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Immunostimulatory activity of low-molecular-weight hyaluronan on dendritic cells stimulated with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis

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Abstract

Objectives

Periodontitis is a chronic inflammatory disease characterized by tooth-supporting tissue destruction, which is elicited by the host’s immune response triggered against periodonto-pathogen bacteria. During periodontal tissue destruction, extracellular matrix components are metabolized and fragmented. Some extracellular matrix component-derived fragments, such as low-molecular-weight hyaluronan (LMW-HA), have potent immunogenic potential, playing a role as damage-associated molecular patterns (DAMPs) during activation of immune cells. Dendritic cells (DCs) play a central role in the host’s immune response displayed during periodontitis; thus, this study aimed to analyze whether LMW-HA has an immunostimulatory activity on DCs when stimulated with periodonto-pathogen bacteria.

Materials and methods

LMW-HA-treated and non-treated DCs were stimulated with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis and the mRNA expression for cytokines tumor necrosis factor-α (TNF-alpha), interleukin-1β (IL-1B), interleukin-6 (IL-6), and interleukin-23 (IL-23A) was quantified by RT-qPCR. In addition, transcription factors interferon regulatory factor 4 (IRF4), interferon regulatory factor 8 (IRF8), neurogenic locus notch homolog protein 2 (NOTCH2), and basic leucine zipper ATF-like transcription factor 3 (BATF3), involved in DC activation, were analyzed.

Results

Higher expression levels of TNF-alpha, IL-1B, IL-6, and IL-23A were detected in LMW-HA-treated DCs after bacterial infection, as compared with non-treated DCs. When LMW-HA-treated DCs were infected with A. actinomycetemcomitans, higher levels of IRF4, NOTCH2, and BATF3 were detected compared with non-treated cells; whereas against P. gingivalis infection, increased levels of IRF4 and NOTCH2 were detected.

Conclusion

LMW-HA plays an immunostimulatory role on the immune response triggered by DCs during infection with A. actinomycetemcomitans or P. gingivalis.

Clinical relevance

Detection of extracellular matrix component-derived fragments produced during periodontal tissue destruction, such as LMW-HA, could explain at least partly unsuccessful periodontal treatment and the chronicity of the disease.

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References

  1. Bansal J, Kedige SD, Anand S (2010) Hyaluronic acid: a promising mediator for periodontal regeneration. Indian J Dent Res 21(4):575

    Article  PubMed  Google Scholar 

  2. Jiang D, Liang J, Noble PW (2011) Hyaluronan as an immune regulator in human diseases. Physiol Rev 91(1):221–264

    Article  PubMed  Google Scholar 

  3. Necas J, Bartosikova L, Brauner P, Kolar J (2008) Hyaluronic acid (hyaluronan): a review. Vet Med 53(8):397–411

    Article  Google Scholar 

  4. Bowden DJ, Byrne CA, Alkhayat A, Eustace SJ, Kavanagh EC (2017) Injectable viscoelastic supplements: a review for radiologists. AJR Am J Roentgenol 209(4):883–888

    Article  PubMed  Google Scholar 

  5. Powell JD, Horton MR (2005) Threat matrix. Low-molecular-weight hyaluronan (HA) as a danger signal. Immunol Res 31(3):207–218

    Article  PubMed  Google Scholar 

  6. Petrey AC, de la Motte CA (2014) Hyaluronan, a crucial regulator of inflammation. Front Immunol 5:101

    Article  PubMed  PubMed Central  Google Scholar 

  7. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177(2):1272–1281

    Article  PubMed  Google Scholar 

  8. Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195(1):99–111

    Article  PubMed  PubMed Central  Google Scholar 

  9. Song L, Dong G, Guo L, Graves DT (2018) The function of dendritic cells in modulating the host response. Mol Oral Microbiol 33(1):13–21

    Article  PubMed  Google Scholar 

  10. Mildner A, Jung S (2014) Development and function of dendritic cell subsets. Immunity 40(5):642–656

    Article  PubMed  Google Scholar 

  11. Satpathy AT, Wu X, Albring JC, Murphy KM (2012) Re(de)fining the dendritic cell lineage. Nat Immunol 13(12):1145–1154

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chandra J, Kuo PT, Hahn AM, Belz GT, Frazer IH (2017) Batf3 selectively determines acquisition of CD8+ dendritic cell phenotype and function. Immunol Cell Biol 95(2):215–223

