Resource | Published:

Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages

Nature Immunology volume 13, pages 11181128 (2012) | Download Citation

Abstract

We assessed gene expression in tissue macrophages from various mouse organs. The diversity in gene expression among different populations of macrophages was considerable. Only a few hundred mRNA transcripts were selectively expressed by macrophages rather than dendritic cells, and many of these were not present in all macrophages. Nonetheless, well-characterized surface markers, including MerTK and FcγR1 (CD64), along with a cluster of previously unidentified transcripts, were distinctly and universally associated with mature tissue macrophages. TCEF3, C/EBP-α, Bach1 and CREG-1 were among the transcriptional regulators predicted to regulate these core macrophage-associated genes. The mRNA encoding other transcription factors, such as Gata6, was associated with single macrophage populations. We further identified how these transcripts and the proteins they encode facilitated distinguishing macrophages from dendritic cells.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    & The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

  2. 2.

    & Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

  3. 3.

    Differentiation and heterogeneity in the mononuclear phagocyte system. Mucosal Immunol. 1, 432–441 (2008).

  4. 4.

    & Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

  5. 5.

    , , , & Unraveling mononuclear phagocyte heterogeneity. Nat. Rev. Immunol. 10, 453–460 (2010).

  6. 6.

    et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).

  7. 7.

    et al. Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat. Immunol. 8, 1207–1216 (2007).

  8. 8.

    et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009).

  9. 9.

    et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322, 1097–1100 (2008).

  10. 10.

    Development and differentiation of macrophages and related cells: Historical review and current concepts. J. Clin. Exp. Hematop. 41, 1–33 (2001).

  11. 11.

    et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

  12. 12.

    et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

  13. 13.

    , , & MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326, 867–871 (2009).

  14. 14.

    & Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

  15. 15.

    et al. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457, 318–321 (2009).

  16. 16.

    & Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).

  17. 17.

    et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

  18. 18.

    et al. Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J. Exp. Med. 204, 3133–3146 (2007).

  19. 19.

    , & Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).

  20. 20.

    et al. Endogenous MHC-related protein 1 is transiently expressed on the plasma membrane in a conformation that activates mucosal-associated invariant T cells. J. Immunol. 186, 4744–4750 (2011).

  21. 21.

    , , , & Platelet-activating factor acetylhydrolase increases during macrophage differentiation. A novel mechanism that regulates accumulation of platelet-activating factor. J. Biol. Chem. 264, 8467–8470 (1989).

  22. 22.

    et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

  23. 23.

    et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069–1082 (2011).

  24. 24.

    et al. Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. J. Exp. Med. 209, 1135–1152 (2012).

  25. 25.

    , , , & Selective depletion of eosinophils or neutrophils in mice impacts the efficiency of apoptotic cell clearance in the thymus. PLoS ONE 5, e11439 (2010).

  26. 26.

    et al. A major lung CD103 (αE)-β7 integrin-positive epithelial dendritic cell population expressing langerin and tight junction proteins. J. Immunol. 176, 2161–2172 (2006).

  27. 27.

    et al. CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J. Exp. Med. 208, 1789–1797 (2011).

  28. 28.

    et al. Deciphering the transcriptional network of the dendritic cell lineage. Nat. Immunol. 13, 888–899 (2012).

  29. 29.

    et al. Bach1 regulates osteoclastogenesis via both heme oxygenase-1 dependent and independent pathways. Arthritis Rheum. 64, 1518–1528 (2012).

  30. 30.

    et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 21, 5216–5224 (2002).

  31. 31.

    , , & A cellular repressor of E1A-stimulated genes that inhibits activation by E2F. Mol. Cell. Biol. 18, 5032–5041 (1998).

  32. 32.

    et al. The crystal structure of CREG, a secreted glycoprotein involved in cellular growth and differentiation. Proc. Natl. Acad. Sci. USA 102, 18326–18331 (2005).

  33. 33.

    , , & The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells. Oncogene 19, 2120–2128 (2000).

  34. 34.

    & CREG1 enhances p16INK4a-induced cellular senescence. Cell Cycle 10, 518–530 (2011).

  35. 35.

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

  36. 36.

    , , , & Antibody to Langerin/CD207 localizes large numbers of CD8α+ dendritic cells to the marginal zone of mouse spleen. Proc. Natl. Acad. Sci. USA 106, 1524–1529 (2009).

  37. 37.

    et al. Intrathymic programming of effector fates in three molecularly distinct gammadelta T cell subtypes. Nat. Immunol. 13, 511–518 (2012).

  38. 38.

    , & Superparamagnetic clustering of data. Phys. Rev. Lett. 76, 3251–3254 (1996).

Download references

Acknowledgements

We thank our colleagues of the ImmGen Project consortium; V. Jojic, J. Ericson, S. Davis and C. Benoist for contributions; eBioscience and Affymetrix for material support of the ImmGen Project; and M. Colonna (Washington University School of Medicine) for monoclonal antibodies (including anti-Siglec-H) and other reagents. Supported by the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (R24 AI072073 to fund the ImmGen Project, spearheaded by C. Benoist), the US National Institutes of Health (R01AI049653 and R01AI061741 to G.J.R.; P50GM071558-03 and R01DK08854 to A.M.; and5T32DA007135-27 to A.R.M.) and the American Heart Association (10POST4160140 to E.L.G.).

Author information

Affiliations

  1. Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York, USA.

