Abstract
Periodontitis is a multifactorial, chronic inflammatory disease affecting the supporting structures of teeth triggered by the complex interactions between a dysbiotic bacterial biofilm and the host’s immune response that results in the characteristic loss of periodontal attachment and alveolar bone. The differential phenotypic presentations of periodontitis emerge from inter-individual differences in immune response regulatory mechanisms. The monocyte-macrophage system has a crucial role in innate immunity and the initiation of the T and B lymphocyte adaptive immune responses. Macrophages involve a heterogeneous cell population that shows wide plasticity and differentiation dynamics. In response to the inflammatory milieu, they can skew at the time of TLR ligation to predominant M1 –pro-inflammatory- or M2 –anti-inflammatory/healing- functional phenotypes. The perpetuation of inflammation by M1 macrophages leads to the recruitment of the adaptive immune response, promoting Th1, Th17, and Th22 differentiation, which are directly associated with periodontal breakdown. In contrast, M2 macrophages induce Th2 and Treg responses which are associated with periodontal homeostasis. In this article, we review the recent advances comprising the role of macrophages and lymphocyte polarization profiles and their reprogramming as potential therapeutic strategies. For this purpose, we reviewed the available literature targeting periodontitis, macrophage, and lymphocyte subpopulations with an emphasis in the later 5 years. The active reprogramming of macrophages and lymphocytes polarization crosstalk opens a promising area for therapeutic development.
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References
Almubarak A, Tanagala KKK, Papapanou PN, Lalla E, Momen-Heravi F (2020) Disruption of monocyte and macrophage homeostasis in periodontitis. Front Immunol 11:330. https://doi.org/10.3389/fimmu.2020.00330
Alvarado-Vazquez PA, Bernal L, Paige CA, Grosick RL, Moracho Vilrriales C, Ferreira DW, Ulecia-Moron C, Romero-Sandoval EA (2017) Macrophage-specific nanotechnology-driven CD163 overexpression in human macrophages results in an M2 phenotype under inflammatory conditions. Immunobiology 222(8–9):900–912. S0171-2985(17)30093-1 [pii]
Alvarez C, Monasterio G, Cavalla F, Cordova LA, Hernandez M, Heymann D, Garlet GP, Sorsa T, Parnanen P, Lee HM, Golub LM, Vernal R, Kantarci A (2019) Osteoimmunology of oral and maxillofacial diseases: translational applications based on biological mechanisms. Front Immunol 10:1664. https://doi.org/10.3389/fimmu.2019.01664
Alvarez C, Rojas C, Rojas L, Cafferata EA, Monasterio G, Vernal R (2018) Regulatory T lymphocytes in periodontitis: a translational view. Mediat Inflamm 2018:7806912. https://doi.org/10.1155/2018/7806912
Alvarez C, Suliman S, Almarhoumi R, Vega ME, Rojas C, Monasterio G, Galindo M, Vernal R, Kantarci A (2020) Regulatory T cell phenotype and anti-osteoclastogenic function in experimental periodontitis. Sci Rep 10(1):19018. https://doi.org/10.1038/s41598-020-76038-w
Ambarus CA, Krausz S, van Eijk M, Hamann J, Radstake TR, Reedquist KA, Tak PP, Baeten DL (2012) Systematic validation of specific phenotypic markers for in vitro polarized human macrophages. J Immunol Methods 375(1–2):196–206. https://doi.org/10.1016/j.jim.2011.10.013. S0022–1759(11)00294–8 [pii]
Araujo-Pires AC, Biguetti CC, Repeke CE, Rodini Cde O, Campanelli AP, Trombone AP, Letra A, Silva RM, Garlet GP (2014) Mesenchymal stem cells as active prohealing and immunosuppressive agents in periapical environment: evidence from human and experimental periapical lesions. J Endod 40(10):1560–1565. https://doi.org/10.1016/j.joen.2014.02.012
Araujo-Pires AC, Vieira AE, Francisconi CF, Biguetti CC, Glowacki A, Yoshizawa S, Campanelli AP, Trombone AP, Sfeir CS, Little SR, Garlet GP (2015) IL-4/CCL22/CCR4 axis controls regulatory T-cell migration that suppresses inflammatory bone loss in murine experimental periodontitis. J Bone Miner Res 30(3):412–422. https://doi.org/10.1002/jbmr.2376
Baeza M, Morales A, Cisterna C, Cavalla F, Jara G, Isamitt Y, Pino P, Gamonal J (2020) Effect of periodontal treatment in patients with periodontitis and diabetes: systematic review and meta-analysis. J Appl Oral Sci 28:e20190248. https://doi.org/10.1590/1678-7757-2019-0248
Barbi J, Pardoll D, Pan F (2014) Treg functional stability and its responsiveness to the microenvironment. Immunol Rev 259(1):115–139. https://doi.org/10.1111/imr.12172
Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G (2013) Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One 8(11):e80908. https://doi.org/10.1371/journal.pone.0080908
Belfield LA, Bennett JH, Abate W, Jackson SK (2017) Exposure to Porphyromonas gingivalis LPS during macrophage polarisation leads to diminished inflammatory cytokine production. Arch Oral Biol 81:41–47. https://doi.org/10.1016/j.archoralbio.2017.04.021
Bi CS, Sun LJ, Qu HL, Chen F, Tian BM, Chen FM (2019) The relationship between T-helper cell polarization and the RANKL/OPG ratio in gingival tissues from chronic periodontitis patients. Clin Exp Dent Res 5(4):377–388. https://doi.org/10.1002/cre2.192
Bunte K, Beikler T (2019) Th17 cells and the IL-23/IL-17 Axis in the pathogenesis of periodontitis and immune-mediated inflammatory diseases. Int J Mol Sci 20(14):doi:10.3390/ijms20143394
Cavalla F, Biguetti CC, Melchiades JL, Tabanez AP, Azevedo MCS, Trombone APF, Faveri M, Feres M, Garlet GP (2018) Genetic association with subgingival bacterial colonization in chronic periodontitis. Genes (Basel) 9(6):doi:10.3390/genes9060271
Cavalla F, Letra A, Silva RM, Garlet GP (2021) Determinants of periodontal/periapical lesion stability and progression. J Dent Res 100(1):29–36. https://doi.org/10.1177/0022034520952341
Chen XT, Chen LL, Tan JY, Shi DH, Ke T, Lei LH (2016) Th17 and Th1 lymphocytes are correlated with chronic periodontitis. Immunol Investig 45(3):243–254. https://doi.org/10.3109/08820139.2016.1138967
Deeks ED (2018) Denosumab: a review in postmenopausal osteoporosis. Drugs Aging 35(2):163–173. https://doi.org/10.1007/s40266-018-0525-7
Deng G, Song X, Fujimoto S, Piccirillo CA, Nagai Y, Greene MI (2019) Foxp3 post-translational modifications and Treg suppressive activity. Front Immunol 10:2486. https://doi.org/10.3389/fimmu.2019.02486
Derlindati E, Dei Cas A, Montanini B, Spigoni V, Curella V, Aldigeri R, Ardigo D, Zavaroni I, Bonadonna RC (2015) Transcriptomic analysis of human polarized macrophages: more than one role of alternative activation? PLoS One 10(3):e0119751. https://doi.org/10.1371/journal.pone.0119751
Diaz-Zuniga J, Melgar-Rodriguez S, Monasterio G, Pujol M, Rojas L, Alvarez C, Carvajal P, Vernal R (2017) Differential human Th22-lymphocyte response triggered by Aggregatibacter actinomycetemcomitans serotypes. Arch Oral Biol 78:26–33. https://doi.org/10.1016/j.archoralbio.2017.02.008
Epelman S, Lavine KJ, Randolph GJ (2014) Origin and functions of tissue macrophages. Immunity 41(1):21–35. https://doi.org/10.1016/j.immuni.2014.06.013
