Skip to main content


Log in

Macrophage polarization differs between apical granulomas, radicular cysts, and dentigerous cysts

  • Original Article
  • Published:
Clinical Oral Investigations Aims and scope Submit manuscript



Apical periodontitis can appear clinically as apical granulomas or radicular cysts. There is evidence that immunologic factors are involved in the pathogenesis of both pathologies. In contrast to radicular cysts, the dentigerous cysts have a developmental origin. Macrophage polarization (M1 vs M2) is a main regulator of tissue homeostasis and differentiation. There are no studies comparing macrophage polarization in apical granulomas, radicular cysts, and dentigerous cysts.

Materials and methods

Forty-one apical granulomas, 23 radicular cysts, and 23 dentigerous cysts were analyzed in this study. A tissue microarray (TMA) of the 87 consecutive specimens was created, and CD68-, CD11c-, CD163-, and MRC1-positive macrophages were detected by immunohistochemical methods. TMAs were digitized, and the expression of macrophage markers was quantitatively assessed.


Radicular cysts are characterized by M1 polarization of macrophages while apical granulomas show a significantly higher degree of M2 polarization. Dentigerous cysts have a significantly lower M1 polarization than both analyzed periapical lesions (apical granulomas and radicular cysts) and accordingly, a significantly higher M2 polarization than radicular cysts. Macrophage cell density in dentigerous cysts is significantly lower than in the periapical lesions.


The development of apical periodontitis towards apical granulomas or radicular cysts might be directed by macrophage polarization. Radicular cyst formation is associated with an increased M1 polarization of infiltrating macrophages. In contrast to radicular cysts, dentigerous cysts are characterized by a low macrophage infiltration and a high degree of M2 polarization, possibly reflecting their developmental rather than inflammatory origin.

Clinical relevance

As M1 polarization of macrophages is triggered by bacterial antigens, these results underline the need for sufficient bacterial clearance during endodontic treatment to prevent a possible M1 macrophage-derived stimulus for radicular cyst formation.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others


  1. Garcia CC, Sempere FV, Diago MP, Bowen EM (2007) The post-endodontic periapical lesion: histologic and etiopathogenic aspects. Medicina oral, patologia oral y cirugia bucal 12(8):E585–E590

    PubMed  Google Scholar 

  2. Fukada SY, Silva TA, Garlet GP, Rosa AL, da Silva JS, Cunha FQ (2009) Factors involved in the T helper type 1 and type 2 cell commitment and osteoclast regulation in inflammatory apical diseases. Oral Microbiol Immunol 24(1):25–31. doi:10.1111/j.1399-302X.2008.00469.x

    Article  PubMed  Google Scholar 

  3. Xiong J, Gronthos S, Bartold PM (2013) Role of the epithelial cell rests of Malassez in the development, maintenance and regeneration of periodontal ligament tissues. Periodontology 63(1):217–233. doi:10.1111/prd.12023

    Article  Google Scholar 

  4. Lin LM, Huang GT, Rosenberg PA (2007) Proliferation of epithelial cell rests, formation of apical cysts, and regression of apical cysts after periapical wound healing. J Endod 33(8):908–916. doi:10.1016/j.joen.2007.02.006

    Article  PubMed  Google Scholar 

  5. Leonardi R, Caltabiano R, Loreto C (2005) Collagenase-3 (MMP-13) is expressed in periapical lesions: an immunohistochemical study. Int Endod J 38(5):297–301. doi:10.1111/j.1365-2591.2005.00943.x

    Article  PubMed  Google Scholar 

  6. Teixeira-Salum TB, Rodrigues DB, Gervasio AM, Souza CJ, Rodrigues V Jr, Loyola AM (2010) Distinct Th1, Th2 and Treg cytokines balance in chronic periapical granulomas and radicular cysts. J Oral Pathol Med 39(3):250–256. doi:10.1111/j.1600-0714.2009.00863.x

    Article  PubMed  Google Scholar 

  7. Stashenko P, Teles R, D’Souza R (1998) Periapical inflammatory responses and their modulation. Crit Rev Oral Biol Med 9(4):498–521

    Article  PubMed  Google Scholar 

  8. Locati M, Mantovani A, Sica A (2013) Macrophage activation and polarization as an adaptive component of innate immunity. Adv Immunol 120:163–184. doi:10.1016/B978-0-12-417028-5.00006-5

    Article  PubMed  Google Scholar 

  9. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185. doi:10.1002/path.4133

    Article  PubMed  Google Scholar 

  10. Mantovani A, Sica A, Locati M (2007) New vistas on macrophage differentiation and activation. Eur J Immunol 37(1):14–16. doi:10.1002/eji.200636910

    Article  PubMed  Google Scholar 

  11. Hirata Y, Tabata M, Kurobe H, Motoki T, Akaike M, Nishio C, Higashida M, Mikasa H, Nakaya Y, Takanashi S, Igarashi T, Kitagawa T, Sata M (2011) Coronary atherosclerosis is associated with macrophage polarization in epicardial adipose tissue. J Am Coll Cardiol 58(3):248–255. doi:10.1016/j.jacc.2011.01.048

    Article  PubMed  Google Scholar 

  12. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795. doi:10.1172/JCI59643

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lan C, Huang X, Lin S, Huang H, Cai Q, Wan T, Lu J, Liu J (2013) Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat 12(3):259–267. doi:10.7785/tcrt.2012.500312

    Article  PubMed  Google Scholar 

  14. Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM (2012) Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012:948098. doi:10.1155/2012/948098

    Article  PubMed  PubMed Central  Google Scholar 

  15. Weber M, Buttner-Herold M, Hyckel P, Moebius P, Distel L, Ries J, Amann K, Neukam FW, Wehrhan F (2014) Small oral squamous cell carcinomas with nodal lymphogenic metastasis show increased infiltration of M2 polarized macrophages--an immunohistochemical analysis. J Cranio-Maxillo-Facial Surg 42(7):1087–1094. doi:10.1016/j.jcms.2014.01.035

    Article  Google Scholar 

  16. Weber M, Iliopoulos C, Moebius P, Buttner-Herold M, Amann K, Ries J, Preidl R, Neukam FW, Wehrhan F (2016) Prognostic significance of macrophage polarization in early stage oral squamous cell carcinomas. Oral Oncol 52:75–84. doi:10.1016/j.oraloncology.2015.11.001

    Article  PubMed  Google Scholar 

  17. Lu CF, Huang CS, Tjiu JW, Chiang CP (2010) Infiltrating macrophage count: a significant predictor for the progression and prognosis of oral squamous cell carcinomas in Taiwan. Head Neck 32(1):18–25. doi:10.1002/hed.21138

    PubMed  Google Scholar 

  18. Kurahara H, Shinchi H, Mataki Y, Maemura K, Noma H, Kubo F, Sakoda M, Ueno S, Natsugoe S, Takao S (2011) Significance of M2-polarized tumor-associated macrophage in pancreatic cancer. J Surg Res 167(2):e211–e219. doi:10.1016/j.jss.2009.05.026

    Article  PubMed  Google Scholar 

  19. Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, Takigami M, Kondo T, Atsumi T (2013) The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis 22(7):910–918. doi:10.1016/j.jstrokecerebrovasdis.2012.11.020

    Article  PubMed  Google Scholar 

  20. Kawamura K, Komohara Y, Takaishi K, Katabuchi H, Takeya M (2009) Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathol Int 59(5):300–305. doi:10.1111/j.1440-1827.2009.02369.x

    Article  PubMed  Google Scholar 

  21. Pejnovic NN, Pantic JM, Jovanovic IP, Radosavljevic GD, Milovanovic MZ, Nikolic IG, Zdravkovic NS, Djukic AL, Arsenijevic NN, Lukic ML (2013) Galectin-3 deficiency accelerates high-fat diet-induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. Diabetes 62(6):1932–1944. doi:10.2337/db12-0222

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fischer-Posovszky P, Wang QA, Asterholm IW, Rutkowski JM, Scherer PE (2011) Targeted deletion of adipocytes by apoptosis leads to adipose tissue recruitment of alternatively activated M2 macrophages. Endocrinology 152(8):3074–3081. doi:10.1210/en.2011-1031

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cao X, Shen D, Patel MM, Tuo J, Johnson TM, Olsen TW, Chan CC (2011) Macrophage polarization in the maculae of age-related macular degeneration: a pilot study. Pathol Int 61(9):528–535. doi:10.1111/j.1440-1827.2011.02695.x

    Article  PubMed  PubMed Central  Google Scholar 

  24. Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, Aissat A, Guerre-Millo M, Clement K (2009) Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. J Clin Endocrinol Metab 94(11):4619–4623. doi:10.1210/jc.2009-0925

    Article  PubMed  Google Scholar 

  25. Hasan D, Chalouhi N, Jabbour P, Hashimoto T (2012) Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflammation 9:222. doi:10.1186/1742-2094-9-222

    Article  PubMed  PubMed Central  Google Scholar 

  26. van Putten SM, Ploeger DT, Popa ER, Bank RA (2013) Macrophage phenotypes in the collagen-induced foreign body reaction in rats. Acta Biomater 9(5):6502–6510. doi:10.1016/j.actbio.2013.01.022

    Article  PubMed  Google Scholar 

  27. Johnson NR, Gannon OM, Savage NW, Batstone MD (2014) Frequency of odontogenic cysts and tumors: a systematic review. J Investig Clin Dent 5(1):9–14. doi:10.1111/jicd.12044

    Article  PubMed  Google Scholar 

  28. Wright JM, Odell EW, Speight PM, Takata T (2014) Odontogenic tumors, WHO 2005: where do we go from here? Head Neck Pathol 8(4):373–382. doi:10.1007/s12105-014-0585-x

    Article  PubMed  PubMed Central  Google Scholar 

  29. Weber M, Moebius P, Buttner-Herold M, Amann K, Preidl R, Neukam FW, Wehrhan F (2015) Macrophage polarisation changes within the time between diagnostic biopsy and tumour resection in oral squamous cell carcinomas--an immunohistochemical study. Br J Cancer 113(3):510–519. doi:10.1038/bjc.2015.212

    Article  PubMed  PubMed Central  Google Scholar 

  30. Nair PN (2004) Pathogenesis of apical periodontitis and the causes of endodontic failures. Crit Rev Oral Biol Med 15(6):348–381. doi:10.1177/154411130401500604

    Article  PubMed  Google Scholar 

  31. de Carvalho Fraga CA, Alves LR, de Sousa AA, de Jesus SF, Vilela DN, Pereira CS, Batista Domingos PL, Viana AG, Jham BC, Batista de Paula AM, Sena Guimaraes AL (2013) Th1 and Th2-like protein balance in human inflammatory radicular cysts and periapical granulomas. J Endod 39(4):453–455. doi:10.1016/j.joen.2012.11.054

    Article  PubMed  Google Scholar 

  32. Silva TA, Garlet GP, Lara VS, Martins W Jr, Silva JS, Cunha FQ (2005) Differential expression of chemokines and chemokine receptors in inflammatory periapical diseases. Oral Microbiol Immunol 20(5):310–316. doi:10.1111/j.1399-302X.2005.00232.x

    Article  PubMed  Google Scholar 

  33. Schmidt A, Zhang XM, Joshi RN, Iqbal S, Wahlund C, Gabrielsson S, Harris RA, Tegner J (2016) Human macrophages induce CD4(+)Foxp3(+) regulatory T cells via binding and re-release of TGF-beta. Immunol Cell Biol 94(8):747–762. doi:10.1038/icb.2016.34

    Article  PubMed  Google Scholar 

  34. Qureshi W, Asif M, Qari IH, Qazi JA (2010) Role of interleukin-1 in pathogenesis of radicular cyst. J Ayub Med Coll Abbottabad 22(2):86–87

    PubMed  Google Scholar 

  35. Li J, Hsu HC, Mountz JD (2013) The dynamic duo-inflammatory M1 macrophages and Th17 cells in rheumatic diseases. J Orthop Rheumatol 1(1):4. doi:10.13188/2334-2846.1000002

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sa MC, de Matos FR, Conceicao TS, AC HL, Freitas RA (2016) Immunoexpression of tumor necrosis factor-alpha, interleukin-1alpha and interleukin-10 on odontogenic cysts and tumours. Int Endod J. doi:10.1111/iej.12640

  37. de Moraes M, da Rocha Neto PC, de Matos FR, Lopes ML, de Azevedo PR, Costa Ade L (2014) Immunoexpression of transforming growth factor beta and interferon gamma in radicular and dentigerous cysts. J Endod 40(9):1293–1297. doi:10.1016/j.joen.2014.01.010

    Article  PubMed  Google Scholar 

  38. Bracks IV, Armada L, Goncalves LS, Pires FR (2014) Distribution of mast cells and macrophages and expression of interleukin-6 in periapical cysts. J Endod 40(1):63–68. doi:10.1016/j.joen.2013.09.037

    Article  PubMed  Google Scholar 

  39. Wehrhan F, Buttner-Herold M, Hyckel P, Moebius P, Preidl R, Distel L, Ries J, Amann K, Schmitt C, Neukam FW, Weber M (2014) Increased malignancy of oral squamous cell carcinomas (oscc) is associated with macrophage polarization in regional lymph nodes - an immunohistochemical study. BMC Cancer 14(1):522. doi:10.1186/1471-2407-14-522

    Article  PubMed  PubMed Central  Google Scholar 

  40. Cho KY, Miyoshi H, Kuroda S, Yasuda H, Kamiyama K, Nakagawara J, Takigami M, Kondo T, Atsumi T (2012) The phenotype of infiltrating macrophages influences arteriosclerotic plaque vulnerability in the carotid artery. J Stroke Cerebrovasc Dis. doi:10.1016/j.jstrokecerebrovasdis.2012.11.020

  41. van Putten SM, Ploeger DT, Popa ER, Bank RA (2013) Macrophage phenotypes in the collagen-induced foreign body reaction in rats. Acta Biomater. doi:10.1016/j.actbio.2013.01.022

Download references


The authors thank Luitpold Distel for his assistance in the cell counting procedure. The authors also thank Christian Dittmann for providing the vector graphics for Fig. 5. We would like to thank Rudolf Jung for manufacturing the TMAs and Susanne Schoenherr and Elke Diebel for technical assistance. We would also like to thank the dental student Lena Marsing for processing the tissue specimens and operating the immunohistochemistry autostainer apparatus.

Author information

Authors and Affiliations



The authors’ initials are used.

MW formulated the hypothesis, initiated and conducted the study, interpreted the data, and wrote the manuscript. FW formulated the hypothesis, conducted the study, interpreted the data, and contributed relevantly to the manuscript. TS selected the patient collective, analyzed the medical records, interpreted the data and contributed to the manuscript. PM performed the immunohistochemical analyses and the whole slide imaging of the specimens, helped with cell counting, and critically reviewed the manuscript. MB and JR helped validate the markers, contributed to the discussion, and critically reviewed the manuscript. FN and RP contributed to the discussion and critically reviewed the manuscript.

All of the authors read and approved the final manuscript.

Corresponding author

Correspondence to Manuel Weber.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.


The study was self-funded by the authors and their institutions.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study, formal consent is not required.

Additional information

This study was not financially supported by a third party.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weber, M., Schlittenbauer, T., Moebius, P. et al. Macrophage polarization differs between apical granulomas, radicular cysts, and dentigerous cysts. Clin Oral Invest 22, 385–394 (2018).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: