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.

  • Letter
  • Published:

Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages

Nature volume 495, pages 524–528 (2013)Cite this article

Subjects

Abstract

Macrophages consist of at least two subgroups, M1 and M2 (refs 1, 2, 3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections4,5, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression6. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase7. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism8,9,10. Here we show that Trib1 is critical for the differentiation of F4/80+MR+ tissue-resident macrophages—that share characteristics with M2 macrophages (which we term M2-like macrophages)—and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Lack of tissue-resident M2-like macrophages and eosinophils in Trib1 -deficient mice.
Figure 2: Trib1 controls macrophage, eosinophil and neutrophil differentiation via the ubiquitin-binding domain.
Figure 3: Impact of Trib1 deficiency on lipodystrophy.
Figure 4: Mice lacking Trib1 in haematopoietic cells develop exacerbated metabolic disorders on a high-fat diet.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Data have been deposited in the GEO under accession number GSE43563.

References

  1. Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009)

    Article  CAS  Google Scholar 

  2. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 11, 889–896 (2010)

    Article  CAS  Google Scholar 

  3. Mantovani, A. & Sica, A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr. Opin. Immunol. 22, 231–237 (2010)

    Article  CAS  Google Scholar 

  4. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010)

    Article  CAS  Google Scholar 

  5. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008)

    Article  ADS  CAS  Google Scholar 

  6. Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 122, 787–795 (2012)

    Article  CAS  Google Scholar 

  7. Yokoyama, T. et al. Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis. Blood 116, 2768–2775 (2010)

    Article  CAS  Google Scholar 

  8. Varbo, A., Benn, M., Tybjaerg-Hansen, A., Grande, P. & Nordestgaard, B. G. TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population. Arterioscler. Thromb. Vasc. Biol. 31, 451–457 (2011)

    Article  CAS  Google Scholar 

  9. Aung, L. H. et al. Association of the TRIB1 tribbles homolog 1 gene rs17321515 A>G polymorphism and serum lipid levels in the Mulao and Han populations. Lipids Health Dis. 10, 230 (2011)

    Article  CAS  Google Scholar 

  10. Chambers, J. C. et al. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genet. 43, 1131–1138 (2011)

    Article  CAS  Google Scholar 

  11. Yamamoto, M. et al. Enhanced TLR-mediated NF-IL6 dependent gene expression by Trib1 deficiency. J. Exp. Med. 204, 2233–2239 (2007)

    Article  CAS  Google Scholar 

  12. Jin, G. et al. Trib1 and Evi1 cooperate with Hoxa and Meis1 in myeloid leukemogenesis. Blood 109, 3998–4005 (2007)

    Article  CAS  Google Scholar 

  13. Keeshan, K. et al. Tribbles homolog 2 inactivates C/EBPα and causes acute myelogenous leukemia. Cancer Cell 10, 401–411 (2006)

    Article  CAS  Google Scholar 

  14. Du, K., Herzig, S., Kulkarni, R. N. & Montminy, M. TRB3: A tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300, 1574–1577 (2003)

    Article  ADS  CAS  Google Scholar 

  15. Okamoto, H. et al. Genetic deletion of Trb3, the mammalian Drosophila tribbles homolog, displays normal hepatic insulin signaling and glucose homeostasis. Diabetes 56, 1350–1356 (2007)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  17. De Domenico, I., McVey Ward, D. & Kaplan, J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nature Rev. Mol. Cell Biol. 9, 72–81 (2008)

    Article  CAS  Google Scholar 

  18. Hong, S., Skaist, A. M., Wheelan, S. J. & Friedman, A. D. AP-1 protein induction during monopoiesis favors C/EBP: AP-1 heterodimers over C/EBP homodimerization and stimulates FosB transcription. J. Leukoc. Biol. 90, 643–651 (2011)

    Article  CAS  Google Scholar 

  19. Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011)

    Article  CAS  Google Scholar 

  20. Lumeng, C. N., Bodzin, J. L. & Saltiel, A. R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007)

    Article  CAS  Google Scholar 

  21. Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007)

    Article  ADS  CAS  Google Scholar 

  22. Reese, T. A. et al. Chitin induces accumulation in tissue of innate immune cells associated with allergy. Nature 447, 92–96 (2007)

    Article  ADS  CAS  Google Scholar 

  23. Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nature Immunol. 11, 936–944 (2010)

    Article  CAS  Google Scholar 

  24. Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nature Rev. Immunol. 11, 738–749 (2011)

    Article  CAS  Google Scholar 

  25. Gregor, M. F. & Hotamisligil, G. S. Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415–445 (2011)

    Article  CAS  Google Scholar 

  26. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006)

    Article  ADS  CAS  Google Scholar 

  27. Wellen, K. E. & Hotamisligil, G. S. Obesity-induced inflammatory changes in adipose tissue. J. Clin. Invest. 112, 1785–1788 (2003)

    Article  CAS  Google Scholar 

  28. Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011)

    Article  ADS  CAS  Google Scholar 

  29. Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008)

    Article  CAS  Google Scholar 

  30. Ricardo-Gonzalez, R. R. et al. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc. Natl Acad. Sci. USA 107, 22617–22622 (2010)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank I. Shimomura and Y. Miyata for providing us with the key protocols for the metabolic experiments; T. Kitamura for providing the PlatE cells; M. Higa, H. Tanaka, N. Miyamoto, K. Miura, D. Ori, T. Uehata and K. Kuniyoshi for assistance with the experiments; and T. Kawai, S. Uematsu, T. Saitoh and Y. Kumagai for discussions. We also thank E. Kamada and M. Kageyama for secretarial assistance, and N. Umano, Y. Matsumoto and M. Kumagai for technical assistance. This work was supported by the Special Coordination Funds of the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare in Japan, the Japan Society for the Promotion of Science through the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program).

Author information

Authors and Affiliations

  1. Laboratory of Host Defense, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan ,

    Takashi Satoh, Naoki Takemura, Katsuhiro Nakagawa, Osamu Takeuchi & Shizuo Akira

  2. Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Takashi Satoh, Naoki Takemura, Katsuhiro Nakagawa, Osamu Takeuchi & Shizuo Akira

  3. Department of Signal Transduction, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Hiroyasu Kidoya, Hisamichi Naito & Nobuyuki Takakura

  4. Laboratory of immunoparasitology, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan ,

    Masahiro Yamamoto

  5. Department of Immunoparasitology, Research Institute for Microbial Diseases (RIMD), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Masahiro Yamamoto

  6. Laboratory of Biofunctional Imaging, WPI Immunology Frontier Research Center (WPI IFReC), Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan ,

    Yoshichika Yoshioka

  7. Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan,

    Eiichi Morii

  8. Laboratory of Infection and Prevention, Institute for Virus Research, Kyoto University, 53 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan ,

    Osamu Takeuchi

Authors
  1. Takashi Satoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyasu Kidoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hisamichi Naito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masahiro Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoki Takemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Katsuhiro Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshichika Yoshioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eiichi Morii
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Nobuyuki Takakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Osamu Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shizuo Akira
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.S. designed and performed the experiments and wrote the manuscript. H.K., H.N. and N. Takakura performed the colony-forming assays. M.Y. generated the Trib1−/−, Trib2−/− and Trib3−/− mice. N. Takemura helped with experiments. K.N. performed microarray analysis. Y.Y. performed the MRI experiments. E.M. performed the histological analyses. O.T. and S.A. designed experiments and wrote the manuscript. S.A. supervised the project.

Corresponding author

Correspondence to Shizuo Akira.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-24. (PDF 3629 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Satoh, T., Kidoya, H., Naito, H. et al. Critical role of Trib1 in differentiation of tissue-resident M2-like macrophages. Nature 495, 524–528 (2013). https://doi.org/10.1038/nature11930

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11930

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced 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