    • Emmanuel L Gautier
    • , Claudia Jakubzick
    •  & Gwendalyn J Randolph
  2. The Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA.

    • Emmanuel L Gautier
    • , Jennifer Miller
    • , Melanie Greter
    • , Claudia Jakubzick
    • , Julie Helft
    • , Andrew Chow
    • , Miriam Merad
    •  & Gwendalyn J Randolph
  3. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Emmanuel L Gautier
    • , Stoyan Ivanov
    • , Wei-Jen Chua
    • , Ted H Hansen
    •  & Gwendalyn J Randolph
  4. Broad Institute, Cambridge, Massachusetts, USA.

    • Tal Shay
  5. Department of Oncological Sciences and Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.

    • Jennifer Miller
    • , Melanie Greter
    • , Julie Helft
    • , Andrew Chow
    •  & Miriam Merad
  6. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Kutlu G Elpek
    •  & Shannon J Turley
  7. Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Boston, Massachusetts, USA.

    • Kutlu G Elpek
    •  & Shannon J Turley
  8. Department of Pharmacology and Systems Therapeutics & Systems Biology Center New York, Mount Sinai School of Medicine, New York, New York, USA.

    • Simon Gordonov
    • , Amin R Mazloom
    •  & Avi Ma'ayan
  9. Icahn Medical Institute, Mount Sinai Hospital, New York, New York, USA.

    • Emmanuel L Gautier
    • , Claudia Jakubzick
    • , Gwendalyn J Randolph
    • , Jennifer Miller
    • , Brian Brown
    •  & Miriam Merad
  10. Department of Pathology & Immunology, Washington University, St. Louis, Missouri, USA.

    • Emmanuel L Gautier
    •  & Gwendalyn J Randolph
  11. Division of Biological Sciences, University of California San Diego, La Jolla, California, USA.

    • Adam J Best
    • , Jamie Knell
    •  & Ananda Goldrath
  12. Computer Science Department, Stanford University, Stanford, California, USA.

    • Vladimir Jojic
    • , Daphne Koller
    •  & Taras Kreslavsky
  13. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Nadia Cohen
    • , Patrick Brennan
    •  & Michael Brenner
  14. Broad Institute, Cambridge, Massachusetts, USA.

    • Tal Shay
    •  & Aviv Regev
  15. Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.

    • Anne Fletcher
    • , Kutlu Elpek
    • , Angelique Bellemare-Pelletier
    • , Deepali Malhotra
    •  & Shannon Turley
  16. Computer Science Department, Brown University, Providence, Rhode Island, USA.

    • Radu Jianu
    •  & David Laidlaw
  17. Department of Biomedical Engineering, Howard Hughes Medical Institute, Boston University, Boston, Massachusetts, USA.

    • Jim Collins
  18. Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Kavitha Narayan
    • , Katelyn Sylvia
    •  & Joonsoo Kang
  19. Immune Diseases Institute, Children's Hospital, Boston, Massachusetts, USA.

    • Roi Gazit
    • , Brian S Garrison
    •  & Derrick J Rossi
  20. Joslin Diabetes Center, Boston, Massachusetts, USA.

    • Francis Kim
    • , Tata Nageswara Rao
    •  & Amy Wagers
  21. Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • Susan A Shinton
    •  & Richard R Hardy
  22. Department of Medicine, Boston University, Boston, Massachusetts, USA.

    • Paul Monach
  23. Department of Microbiology & Immunology, University of California San Francisco, San Francisco, California, USA.

    • Natalie A Bezman
    • , Joseph C Sun
    • , Charlie C Kim
    •  & Lewis L Lanier
  24. Division of Immunology, Department of Microbiology & Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Tracy Heng
    • , Michio Painter
    • , Jeffrey Ericson
    • , Scott Davis
    • , Diane Mathis
    •  & Christophe Benoist

Consortia

  1. the Immunological Genome Consortium

Authors

  1. Search for Emmanuel L Gautier in:

  2. Search for Tal Shay in:

  3. Search for Jennifer Miller in:

  4. Search for Melanie Greter in:

  5. Search for Claudia Jakubzick in:

  6. Search for Stoyan Ivanov in:

  7. Search for Julie Helft in:

  8. Search for Andrew Chow in:

  9. Search for Kutlu G Elpek in:

  10. Search for Simon Gordonov in:

  11. Search for Amin R Mazloom in:

  12. Search for Avi Ma'ayan in:

  13. Search for Wei-Jen Chua in:

  14. Search for Ted H Hansen in:

  15. Search for Shannon J Turley in:

  16. Search for Miriam Merad in:

  17. Search for Gwendalyn J Randolph in:

Contributions

E.L.G. purified macrophage populations, designed and did experiments, analyzed data and wrote the manuscript; G.J.R. designed and supervised experiments, analyzed data and wrote the manuscript; T.S. analyzed data and wrote the manuscript; J.M. designed analytical strategies and analyzed data; M.G., C.J., J.H., A.C. and K.G.E. purified macrophage and DC populations; S.I. did experiments; S.G., A.R.M. and A.M. analyzed data; W.-J.C. and T.H.H. provided reagents and supervised experiments; and S.J.T. and M.M. designed and supervised experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Gwendalyn J Randolph.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6, Tables 1 and 4–6 and Notes 1–2

Excel files

  1. 1.

    Supplementary Table 2

    Probeset levels of the macrophage core signature genes.

  2. 2.

    Supplementary Table 3

    Probeset levels of the extended macrophage core signature genes.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.2419

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing