, Volume 41, Issue 2, pp 409–417 | Cite as

AIM2 Inflammasome Is Critical for dsDNA-Induced IL-1β Secretion in Human Dental Pulp Cells

  • Shuheng Huang
  • Zhi Song
  • Qiting Huang
  • Lan Jiang
  • Lingling Chen
  • Runfu Wang
  • Zhengmei Lin


The AIM2 inflammasome pathway has been determined to play an important role in cellular immune defense against bacterial and viral infections; however, its function and regulatory mechanism in human dental pulp cells (HDPCs) during pulpitis remains poorly understood. In this study, we explored whether the AIM2 inflammasome pathway was activated in HDPCs in response to dsDNA and defined its role in regulating IL-1β secretion. We demonstrated that stimulation with IFN-γ and cytoplasmic DNA significantly activated the AIM2 inflammasome and increased IL-1β secretion in HDPCs. Moreover, AIM2 overexpression significantly up-regulated both cleaved Caspase-1 expression and IL-1β release in HDPCs, while suppression of ASC and Caspase-1 resulted in down-regulation of cleaved Caspase-1 and IL-1β secretion. These results suggest that Caspase-1-dependent IL-1β processing and secretion require the AIM2 inflammasome pathway in HDPCs and that the AIM2 inflammasome pathway is critical for regulation of the dental pulp immune response.


absent in melanoma 2 (AIM2) inflammasome pathway cytoplasmic DNA IL-1β human dental pulp 



