Skip to main content

Advertisement

SpringerLink
Log in

MSU Crystals Enhance TDB-Mediated Inflammatory Macrophage IL-1β Secretion

  • ORIGINAL ARTICLE
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The tumour microenvironment predominantly consists of macrophages with phenotypes ranging from pro-inflammatory (M1-like) to anti-inflammatory (M2-like). Trehalose-6,6′-dibehenate (TDB) displays moderate anti-tumour activity and stimulates M1-like macrophages via the macrophage inducible C-type lectin (Mincle) resulting in IL-1β production. In this study, we examined if monosodium urate (MSU), a known vaccine adjuvant, can boost IL-1β production by TDB-stimulated macrophages. We investigated the effect of MSU/TDB co-treatment on IL-1β production by GM-CSF (M1-like) and M-CSF/IL-4 (M2-like) differentiated mouse bone marrow macrophages (BMMs) and found that MSU/TDB co-treatment of GM-CSF BMMs significantly enhanced IL-1β production in a Mincle-dependent manner. Western blot analysis showed that increased IL-1β production by GM-CSF BMMs was associated with the induction of pro-IL-1β expression by TDB rather than MSU. Flow cytometry analysis showed that MSU/TDB co-stimulation of GM-CSF BMMs led to greater expansion of CD86high/MHC IIhigh and CD86low/MHC IIlow subpopulations; however, only the latter showed increased production of IL-1β. Together, these findings provide evidence of the potential to use MSU/TDB co-treatment to boost IL-1β-mediated anti-tumour activity in M1-like tumour-associated macrophages.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

BMMs:

Bone marrow macrophages

GM-CSF:

Granulocyte macrophage-colony stimulating factor

M-CSF/IL-4:

Macrophage-colony stimulating factor/interleukin-4

MSU:

Monosodium urate

TDB:

Trehalose dibehenate

References

  1. Temizoz, B., E. Kuroda, and K.J. Ishii. 2016. Vaccine adjuvants as potential cancer immunotherapeutics. International Immunology 28: 329–338.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Bowen, W.J., K.S. Abhishek, L. Batra, H. Barsoumian, and H. Shirwan. 2018. Current challenges for cancer vaccine adjuvant development. Expert Review of Vaccines 17: 207–215.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Pasquale, A.D., S. Preiss, F.T. Da Silva, and N. Garcon. 2015. Vaccine adjuvants: From 1920 to 2015 and beyond. Vaccines 3: 320–343.

    PubMed  PubMed Central  Google Scholar 

  4. Zepp, F. 2016. Principles of vaccination. Methods in Molecular Biology 1403: 57–84.

    PubMed  Google Scholar 

  5. van Ravenswaay Claasen, H.H., P.M. Kluin, and G.J. Fleuren. 1992. Tumor infiltrating cells in human cancer. On the possible role of CD16+ macrophages in antitumor cytotoxicity. Laboratory Investigation 67: 166–174.

    PubMed  Google Scholar 

  6. Mosser, D.M., and J.P. Edwards. 2008. Exploring the full spectrum of macrophage activation. Nature Reviews. Immunology 8: 958–969.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mantovani, A., F. Marchesi, A. Malesci, L. Laghi, and P. Allavena. 2017. Tumour-associated macrophages as treatment targets in oncology. Nature Reviews Clinical Oncology 14: 399–416.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Buhtoiarov, I.N., P.M. Sondel, J.M. Wigginton, T.N. Buhtoiarova, E.M. Yanke, D.A. Mahvi, and A.L. Rakhmilevich. 2011. Anti-tumour synergy of cytotoxic chemotherapy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology 132: 226–239.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Shi, Y., M.A.R. Felder, P.M. Sondel, and A.L. Rakhmilevich. 2015. Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages. Molecular Immunology 66: 208–215.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dewan, M.Z., C. Vanpouille-Box, N. Kawashima, S. DiNapoli, J.S. Babb, S.C. Formenti, S. Adams, and S. Demaria. 2012. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clinical Cancer Research 18: 6668–6678.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hussain, S.F., L.-Y. Kong, J. Jordan, C. Conrad, T. Madden, I. Fokt, W. Priebe, and A.B. Heimberger. 2007. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer Research 67: 9630–9636.

