Advertisement

Glycoconjugate Journal

, Volume 36, Issue 1, pp 69–78 | Cite as

The effects of trehalose glycolipid presentation on cytokine production by GM-CSF macrophages

  • Bridget L. StockerEmail author
  • Kristel Kodar
  • Kanu Wahi
  • Amy J. Foster
  • Jacquie L. Harper
  • Daiki Mori
  • Sho Yamasaki
  • Mattie S. M. TimmerEmail author
Original Article
  • 104 Downloads

Abstract

Trehalose glycolipids (TGLs) are promising vaccine adjuvants, however effects of glycolipid presentation in the in vitro evaluation, and ultimate selection, of lead vaccine adjuvants are often overlooked. To this end, we synthesised a variety of TGLs and determined how the physicochemical presentation of these lipids influenced the cytokine response by bone marrow derived macrophages (BMMs). The TGLs were presented to wild-type and Mincle−/− BMMs as micellar solutions, coated on plates, coated on beads or surfactant solubilised. Medium to long-chain TGLs, either coated on plates or surfactant solubilised, resulted in the highest BMM activation. Stimulation of BMMs with TGLs coated on beads led to a decreased cytokine response, as compared to TGLs alone. All the TGL responses were Mincle dependent, however the mode of presentation did not have the same effect for each individual TGL. This was most apparent for the C22 trehalose monoester, which showed reduced activity compared to its diester counterpart when presented on a plate, but similar activity to the diester when presented as micelles or on beads. Taken together, our findings support the use of several in vitro assays for selecting lead vaccine adjuvants, particularly if structural differences between the adjuvants are pronounced.

Graphical abstract

The mode of glycolipid presentation, such as micellar solutions, coated on plates, coated on beads or surfactant solubilised, influences the immune response to trehalose glycolipids

Keywords

Trehalose glycolipid Mincle Macrophage Adjuvant 

Notes

Acknowledgements

The authors would like to thank the Health Research Council (Hercus Fellowship, BLS, 2013/33) and the Cancer Society of New Zealand (2013/33) for financial support.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All experimental procedures were approved by the Victoria University Animal Ethics Committee in accordance with their guidelines for the care of animals (protocol nr 22,371).

Supplementary material

10719_2018_9857_MOESM1_ESM.pdf (729 kb)
ESM 1 (PDF 729 kb)