This study was supported by the National Natural Science Foundation of China (81670984) and the Science and Technology International Cooperation Projects of Guangdong Province (2016B050502008).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the ethics committee of the Guanghua School of Stomatology, Sun Yat-Sen University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Lamkanfi, Mohamed, and Vishva M. Dixit. 2009. Inflammasomes: Guardians of cytosolic sanctity. Immunological Reviews 227: 95–105. Scholar
  2. 2.
    Franchi, Luigi, Tatjana Eigenbrod, Raúl Muñoz-Planillo, and Gabriel Nuñez. 2009. The inflammasome: A caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nature Immunology 10: 241–247. Scholar
  3. 3.
    Lin, Zheng-Mei, Zhi Song, Wei Qin, Juan Li, Wen-Jie Li, Hai-Yan Zhu, and Zhang Li. 2009. Expression of nucleotide-binding oligomerization domain 2 in normal human dental pulp cells and dental pulp tissues. Journal of Endodontics 35: 838–842. Scholar
  4. 4.
    Song, Zhi, Zhengmei Lin, Feng He, Lan Jiang, Wei Qin, Yaguang Tian, Runfu Wang, and Shuheng Huang. 2012. NLRP3 is expressed in human dental pulp cells and tissues. Journal of Endodontics 38: 1592–1597. Scholar
  5. 5.
    Huang, Shuheng, Zhi Song, Lan Jiang, Lingling Chen, Runfu Wang, Wei Qin, Pengcheng Liu, and Zhengmei Lin. 2015. Absent in melanoma 2 (AIM2) expressed in human dental pulp mediates IL-1β secretion in response to cytoplasmic DNA. Inflammation 38: 566–575. Scholar
  6. 6.
    Jang, Ji-Hyun, Hee Woong Shin, Jung Min Lee, Hyeon-Woo Lee, Eun-Cheol Kim, and Sang Hyuk Park. 2015. An overview of pathogen recognition receptors for innate immunity in dental pulp. Mediators of Inflammation 2015: 794143. Scholar
  7. 7.
    Lee, Sang-Im, Soo-Kyung Kang, Ha-Jin Jung, Yang-Hyun Chun, Young-Dae Kwon, and Eun-Cheol Kim. 2015. Muramyl dipeptide activates human beta defensin 2 and pro-inflammatory mediators through Toll-like receptors and NLRP3 inflammasomes in human dental pulp cells. Clinical Oral Investigations 19: 1419–1428. Scholar
  8. 8.
    Zhang, Ansheng, Peina Wang, Xiaoying Ma, Xiao Yin, Jiguo Li, Haijing Wang, Wenkai Jiang, Qian Jia, and Longxing Ni. 2015. Mechanisms that lead to the regulation of NLRP3 inflammasome expression and activation in human dental pulp fibroblasts. Molecular Immunology 66: 253–262. Scholar
  9. 9.
    Jiang, Wenkai, Haipeng Lv, Haijing Wang, Diya Wang, Shukai Sun, Qian Jia, Peina Wang, Bing Song, and Longxing Ni. 2015. Activation of the NLRP3/caspase-1 inflammasome in human dental pulp tissue and human dental pulp fibroblasts. Cell and Tissue Research 361: 541–555. Scholar
  10. 10.
    Lamkanfi, Mohamed, and Vishva M. Dixit. 2012. Inflammasomes and their roles in health and disease. Annual Review of Cell and Developmental Biology 28: 137–161. Scholar
  11. 11.
    Rathinam, Vijay A.K., Zhaozhao Jiang, Stephen N. Waggoner, Shruti Sharma, Leah E. Cole, Lisa Waggoner, Sivapriya Kailasan Vanaja, Brian G. Monks, Sandhya Ganesan, Eicke Latz, Veit Hornung, Stefanie N. Vogel, Eva Szomolanyi-Tsuda, and Katherine A. Fitzgerald. 2010. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nature Immunology 11: 395–402. Scholar
  12. 12.
    Fernandes-Alnemri, Teresa, Yu Je-Wook, Pinaki Datta, Wu Jianghong, and Emad S. Alnemri. 2009. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458: 509–513. Scholar
  13. 13.
    Hornung, Veit, Andrea Ablasser, Marie Charrel-Dennis, Franz Bauernfeind, Gabor Horvath, Daniel R. Caffrey, Eicke Latz, and Katherine A. Fitzgerald. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458: 514–518. Scholar
  14. 14.
    Fernandes-Alnemri, Teresa, Yu Je-Wook, Christine Juliana, Leobaldo Solorzano, Seokwon Kang, Wu Jianghong, Pinaki Datta, Margaret McCormick, Lan Huang, Erin McDermott, Laurence Eisenlohr, Carlisle P. Landel, and Emad S. Alnemri. 2010. The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nature Immunology 11: 385–393. Scholar
  15. 15.
    Man, Si Ming, Rajendra Karki, and Thirumala-Devi Kanneganti. 2016. AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. European Journal of Immunology 46: 269–280. Scholar
  16. 16.
    Rathinam, Vijay A.K., and Katherine A. Fitzgerald. 2010. Inflammasomes and anti-viral immunity. Journal of Clinical Immunology 30: 632–637. Scholar
  17. 17.
    Strittmatter, Gerhard E., Jennifer Sand, Marlies Sauter, Michael Seyffert, Robin Steigerwald, Cornel Fraefel, Sigrun Smola, Lars E. French, and Hans-Dietmar Beer. 2016. IFN-γ primes keratinocytes for HSV-1-induced inflammasome activation. Journal of Investigative Dermatology 136: 610–620. Scholar
  18. 18.
    Pang, Iris K., and Akiko Iwasaki. 2011. Inflammasomes as mediators of immunity against influenza virus. Trends in Immunology 32: 34–41. Scholar
  19. 19.
    Zhang, Hongbo, Jiadi Luo, John F. Alcorn, Kong Chen, Songqing Fan, Joseph Pilewski, Aizhong Liu, Wei Chen, Jay K. Kolls, and Jieru Wang. 2017. AIM2 inflammasome is critical for influenza-induced lung injury and mortality. Journal of Immunology 198: 4383–4393. Scholar
  20. 20.
    Saiga, Hiroyuki, Shoko Kitada, Yosuke Shimada, Naganori Kamiyama, Megumi Okuyama, Masahiko Makino, Masahiro Yamamoto, and Kiyoshi Takeda. 2012. Critical role of AIM2 in Mycobacterium tuberculosis infection. International Immunology 24: 637–644. Scholar
  21. 21.
    Bostanci, Nagihan, Andre Meier, Bernhard Guggenheim, and Georgios N. Belibasakis. 2011. Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms. Cellular Immunology 270: 88–93. Scholar
  22. 22.
    Zhao, Zheng, Hongchen Liu, and Dongsheng Wang. 2011. ADAM28 manipulates proliferation, differentiation, and apoptosis of human dental pulp stem cells. Journal of Endodontics 37: 332–339. Scholar
  23. 23.
    Gronthos, Stan, M. Mankani, J. Brahim, Pamela G. Robey, and Shundi Shi. 2000. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 97: 13625–13630. Scholar
  24. 24.
    Koning, de, D. Heleen, Judith G.M. Bergboer, Ellen H. van den Bogaard, Ivonne M.J.J. van Vlijmen-Willems, Diana Rodijk-Olthuis, Anna Simon, Patrick L.J.M. Zeeuwen, and Joost Schalkwijk. 2012. Strong induction of AIM2 expression in human epidermis in acute and chronic inflammatory skin conditions. Experimental Dermatology 21: 961–964. Scholar
  25. 25.
    Kopfnagel, Verena, Miriam Wittmann, and Thomas Werfel. 2011. Human keratinocytes express AIM2 and respond to dsDNA with IL-1beta secretion. Experimental Dermatology 20: 1027–1029. Scholar
  26. 26.
    Bauernfeind, Franz G., Gabor Horvath, Andrea Stutz, Emad S. Alnemri, Kelly MacDonald, David Speert, Teresa Fernandes-Alnemri, Wu Jianghong, Brian G. Monks, Katherine A. Fitzgerald, Veit Hornung, and Eicke Latz. 2009. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. Journal of Immunology 183: 787–791. Scholar
  27. 27.
    Schroder, Kate, and Jurg Tschopp. 2010. The inflammasomes. Cell 140: 821–832. Scholar
  28. 28.
    Case, Christopher L. 2011. Regulating caspase-1 during infection: Roles of NLRs, AIM2, and ASC. Yale Journal of Biology and Medicine 84: 333–343.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Martinon, Fabio, Kimberly Burns, and Jürg Tschopp. 2002. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Molecular Cell 10: 417–426. Scholar
  30. 30.
    Yamamoto, Masatatsu, Katsuyuki Yaginuma, Hiroko Tsutsui, Junji Sagara, Xin Guan, Ekihiro Seki, Koubun Yasuda, Masahiro Yamamoto, Shizuo Akira, Kenji Nakanishi, Tetsuo Noda, and Shun'ichiro Taniguchi. 2004. ASC is essential for LPS-induced activation of procaspase-1 independently of TLR-associated signal adaptor molecules. Genes to Cells: Devoted to Molecular and Cellular Mechanisms 9: 1055–1067. Scholar
  31. 31.
    Dinarello, Charles A. 2009. Immunological and inflammatory functions of the interleukin-1 family. Annual Review of Immunology 27: 519–550. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Shuheng Huang
    • 1
    • 2
  • Zhi Song
    • 1
    • 2
  • Qiting Huang
    • 1
    • 2
  • Lan Jiang
    • 1
    • 2
  • Lingling Chen
    • 1
    • 2
  • Runfu Wang
    • 1
    • 2
  • Zhengmei Lin
    • 1
    • 2
  1. 1.Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of StomatologySun Yat-Sen UniversityGuangzhouChina
  2. 2.Guangdong Provincial Key Laboratory of StomatologyGuangzhouChina

Personalised recommendations