    CAS  PubMed  Google Scholar 

  12. Edwards, J.P., and L.A. Emens. 2010. The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE2 in murine macrophages. International Immunopharmacology 10: 1220–1228.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bloch, H., and H. Noll. 1954. Studies on the virulence of tubercle bacilli; the effect of cord factor on murine tuberculosis. British Journal of Experimental Pathology 36: 8–17.

    Google Scholar 

  14. Ishikawa, E., T. Ishikawa, Y.S. Morita, K. Toyonaga, H. Yamada, O. Takeuchi, T. Kinoshita, S. Akira, Y. Yoshikai, and S. Yamasaki. 2009. Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. The Journal of Experimental Medicine 206: 2879–2888.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Schoenen, H., B. Bodendorfer, K. Hitchens, S. Manzanero, K. Werninghaus, F. Nimmerjahn, E.M. Agger, S. Stenger, P. Andersen, J. Ruland, G.D. Brown, C. Wells, and R. Lang. 2010. Cutting edge: Mincle is essential for recognition and Adjuvanticity of the mycobacterial cord factor and its synthetic analog Trehalose-Dibehenate. Journal of Immunology 184: 2756–2760.

    CAS  Google Scholar 

  16. Braganza, C., T. Teunissen, M.S.M. Timmer, and B. Stocker. 2018. Synthetic Mincle ligands. Frontiers in Immunology 8: 1940.

    PubMed  PubMed Central  Google Scholar 

  17. Yarkoni, E., L. Wang, and A. Bekierkunst. 1974. Suppression of growth of Ehrlich ascites tumor cells in mice by trehalose-6,6′-dimycolate (cord factor) and BCG. Infection and Immunity 9: 977–984.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Yarkoni, E., E. Lederer, and H.J. Rapp. 1981. Immunotherapy of experimental cancer with a mixture of synthetic muramyl dipeptide and trehalose dimycolate. Infection and Immunity 32: 273–276.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Watanabe, R., Y.C. Yoo, K. Hata, M. Mitobe, Y. Koike, M. Nishizawa, D.M. Garcia, Y. Nobuchi, H. Imagawa, H. Yamada, and I. Azuma. 1999. Inhibitory effect of trehalose dimycolate (TDM) and its stereoisometric derivatives, trehalose dicorynomycolates (TDCMs), with low toxicity on lung metastasis of tumour cells in mice. Vaccine 17: 1484–1492.

    CAS  PubMed  Google Scholar 

  20. Yamamoto, H., M. Oda, M. Nakano, N. Watanabe, K. Yabiku, M. Shibutani, M. Inoue, H. Imagawa, M. Nagahama, S. Himeno, K. Setsu, J. Sakurai, and M. Nishizawa. 2013. Development of Vizantin, a safe immunostimulant, based on the structure-activity relationship of trehalose-6,6′-dicorynomycolate. Journal of Medicinal Chemistry 56: 381–385.

    CAS  PubMed  Google Scholar 

  21. Pimm, M.V., R.W. Baldwin, J. Polonsky, and E. Lederer. 1979. Immunotherapy of an ascitic rat hepatoma with cord factor (trehalose-6,6′-dimycolate) and synthetic analogues. International Journal of Cancer 24: 780–785.

    CAS  PubMed  Google Scholar 

  22. Nishikawa, Y., T. Katori, K. Kukita, and T. Ikekawa. 1982. Synthesis and anti-tumour effects of 6,6′-di-O-acyl-α,α'-trehaloses. Nippon Kagaku Kaishi 10: 1661–1666.

    Google Scholar 

  23. Kodar, K., J.L. Harper, M.J. McConnell, M.S.M. Timmer, and B.L. Stocker. 2017. The Mincle ligand trehalose dibehenate differentially modulates M1-like and M2-like macrophage phenotype and function via Syk signaling. Immunity, Inflammation and Disease 5: 503–514.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Werninghaus, K., A. Babiak, O. Groß, C. Hölscher, H. Dietrich, E.M. Agger, J. Mages, A. Mocsai, H. Schoenen, K. Finger, F. Nimmerjahn, G.D. Brown, C. Kirschning, A. Heit, P. Andersen, H. Wagner, J. Ruland, and R. Lang. 2009. Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRγ–Syk–Card9–dependent innate immune activation. The Journal of Experimental Medicine 206: 89–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Schweneker, K., O. Gorka, M. Schweneker, H. Poeck, J. Tschopp, C. Peschel, J. Ruland, and O. Groß. 2013. The mycobacterial cord factor adjuvant analogue trehalose-6,6′-dibehenate (TDB) activates the Nlrp3 inflammasome. Immunobiology 218: 664–673.

    CAS  PubMed  Google Scholar 

  26. Giamarellos-Bourboulis, E.J., M. Mouktaroudi, E. Bodar, J. Van Der Ven, B.J. Kullberg, M.G. Netea, et al. 2009. Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 βby mononuclear cells through a caspase 1-mediated process. Annals of the Rheumatic Diseases 68: 273–278.

    CAS  PubMed  Google Scholar 

  27. Chen, C.J., Y. Shi, A. Hearn, K. Fitzgerald, D. Golenbock, G. Reed, S. Akira, and K.L. Rock. 2006. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. The Journal of Clinical Investigation 116: 2262–2271.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Taus, F., M.B. Santucci, E. Greco, M. Morandi, I. Palucci, S. Mariotti, et al. 2015. Monosodium urate crystals promote innate anti-mycobacterial immunity and improve BCG efficacy as a vaccine against tuberculosis. PLoS One 10: 1–16.

    Google Scholar 

  29. Kuhn, S., E.J. Hyde, J. Yang, F.J. Rich, J.L. Harper, J.R. Kirman, and F. Ronchese. 2013. Increased numbers of monocyte-derived dendritic cells during successful tumor immunotherapy with immune-activating agents. Journal of Immunology 191: 1984–1992.

    CAS  Google Scholar 

  30. Shi, Y., J.E. Evans, and K.L. Rock. 2003. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425: 516–521.

    CAS  PubMed  Google Scholar 

  31. Hu, D.-E., A.M. Moore, L.L. Thomsen, and K.M. Brindle. 2004. Uric acid promotes tumor immune rejection. Cancer Research 64: 5059–5062.

    CAS  PubMed  Google Scholar 

  32. Dziaman, T., Z. Banaszkiewicz, K. Roszkowski, D. Gackowski, E. Wisniewska, R. Rozalski, M. Foksinski, A. Siomek, E. Speina, A. Winczura, A. Marszalek, B. Tudek, and R. Olinski. 2014. 8-Oxo-7,8-dihydroguanine and uric acid as efficient predictors of survival in colon cancer patients. International Journal of Cancer 134: 376–383.

    PubMed  Google Scholar 

  33. Slobodnick, A., S. Krasnokutsky, R.A. Lehmann, R.T. Keenan, J. Quach, F. Francois, and M.H. Pillinger. 2018. Colorectal Cancer among gout patients undergoing colonoscopy. Journal of Clinical Rheumatology: 1. https://doi.org/10.1097/RHU.0000000000000893.

  34. Fleetwood, A.J., T. Lawrence, J.A. Hamilton, and A.D. Cook. 2007. Granulocyte-macrophage Colony-stimulating factor (CSF) and macrophage CSF-dependent macrophage phenotypes display differences in cytokine profiles and transcription factor activities: Implications for CSF blockade in inflammation. Journal of Immunology 178: 5245–5252.

    CAS  Google Scholar 

  35. Hamilton, T.A., C. Zhao, P.G. Pavicic, and S. Datta. 2014. Myeloid colony-stimulating factors as regulators of macrophage polarization. Frontiers in Immunology 5: 1–6.

    CAS  Google Scholar 

  36. Khan, A.A., S.H. Chee, R.J. McLaughlin, J.L. Harper, F. Kamena, M.S. Timmer, and B.L. Stocker. 2011. Long-chain lipids are required for the innate immune recognition of trehalose diesters by macrophages. Chembiochem 12: 2572–2576.

    CAS  PubMed  Google Scholar 

  37. Martin, W.J., M. Walton, and J.L. Harper. 2009. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis and Rheumatism 60: 281–289.

    PubMed  Google Scholar 

  38. Haabeth, O.A.W., K.B. Lorvik, H. Yagita, B. Bogen, and A. Corthay. 2016. Interleukin-1 is required for cancer eradication mediated by tumor-specific Th1 cells. Oncoimmunology 5: e1039763.

    PubMed  Google Scholar 

  39. He, Y., H. Hara, and G. Núñez. 2016. Mechanism and regulation of NLRP3 Inflammasome activation. Trends in Biochemical Sciences 41: 1012–1021.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Helft, J., J. Böttcher, P. Chakravarty, S. Zelenay, J. Huotari, B.U. Schraml, D. Goubau, and C. Reise Sousa. 2015. GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c(+)MHCII(+) macrophages and dendritic cells. Immunity 42: 1197–1211.

    CAS  PubMed  Google Scholar 

  41. Na, Y.R., D. Jung, G.J. Gu, and S.H. Seok. 2016. GM-CSF grown bone marrow derived cells are composed of phenotypically different dendritic cells and macrophages. Molecules and Cells 39: 734–741.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Guermonprez, P., J. Valladeau, L. Zitvogel, C. Théry, and S. Amigorena. 2002. Antigen presentaion and T cell stimulation by dendritic cells. Annual Review of Immunology 20: 621–667.

    CAS  PubMed  Google Scholar 

  43. Wang, C., X. Yu, Q. Cao, Y. Wang, G. Zheng, T.K. Tan, et al. 2013. Characterization of murine macrophages from bone marrow, spleen and peritoneum. BMC Immunology 14: 1–10.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Professor Sho Yamasaki for kindly providing the Mincle−/− mice.

Funding

This work was supported by the Cancer Society of New Zealand (2016/25) and the Health Research Council of New Zealand (Hercus Fellowship, BLS).

Author information

Authors and Affiliations

  1. School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand

    Kanu Wahi, Kristel Kodar, Jacquie L. Harper, Mattie S. M. Timmer & Bridget L. Stocker

  2. Centre for Biodiscovery, Victoria University of Wellington, PO Box 600, Wellington, New Zealand

    Kanu Wahi, Kristel Kodar, Melanie J. McConnell, Mattie S. M. Timmer & Bridget L. Stocker

  3. School of Biological Sciences, PO Box 600, Wellington, New Zealand

    Melanie J. McConnell

Authors
  1. Kanu Wahi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kristel Kodar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Melanie J. McConnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jacquie L. Harper
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mattie S. M. Timmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bridget L. Stocker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Mattie S. M. Timmer or Bridget L. Stocker.

Ethics declarations

All experimental procedures were approved by the Victoria University Animal Ethics Committee in accordance with their guidelines for the care of animals (protocol nr 22371).

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wahi, K., Kodar, K., McConnell, M.J. et al. MSU Crystals Enhance TDB-Mediated Inflammatory Macrophage IL-1β Secretion. Inflammation 42, 1129–1136 (2019). https://doi.org/10.1007/s10753-019-00976-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-00976-5

KEY WORDS

Search

Navigation