References

  1. 1.
    Khan, A.A., Stocker, B.L., Timmer, M.S.M.: Trehalose glycolipids-synthesis and biological activities. Carbohydr. Res. 356, 25–36 (2012)CrossRefGoogle Scholar
  2. 2.
    Indrigo, J., Hunter Jr., R.L., Actor, J.K.: Cord factor trehalose 6,6’-dimycolate (TDM) mediates trafficking events during mycobacterial infection of murine macrophages. Microbiology. 149(Pt 8), 2049–2059 (2003)CrossRefGoogle Scholar
  3. 3.
    Indrigo, J., Hunter Jr., R.L., Actor, J.K.: Influence of trehalose 6,6’-dimycolate (TDM) during mycobacterial infection of bone marrow macrophages. Microbiology. 148(Pt 7), 1991–1998 (2002)CrossRefGoogle Scholar
  4. 4.
    Spargo, B.J., Crowe, L.M., Ioneda, T., Beaman, B.L., Crowe, L.M.: Cord factor (□,□-trehalose 6,6’-dimycolate) inhibits fusion between phospholipidvesicles. Proc. Natl. Acad. Sci. USA. 88(3), 737–740 (1991)Google Scholar
  5. 5.
    Khan, A.A., Chee, S.H., McLaughlin, R.J., Harper, J.L., Kamena, F., Timmer, M.S.M., Stocker, B.L.: Long-chain lipids are required for the innate immune recognition of trehalose diesters by macrophages. Chembiochem. 12(17), 2572–2576 (2011)CrossRefGoogle Scholar
  6. 6.
    Stocker, B.L., Khan, A.A., Chee, S.H., Kamena, F., Timmer, M.S.M.: On one leg: Trehalose mono-esters activate macrophages in a Mincle-dependant Manner. Chembiochem. 15(3), 382–388 (2014)CrossRefGoogle Scholar
  7. 7.
    Davidsen, J., Rosenkrands, I., Christensen, D., Vangala, A., Kirby, D., Perrie, Y., Agger, E.M., Andersen, P.: Characterization of cationic liposomes based on dimethyldioctadecylammonium and synthetic cord factor from M. tuberculosis (trehalose 6,6’-dibehenate)-a novel adjuvant inducing both strong CMI and antibody responses. Biochim. Biophys Acta. 1718(1-2), 22–31 (2005)CrossRefGoogle Scholar
  8. 8.
    Schmidt S.T., Foged C., Korsholm K.S., Rades T., Christensen, D.: Liposome-based adjuvants for subunit vaccines: formulation strategies for subunit antigens and immunostimulators. Pharmaceutics. 8(7) (2016)Google Scholar
  9. 9.
    Schoenen, H., Bodendorfer, B., Hitchens, K., Manzanero, S., Werninghaus, K., Nimmerjahn, F., Agger, E.M., Stenger, S., Andersen, P., Ruland, J., Brown, J.D., Wells, C., Lang, R.: Cutting Edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate. J. Immunol. 184(6), 2756–2760 (2010)CrossRefGoogle Scholar
  10. 10.
    Desel, C., Werninghaus, K., Ritter, M., Jozefowski, K., Wenzel, J., Russkamp, N., Schleicher, U., Christensen, D., Wirtz, S., Kirschning, C., Agger, E.M., Prazeres da Costa, C., Lang, R.: The Mincle-activating adjuvant TDB induces MyD88-dependent Th1 and Th17 responses through IL-1R signaling. PLoS One. 8(1), e53531 (2013)CrossRefGoogle Scholar
  11. 11.
    Shenderov, K., Barber, D.L., Mayer-Barber, K.D., Gurcha, S.S., Jankovic, D., Feng, C.G., Oland, S., Hieny, S., Caspar, P., Yamasaki, S., Lin, X., Ting, J.P., Trinchieri, G., Besra, G.S., Cerundolo, V., Sher, A.: Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. J. Immunol. 190(11), 5722–5730 (2013)CrossRefGoogle Scholar
  12. 12.
    Braganza, C.D., Teunissen, T., Timmer, M.S.M., Stocker, B.L.: Identification and Biological Activity of Synthetic Mincle Ligands. Front. Immunol. 8, 1940 (2018)CrossRefGoogle Scholar
  13. 13.
    Bergmann-Leitner, E.S., Leitner, W.W.: Adjuvants in the driver’s seat: How magnitude, type, fine specificity and longevity of immune responses are driven by distinct classes of immune potentiators. Vaccine. 2(2), 252–296 (2014)CrossRefGoogle Scholar
  14. 14.
    Knudsen, N.P.H., Olsen, A., Buonsanti, C., Follmann, F., Zhang, Y., Coler, R.N., Fox, C.B., Meinke, A., Dóro, U., Casini, D., Bonci, A., Billeskov, R., De Gregorio, E., Rappuoli, R., Harandi, A.M., Andersen, P., Agger, E.M.: Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens. Sci. Rep. 6, 19570 (2016)CrossRefGoogle Scholar
  15. 15.
    Schweneker, K., Gorka, O., Schweneker, M., Poeck, H., Tschopp, J., Peschela, C., Ruland, J., Gross, O.: The mycobacterial cord factor adjuvant analogue trehalose-6,6′-dibehenate (TDB) activates the Nlrp3 inflammasome. Immunobiology. 218(4), 664–673 (2013)CrossRefGoogle Scholar
  16. 16.
    Lee, W.B., Kang, J.S., Choi, W.Y., Zhang, Q., Kim, C.H., Choi, U.Y., Kim, H.J., Kim, Y.J.: Mincle-mediated translational regulation is required for strong nitric oxide production and inflammation resolution. Nature Comm. 7, 11322 (2016)CrossRefGoogle Scholar
  17. 17.
    Werninghaus, K., Babiak, A., Gross, O., Hölscher, C., Dietrich, H., Agger, E.M., Mages, J., Mocsai, A., Schoenen, H., Finger, K., Nimmerjahn, F., Brown, G.D., Kirschning, C., Heit, A., Andersen, P., Wagner, H., Ruland, J., Lang, R.: Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-dependent innate immune activation. J. Exp. Med. 206(1), 89–97 (2009)CrossRefGoogle Scholar
  18. 18.
    Huber, A., Kallerup, R.S., Korsholm, K.S., Franzyk, H., Lepenies, B., Christensen, D., Foged, C., Lang, R.: Trehalose diester glycolipids are superior to the monoesters in binding to Mincle, activation of macrophages in vitro and adjuvant activity in vivo. Innate Immunity. 22(6), 405–418 (2016)CrossRefGoogle Scholar
  19. 19.
    Kodar, K., Harper, J.L., McConnell, M.J., Timmer, M.S.M., Stocker, B.L.: The Mincle ligand trehalose dibehenate differentially modulates M1-like and M2-like macrophage phenotype and function via Syk signalling. Immun. Inflam. Dis. 5(4), 503–514 (2017)CrossRefGoogle Scholar
  20. 20.
    Hupfer, T., Schick, J., Jozefowski, K., Voehringer, D., Ostrop, J., Lang, R.: Stat6-dependent inhibition of mincle expression in mouse and human antigen-presenting cells by the Th2 cytokine IL-4. Front. Immunol. 14(7), 423 (2016)Google Scholar
  21. 21.
    Retzinger, G.S., Meredith, S.C., Takayama, K., Hunter, R.L., Kézdy, F.J.: The role of surface in the biological activities of trehalose 6,6-dimycolate. J. Biol. Chem. 256(15), 8208–8216 (1981)Google Scholar
  22. 22.
    Retzinger, G.S., Meredith, S.C., Hunter, R.L., Takayama, K., Kizdy, F.J.: Identification of the physiologically active state of the mycobacterial glycolipid trehalose 6,6’-dimycolate and the role of fibrinogen in the biologic activities of trehalose 6,6’-dimycolate monolayers. J. Immunol. 129(2), 735–744 (1982)Google Scholar
  23. 23.
    Hunter, R.L., Olsen, M.R., Jagannath, C., Actor, J.K.: Multiple roles of cord factor in the pathogenesis of primary, secondary, and cavity tuberculosis, including a revised description of the pathology of secondary disease. Ann. Clin. Lab. Sci. 36(4), 371–386 (2006)Google Scholar
  24. 24.
    Hunter, R.L., Armitige, L., Jagannath, C., Actor, J.K.: TB Research at UT-Houston – A review of cord factor: new approaches to drugs, vaccines and the pathogenesis of tuberculosis. Tuberculosis. 89(sup 1), S18–S25 (2009)CrossRefGoogle Scholar
  25. 25.
    Syed, S.S., Hunter, R.L.: Studies on the toxic effects of quartz and a mycobacterial glycolipid, treahalose 6,6’-dimycolate. Ann. Clin Lab Sci. 27(5), 375–383 (1997)Google Scholar
  26. 26.
    Duque, G.A., Descoteaux, A.: Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 5, 491 (2014).  https://doi.org/10.3389/fimmu.2014.00491 Google Scholar
  27. 27.
    Toubiana, R., Das, B.C., Defaye, J., Mompon, B., Toubiana, M.J.: Cord factor and its analogs. III. Synthesis of cord factor (6,6′-di-O-mycoloyl-alpha, alpha-trehalose) and 6,6′-di-O-palmitoyl-alpha, alpha-trehalose. Carbohydr. Res. 44(2), 308–312 (1975)CrossRefGoogle Scholar
  28. 28.
    Johnson, D.A.: Simple procedure for the preparation of trimethylsilyl ethers of carbohydrates and alcohols. Carbohydr. Res. 237, 313–318 (1992)CrossRefGoogle Scholar
  29. 29.
    Neto, V., Granet, R., Krausz, P.: Novel class of non-ionic monocatenary and bolaform alkylglycoside surfactants. Synthesis by microwave-assisted glycosylation and olefin cross-metathesis or by ‘click-chemistry’: physicochemical studies. Tetrahedron. 66, 4633–4646 (2010)CrossRefGoogle Scholar
  30. 30.
    Yamasaki, S., Matsumoto, M., Takeuchi, O., Matsuzawa, T., Ishikawa, E., Sakuma, M., Tateno, H., Uno, J., Hirabayashi, J., Mikami, Y., Takeda, K., Akira, S., Saito, T.: C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proc Natl Acad Sci USA. 106(6), 1897–1902 (2009)CrossRefGoogle Scholar
  31. 31.
    Berridge, M.V., Herst, P.M., Tan, A.S.: Tetrazolium dyes as tools in cell biology: New insights into their cellular reduction. Biotechnol. Annu. Rev. 11, 127–152 (2005)CrossRefGoogle Scholar
  32. 32.
    Kodar, K., Eising, S., Khan, A.A., Steiger, S., Harper, J.L., Timmer, M.S.M., Stocker, B.L.: The uptake of trehalose glycolipids by macrophages is independent of Mincle. Chembiochem. 16(4), 683–693 (2015)CrossRefGoogle Scholar
  33. 33.
    Martin-Bertelsen, B., Korsholm, K.S., Rose, F., Nordly, P., Franzyk, H., Andersen, P., Agger, E.M., Christensen, D., Yaghmura, A., Foged, C.: The supramolecular structure is decisive for the immunostimulatory properties of synthetic analogues of a mycobacterial lipid in vitro. RSC Adv. 3, 20673–20683 (2013)CrossRefGoogle Scholar
  34. 34.
    Yamasaki, S., Ishikawa, E., Sakuma, M., Hara, H., Ogata, K., Saito, T.: Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat. Immunol. 9(10), 1179–1188 (2008)CrossRefGoogle Scholar
  35. 35.
    Ishikawa, E., Ishikawa, T., Morita, Y.S., Toyonaga, K., Yamada, H., Takeuchi, O., Kinoshita, T., Akira, S., Yoshikai, Y., Yamasaki, S.: Direct recognition of the mycobacterial glycolipid, trehalose dimycolate, by C-type lectin Mincle. J. Exp. Med. 206(13), 2879–2888 (2009)CrossRefGoogle Scholar
  36. 36.
    Bangs Laboratories Inc., TechNote 204. Adsorption to Microspheres, Rev. #003, Active: (2013); 1-5Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Chemical and Physical SciencesVictoria University of WellingtonWellingtonNew Zealand
  2. 2.Centre for BiodiscoveryVictoria University of WellingtonWellingtonNew Zealand
  3. 3.Division of Molecular Immunology, Medical Institute of BioregulationKyushu UniversityFukuokaJapan
  4. 4.Department of Molecular Immunology, Research Institute for Microbial DiseasesOsaka UniversityOsakaJapan
  5. 5.Laboratory of Molecular Immunology, Immunology Frontier Research CenterOsaka UniversitySuitaJapan
  6. 6.Division of Molecular Immunology, Medical Mycology Research CenterChiba UniversityChibaJapan

Personalised recommendations