Article | Published:

Dectin-1 stimulates IL-33 expression in dendritic cells via upregulation of IRF4

Laboratory Investigationvolume 98pages708714 (2018) | Download Citation

Abstract

Interleukin-33 (IL-33) is a potent contributor to antiviral immune responses and antitumor immunity. We recently discovered that IL-33 is overexpressed in dectin-1-activated dendritic cells (DCs). However, mechanisms of dectin-1-induced IL-33 expression in DCs remain elusive. Curdlan, an agonist of dectin-1, was used to mature DCs in this study. We found that dectin-1-induced IL-33 expression in DCs relies on Syk and Raf-1 pathways. By using nuclear factor (NF)-κB inhibitors, we also found that dectin-1-induced IL-33 expression relies on NF-κB signaling. Furthermore, through Syk/Raf-1-NF-κB pathway, dectin-1 signaling stimulates DCs to overexpress interferon regulatory factor 4 (IRF4), which directly upregulates the expression of IL-33 in dectin-1-activated DCs. Thus, our study provides new insights into the mechanisms of dectin-1-induced IL-33 expression in DCs and may provide new targets for improving DC-based cancer immunotherapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Garg AD, Coulie PG, Van den Eynde BJ, et al. Integrating next-generation dendritic cell vaccines into the current cancer immunotherapy landscape. Trends Immunol. 2017;38:577–93.

  2. 2.

    Sabado RL, Bhardwaj N. Cancer immunotherapy: dendritic-cell vaccines on the move. Nature. 2015;519:300–1.

  3. 3.

    Lu Y, Hong B, Li H, et al. Tumor-specific IL-9-producing CD8 + Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. Proc Natl Acad Sci USA. 2014;111:2265–70.

  4. 4.

    Lu Y, Hong S, Li H, et al. Th9 cells promote antitumor immune responses in vivo. J Clin Invest. 2012;122:4160–71.

  5. 5.

    Purwar R, Schlapbach C, Xiao S, et al. Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med. 2012;18:1248–53.

  6. 6.

    Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity. 2015;42:1005–19.

  7. 7.

    Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10:103–10.

  8. 8.

    de Kleer IM, Kool M, de Bruijn MJ, et al. Perinatal activation of the interleukin-33 pathway promotes type 2. Immun Dev Lung Immun. 2016;45:1285–98.

  9. 9.

    Cayrol C, Girard JP. IL-33: an alarmin cytokine with crucial roles in innate immunity, inflammation and allergy. Curr Opin Immunol. 2014;31:31–37.

  10. 10.

    Cohen ES, Scott IC, Majithiya JB, et al. Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation. Nat Commun. 2015;6:8327.

  11. 11.

    Bonilla WV, Frohlich A, Senn K, et al. The alarmin interleukin-33 drives protective antiviral CD8(+) T cell responses. Science. 2012;335:984–9.

  12. 12.

    Villarreal DO, Wise MC, Walters JN, et al. Alarmin IL-33 acts as an immunoadjuvant to enhance antigen-specific tumor immunity. Cancer Res. 2014;74:1789–1800.

  13. 13.

    Mayuzumi N, Matsushima H, Takashima A. IL-33 promotes DC development in BM culture by triggering GM-CSF production. Eur J Immunol. 2009;39:3331–42.

  14. 14.

    Rank MA, Kobayashi T, Kozaki H, et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123:1047–54.

  15. 15.

    Chen J, Zhao Y, Chu X, et al. Dectin-1-activated dendritic cells: a potent Th9 cell inducer for tumor immunotherapy. Oncoimmunology. 2016;5:e1238558.

  16. 16.

    Zhao Y, Chu X, Chen J, et al. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells. Nat Commun. 2016;7:12368.

  17. 17.

    Gringhuis SI, den Dunnen J, Litjens M, et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat Immunol. 2009;10:203–13.

  18. 18.

    Joo H, Upchurch K, Zhang W, et al. Opposing roles of dectin-1 expressed on human plasmacytoid dendritic cells and myeloid dendritic cells in Th2 polarization. J Immunol. 2015;195:1723–31.

  19. 19.

    Chen L, Wang S, Zhou Y, et al. Identification of early growth response protein 1 (EGR-1) as a novel target for JUN-induced apoptosis in multiple myeloma. Blood. 2010;115:61–70.

  20. 20.

    Vegran F, Berger H, Boidot R, et al. The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat Immunol. 2014;15:758–66.

  21. 21.

    Lilly LM, Gessner MA, Dunaway CW, et al. The beta-glucan receptor dectin-1 promotes lung immunopathology during fungal allergy via IL-22. J Immunol. 2012;189:3653–60.

  22. 22.

    Su Z, Lin J, Lu F, et al. Potential autocrine regulation of interleukin-33/ST2 signaling of dendritic cells in allergic inflammation. Mucosal Immunol. 2013;6:921–30.

  23. 23.

    Polumuri SK, Jayakar GG, Shirey KA, et al. Transcriptional regulation of murine IL-33 by TLR and non-TLR agonists. J Immunol. 2012;189:50–60.

  24. 24.

    Williams JW, Tjota MY, Clay BS, et al. Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation. Nat Commun. 2013;4:2990.

  25. 25.

    Sun L, Zhu Z, Cheng N, et al. Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway. Eur J Immunol. 2014;44:2153–64.

Download references

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (no. 81372536 for SW, 81502452 for XC and 81602485 for YZ) and a grant from the Natural Science Foundation of Jilin Province (no. 20170520006JH for XC).

Author information

Affiliations

  1. Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, 130061, China

    • Dongjiao Wang
    • , Ning Liu
    •  & Ying Yue
  2. Department of Hematology, The First Hospital of Jilin University, Changchun, 130061, China

    • Sujun Gao
    •  & Tianxue Qin
  3. Department of Cancer Immunology, The First Hospital of Jilin University, Changchun, 130061, China

    • Jintong Chen
    • , Yinghua Zhao
    • , Yuxue Jiang
    • , Xiao Chu
    • , Qing Yi
    •  & Siqing Wang
  4. Department of Internal Medicine, Linhai First People’s Hospital, Linhai, Zhejiang, 317000, China

    • Xiaohua Wang
  5. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA

    • Qing Yi

Authors

  1. Search for Dongjiao Wang in:

  2. Search for Sujun Gao in:

  3. Search for Jintong Chen in:

  4. Search for Yinghua Zhao in:

  5. Search for Yuxue Jiang in:

  6. Search for Xiao Chu in:

  7. Search for Xiaohua Wang in:

  8. Search for Ning Liu in:

  9. Search for Tianxue Qin in:

  10. Search for Qing Yi in:

  11. Search for Ying Yue in:

  12. Search for Siqing Wang in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Ying Yue or Siqing Wang.

About this article

Publication history

Received

Revised

Accepted

Published

Issue Date

DOI

https://doi.org/10.1038/s41374-018-0047-2