al. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J. Exp. Med. 194, 1361–1373 (2001).

    Article  CAS  Google Scholar 

  30. Serbina, N.V., Jia, T., Hohl, T.M. & Pamer, E.G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452 (2008).

    Article  CAS  Google Scholar 

  31. Narni-Mancinelli, E. et al. Memory CD8+ T cells mediate antibacterial immunity via CCL3 activation of TNF/ROI+ phagocytes. J. Exp. Med. 204, 2075–2087 (2007).

    Article  CAS  Google Scholar 

  32. Auffray, C. et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science 317, 666–670 (2007).

    Article  CAS  Google Scholar 

  33. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    Article  CAS  Google Scholar 

  34. Cros, J. et al. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33, 375–386 (2010).

    Article  CAS  Google Scholar 

  35. Nahrendorf, M. et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J. Exp. Med. 204, 3037–3047 (2007).

    Article  CAS  Google Scholar 

  36. Landsman, L., Varol, C. & Jung, S. Distinct differentiation potential of blood monocyte subsets in the lung. J. Immunol. 178, 2000–2007 (2007).

    Article  CAS  Google Scholar 

  37. Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med. 6, e1000113 (2009).

    Article  Google Scholar 

  38. Auffray, C., Sieweke, M. & Geissmann, F. Blood monocytes: development, heterogeneity, and relationship with dendritic cells. Annu. Rev. Immunol. 27, 669–692 (2009).

    Article  CAS  Google Scholar 

  39. Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007).

    Article  CAS  Google Scholar 

  40. Varol, C. et al. Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. J. Exp. Med. 204, 171–180 (2007).

    Article  CAS  Google Scholar 

  41. Yrlid, U., Jenkins, C.D. & MacPherson, G.G. Relationships between distinct blood monocyte subsets and migrating intestinal lymph dendritic cells in vivo under steady-state conditions. J. Immunol. 176, 4155–4162 (2006).

    Article  CAS  Google Scholar 

  42. Geissmann, F. et al. Development of monocytes, macrophages, and dendritic cells. Science 327, 656–661 (2010).

    Article  CAS  Google Scholar 

  43. Woollard, K.J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nat. Rev. Cardiol. 7, 77–86 (2010).

    Article  Google Scholar 

  44. Infante, A. et al. E2F2 represses cell cycle regulators to maintain quiescence. Cell Cycle 7, 3915–3927 (2008).

    Article  CAS  Google Scholar 

  45. Trikha, P. et al. E2f1–3 are critical for myeloid development. J. Biol. Chem. 286, 4783–4795 (2011).

    Article  CAS  Google Scholar 

  46. Landsman, L. et al. CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood 113, 963–972 (2009).

    Article  CAS  Google Scholar 

  47. Auffray, C. et al. CX3CR1+CD115+CD135+ common macrophage/DC precursors and the role of CX3CR1 in their response to inflammation. J. Exp. Med. 206, 595–606 (2009).

    Article  CAS  Google Scholar 

  48. You, B., Jiang, Y.Y., Chen, S., Yan, G. & Sun, J. The orphan nuclear receptor Nur77 suppresses endothelial cell activation through induction of IkappaBalpha expression. Circ. Res. 104, 742–749 (2009).

    Article  CAS  Google Scholar 

  49. Swirski, F.K. et al. Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J. Clin. Invest. 117, 195–205 (2007).

    Article  CAS  Google Scholar 

  50. Moran, A.E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    Article  CAS  Google Scholar 

  51. Mack, M. et al. Expression and characterization of the chemokine receptors CCR2 and CCR5 in mice. J. Immunol. 166, 4697–4704 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K.A. Hogquist (University of Minnesota) for NR4A1-GFP reporter mice; M. Mack (Klinikum der Universitat Regensburg) for antibody to CCR2 (MC-21); K. Ley and I. Shaked for discussions; and A. Blatchley, D. Yoakum and D. Huynh for assistance with management of the mouse colony. Supported by the US National Institutes of Health (R01 HL071141 and R01 HL079621 to C.C.H.).

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Authors and Affiliations

  1. Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA

    Richard N Hanna, Angela M Green & Catherine C Hedrick

  2. Centre for Molecular and Cellular Biology of Inflammation, King's College London, London, UK

    Leo M Carlin & Frederic Geissmann

  3. Department of Biology, Haverford College, Haverford, Pennsylvania, USA

    Harper G Hubbeling & Jennifer A Punt

  4. Department of Genetics of Microorganisms, University of Lodz, Lodz, Poland

    Dominika Nackiewicz

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Contributions

R.N.H. and L.M.C. designed and did experiments, analyzed data and contributed to the writing of the manuscript; H.G.H. did experiments with NR4A1-GFP mice; D.N. and A.M.G. did experiments; J.A.P. conceived of the studies of NR4A1-GFP mice, analyzed data and contributed to the writing of the manuscript; F.G. conceived of and directed the research related to intravital microscopy, analyzed data and contributed to the writing of the manuscript; and C.C.H. conceived of the research, directed the study, assisted with experimental design and contributed to the writing of the manuscript.

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Correspondence to Catherine C Hedrick.

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Hanna, R., Carlin, L., Hubbeling, H. et al. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C− monocytes. Nat Immunol 12, 778–785 (2011). https://doi.org/10.1038/ni.2063

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