    Article  PubMed  Google Scholar 

  13. Nizzoli G, Krietsch J, Weick A, Steinfelder S, Facciotti F, Gruarin P, Bianco A, Steckel B, Moro M, Crosti M, Romagnani C, Stölzel K, Torretta S, Pignataro L, Scheibenbogen C, Neddermann P, De Francesco R, Abrignani S, Geginat J (2013) Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses. Blood 122(6):932–942

    Article  PubMed  Google Scholar 

  14. Tussiwand R, Gautier EL (2015) Transcriptional regulation of mononuclear phagocyte development. Front Immunol 6:533

    Article  PubMed  PubMed Central  Google Scholar 

  15. Bedoui S, Heath WR (2015) Krüppel-ling of IRF4-dependent DCs into two functionally distinct DC subsets. Immunity 42(5):785–787

    Article  PubMed  Google Scholar 

  16. Persson EK, Uronen-Hansson H, Semmrich M, Rivollier A, Hägerbrand K, Marsal J, Gudjonsson S, Håkansson U, Reizis B, Kotarsky K, Agace WW (2013) IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38(5):958–969

    Article  PubMed  Google Scholar 

  17. Schlitzer A, McGovern N, Teo P, Zelante T, Atarashi K, Low D, Ho AW, See P, Shin A, Wasan PS, Hoeffel G, Malleret B, Heiseke A, Chew S, Jardine L, Purvis HA, Hilkens CM, Tam J, Poidinger M, Stanley ER, Krug AB, Renia L, Sivasankar B, Ng LG, Collin M, Ricciardi-Castagnoli P, Honda K, Haniffa M, Ginhoux F (2013) IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38(5):970–983

    Article  PubMed  PubMed Central  Google Scholar 

  18. Casale M, Moffa A, Vella P, Sabatino L, Capuano F, Salvinelli B, Lopez MA, Carinci F, Salvinelli F (2016) Hyaluronic acid: perspectives in dentistry. A systematic review. Int J Immunopathol Pharmacol 29(4):572–582

    Article  PubMed  PubMed Central  Google Scholar 

  19. Yamalik N, Kilinç K, Çağlayan F, Eratalay K, Çağlayan G (1998) Molecular size distribution analysis of human gingival proteoglycans and glycosaminoglycans in specific periodontal diseases. J Clin Periodontol 25(2):145–152

    Article  PubMed  Google Scholar 

  20. Vernal R, Leon R, Herrera D, Garcia-Sanz JA, Silva A, Sanz M (2008) Variability in the response of human dendritic cells stimulated with Porphyromonas gingivalis or Aggregatibacter actinomycetemcomitans. J Periodontal Res 43(6):689–697

    Article  PubMed  Google Scholar 

  21. Ke C, Wang D, Sun Y, Qiao D, Ye H, Zeng X (2013) Immunostimulatory and antiangiogenic activities of low molecular weight hyaluronic acid. Food Chem Toxicol 58:401–407

    Article  PubMed  Google Scholar 

  22. Rizzo M, Bayo J, Piccioni F, Malvicini M, Fiore E, Peixoto E, García MG, Aquino JB, Gonzalez Campaña A, Podestá G, Terres M, Andriani O, Alaniz L, Mazzolini G (2014) Low molecular weight hyaluronan-pulsed human dendritic cells showed increased migration capacity and induced resistance to tumor chemoattraction. PLoS One 9(9):e107944

    Article  PubMed  PubMed Central  Google Scholar 

  23. Braza F, Brouard S, Chadban S, Goldstein DR (2016) Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat Rev Nephrol 12(5):281–290

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hull RL, Bogdani M, Nagy N, Johnson PY, Wight TN (2015) Hyaluronan: a mediator of islet dysfunction and destruction in diabetes? J Histochem Cytochem 63(8):592–603

    Article  PubMed  PubMed Central  Google Scholar 

  25. Fujioka-Kobayashi M, Müller HD, Mueller A, Lussi A, Sculean A, Schmidlin PR, Miron RJ (2017) In vitro effects of hyaluronic acid on human periodontal ligament cells. BMC Oral Health 17(1):44

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tanne Y, Tanimoto K, Okuma S, Kunimatsu R, Hirose N, Mitsuyoshi T, Tanne K (2013) Effects of hyaluronan oligosaccharides on apoptosis of human gingival fibroblasts. Open J Stomatol 3(01):19

    Article  Google Scholar 

  27. Wang Y, Han G, Guo B, Huang J (2016) Hyaluronan oligosaccharides promote diabetic wound healing by increasing angiogenesis. Pharmacol Rep 68(6):1126–1132

    Article  PubMed  Google Scholar 

  28. Yamawaki H, Hirohata S, Miyoshi T, Takahashi K, Ogawa H, Shinohata R, Demircan K, Kusachi S, Yamamoto K, Ninomiya Y (2009) Hyaluronan receptors involved in cytokine induction in monocytes. Glycobiology 19(1):83–92

    Article  PubMed  Google Scholar 

  29. Murphy KM (2013) Transcriptional control of dendritic cell development. Adv Immunol 120:239–267

    Article  PubMed  Google Scholar 

  30. Bluestone JA, Mackay CR, O’Shea JJ, Stockinger B (2009) The functional plasticity of T cell subsets. Nat Rev Immunol 9(11):811–816

    Article  PubMed  PubMed Central  Google Scholar 

  31. Collin M, Bigley V (2018) Human dendritic cell subsets: an update. Immunology 154(1):3–20

    Article  PubMed  PubMed Central  Google Scholar 

  32. Geginat J, Nizzoli G, Paroni M, Maglie S, Larghi P, Pascolo S, Abrignani S (2015) Immunity to pathogens taught by specialized human dendritic cell subsets. Front Immunol 6:527

    Article  PubMed  PubMed Central  Google Scholar 

  33. Briseño CG, Haldar M, Kretzer NM, Wu X, Theisen DJ, Kc W, Durai V, Grajales-Reyes GE, Iwata A, Bagadia P, Murphy TL, Murphy KM (2016) Distinct transcriptional programs control cross-priming in classical and monocyte-derived dendritic cells. Cell Rep 15(11):2462–2474

    Article  PubMed  PubMed Central  Google Scholar 

  34. Balan S, Ollion V, Colletti N, Chelbi R, Montanana-Sanchis F, Liu H, Vu Manh TP, Sanchez C, Savoret J, Perrot I, Doffin AC, Fossum E, Bechlian D, Chabannon C, Bogen B, Asselin-Paturel C, Shaw M, Soos T, Caux C, Valladeau-Guilemond J, Dalod M (2014) Human XCR1+ dendritic cells derived in vitro from CD34+ progenitors closely resemble blood dendritic cells, including their adjuvant responsiveness, contrary to monocyte-derived dendritic cells. J Immunol 193(4):1622–1635

    Article  PubMed  PubMed Central  Google Scholar 

  35. Termeer CC, Hennies J, Voith U, Ahrens T, Weiss JM, Prehm P, Simon JC (2000) Oligosaccharides of hyaluronan are potent activators of dendritic cells. J Immunol 165(4):1863–1870

    Article  PubMed  Google Scholar 

  36. Martín-Fontecha A, Sebastiani S, Höpken UE, Uguccioni M, Lipp M, Lanzavecchia A, Sallusto F (2003) Regulation of dendritic cell migration to the draining lymph node: impact on T lymphocyte traffic and priming. J Exp Med 198(4):615–621

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Ms. Darna Venegas and Daniela Salinas (Microbiology Laboratory, Faculty of Dentistry, Universidad de Chile) for sharing their expertise on bacterial cultures.

Funding

This study was supported by grant FONDECYT 1181780 from Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) from the Chilean Government.

Author information

Authors and Affiliations

  1. Periodontal Biology Laboratory, Faculty of Dentistry, Universidad de Chile, Sergio Livingstone Pohlhammer 943, 8380492, Independencia, Santiago, Chile

    Gustavo Monasterio, José Guevara, Juan Pablo Ibarra, Francisca Castillo, Jaime Díaz-Zúñiga, Carla Alvarez, Emilio A. Cafferata & Rolando Vernal

  2. Faculty of Dentistry, Universidad Peruana Cayetano Heredia, Lima, Peru

    Emilio A. Cafferata

  3. Dentistry Unit, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile

    Rolando Vernal

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  1. Gustavo Monasterio
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  2. José Guevara
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  4. Francisca Castillo
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Correspondence to Rolando Vernal.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1975 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol (Protocol 2010/14) was approved by the Ethics Committee for Human Research of Faculty of Dentistry, Universidad de Chile.

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

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Monasterio, G., Guevara, J., Ibarra, J.P. et al. Immunostimulatory activity of low-molecular-weight hyaluronan on dendritic cells stimulated with Aggregatibacter actinomycetemcomitans or Porphyromonas gingivalis. Clin Oral Invest 23, 1887–1894 (2019). https://doi.org/10.1007/s00784-018-2641-5

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  • DOI: https://doi.org/10.1007/s00784-018-2641-5

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