Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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 options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Analysis of macrophage diversity.
Figure 2: Unique gene-expression profiles of macrophages from various organs.
Figure 3: Identification of gene modules enriched for macrophage-related gene signatures and their predicted regulators.
Figure 4: Expression of genes of the macrophage core signature by other populations of mononuclear phagocytes.
Figure 5: Transcripts of the macrophage core signature, assessed as protein in various tissues.

Accession codes

Primary accessions

Gene Expression Omnibus

References

  1. 1

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

    CAS  PubMed  Google Scholar 

  2. 2

    Gordon, S. & Taylor, P.R. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5, 953–964 (2005).

    CAS  Article  Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

    Mosser, D.M. & Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Geissmann, F., Gordon, S., Hume, D.A., Mowat, A.M. & Randolph, G.J. Unraveling mononuclear phagocyte heterogeneity. Nat. Rev. Immunol. 10, 453–460 (2010).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Onai, N. 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).

    CAS  Article  Google Scholar 

  8. 8

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

    CAS  Article  Google Scholar 

  9. 9

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

    CAS  Article  Google Scholar 

  10. 10

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

    Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Aziz, A., Soucie, E., Sarrazin, S. & Sieweke, M.H. MafB/c-Maf deficiency enables self-renewal of differentiated functional macrophages. Science 326, 867–871 (2009).

    CAS  Article  Google Scholar 

  14. 14

    Teitelbaum, S.L. & Ross, F.P. Genetic regulation of osteoclast development and function. Nat. Rev. Genet. 4, 638–649 (2003).

    CAS  Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

    Lemke, G. & Rothlin, C.V. Immunobiology of the TAM receptors. Nat. Rev. Immunol. 8, 327–336 (2008).

    CAS  Article  Google Scholar 

  17. 17

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

    CAS  Article  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

    Hashimoto, D., Miller, J. & Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Chua, W.J. 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).

    CAS  Article  Google Scholar 

  21. 21

    Elstad, M.R., Stafforini, D.M., McIntyre, T.M., Prescott, S.M. & Zimmerman, G.A. 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).

    CAS  PubMed  Google Scholar 

  22. 22

    Chow, A. 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).

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Kim, H.J., Alonzo, E.S., Dorothee, G., Pollard, J.W. & Sant'Angelo, D.B. Selective depletion of eosinophils or neutrophils in mice impacts the efficiency of apoptotic cell clearance in the thymus. PLoS ONE 5, e11439 (2010).

    Article  Google Scholar 

  26. 26

    Sung, S.S. 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).

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

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

    CAS  Article  Google Scholar 

  30. 30

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

    CAS  Article  Google Scholar 

  31. 31

    Veal, E., Eisenstein, M., Tseng, Z.H. & Gill, G. A cellular repressor of E1A-stimulated genes that inhibits activation by E2F. Mol. Cell. Biol. 18, 5032–5041 (1998).

    CAS  Article  Google Scholar 

  32. 32

    Sacher, M. 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).

    CAS  Article  Google Scholar 

  33. 33

    Veal, E., Groisman, R., Eisenstein, M. & Gill, G. The secreted glycoprotein CREG enhances differentiation of NTERA-2 human embryonal carcinoma cells. Oncogene 19, 2120–2128 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Moolmuang, B. & Tainsky, M.A. CREG1 enhances p16INK4a-induced cellular senescence. Cell Cycle 10, 518–530 (2011).

    CAS  Article  Google Scholar 

  35. 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).

    CAS  Article  Google Scholar 

  36. 36

    Idoyaga, J., Suda, N., Suda, K., Park, C.G. & Steinman, R.M. 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).

    CAS  Article  Google Scholar 

  37. 37

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

    CAS  Article  Google Scholar 

  38. 38

    Blatt, M., Wiseman, S. & Domany, E. Superparamagnetic clustering of data. Phys. Rev. Lett. 76, 3251–3254 (1996).

    CAS  Article  Google Scholar 

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

Authors

Consortia

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.

Corresponding author

Correspondence to Gwendalyn J Randolph.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Tables 1 and 4–6 and Notes 1–2 (PDF 3836 kb)

Supplementary Table 2

Probeset levels of the macrophage core signature genes. (XLS 27 kb)

Supplementary Table 3

Probeset levels of the extended macrophage core signature genes. (XLS 77 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gautier, E., Shay, T., Miller, J. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol 13, 1118–1128 (2012). https://doi.org/10.1038/ni.2419

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

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