Ferreira LMR, Muller YD, Bluestone JA, Tang Q (2019) Next-generation regulatory T cell therapy. Nat Rev Drug Discov 18(10):749–769. https://doi.org/10.1038/s41573-019-0041-4
Francisconi CF, Vieira AE, Biguetti CC, Glowacki AJ, Trombone AP, Letra A, Menezes Silva R, Sfeir CS, Little SR, Garlet GP (2016) Characterization of the protective role of regulatory T cells in experimental periapical lesion development and their Chemoattraction manipulation as a therapeutic tool. J Endod 42(1):120–126. https://doi.org/10.1016/j.joen.2015.09.022
Galarraga-Vinueza ME, Dohle E, Ramanauskaite A, Al-Maawi S, Obreja K, Magini R, Sader R, Ghanaati S, Schwarz F (2020) Anti-inflammatory and macrophage polarization effects of Cranberry Proanthocyanidins (PACs) for periodontal and peri-implant disease therapy. J Periodontal Res 55(6):821–829. https://doi.org/10.1111/jre.12773
Garaicoa-Pazmino C, Fretwurst T, Squarize CH, Berglundh T, Giannobile WV, Larsson L, Castilho RM (2019) Characterization of macrophage polarization in periodontal disease. J Clin Periodontol 46(8):830–839. https://doi.org/10.1111/jcpe.13156
Garlet GP, Cardoso CR, Campanelli AP, Garlet TP, Avila-Campos MJ, Cunha FQ, Silva JS (2008) The essential role of IFN-gamma in the control of lethal Aggregatibacter actinomycetemcomitans infection in mice. Microbes Infect 10(5):489–496. https://doi.org/10.1016/j.micinf.2008.01.010
Garlet GP, Cardoso CR, Mariano FS, Claudino M, de Assis GF, Campanelli AP, Avila-Campos MJ, Silva JS (2010) Regulatory T cells attenuate experimental periodontitis progression in mice. J Clin Periodontol 37(7):591–600. https://doi.org/10.1111/j.1600-051X.2010.01586.x
Glowacki AJ, Yoshizawa S, Jhunjhunwala S, Vieira AE, Garlet GP, Sfeir C, Little SR (2013) Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes. Proc Natl Acad Sci U S A 110(46):18525–18530. https://doi.org/10.1073/pnas.1302829110
Hajishengallis G (2015) Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 15(1):30–44. https://doi.org/10.1038/nri3785
Haribhai D, Chatila TA, Williams CB (2016) Immunotherapy with iTreg and nTreg cells in a murine model of inflammatory bowel disease. Methods Mol Biol 1422:197–211. https://doi.org/10.1007/978-1-4939-3603-8_19
Hernandez M, Dutzan N, Garcia-Sesnich J, Abusleme L, Dezerega A, Silva N, Gonzalez FE, Vernal R, Sorsa T, Gamonal J (2011) Host-pathogen interactions in progressive chronic periodontitis. J Dent Res 90(10):1164–1170. doi:0022034511401405 [pii]
Holden JA, Attard TJ, Laughton KM, Mansell A, O'Brien-Simpson NM, Reynolds EC (2014) Porphyromonas gingivalis lipopolysaccharide weakly activates M1 and M2 polarized mouse macrophages but induces inflammatory cytokines. Infect Immun 82(10):4190–4203. https://doi.org/10.1128/IAI.02325-14
Hou Y, Yu H, Liu X, Li G, Pan J, Zheng C, Yu W (2017) Gingipain of Porphyromonas gingivalis manipulates M1 macrophage polarization through C5a pathway. In Vitro Cell Dev Biol Anim 53(7):593–603. https://doi.org/10.1007/s11626-017-0164-z
Huang CB, Alimova Y, Ebersole JL (2016) Macrophage polarization in response to oral commensals and pathogens. Pathog Dis 74(3). https://doi.org/10.1093/femspd/ftw011
Huang Y, Tian C, Li Q, Xu Q (2019) TET1 knockdown inhibits Porphyromonas gingivalis LPS/IFN-gamma-induced M1 macrophage polarization through the NF-kappaB pathway in THP-1 cells. Int J Mol Sci 20(8):doi:10.3390/ijms20082023
Jepsen S, Suvan J, Deschner J (2020) The association of periodontal diseases with metabolic syndrome and obesity. Periodontology 2000 83(1):125–153. https://doi.org/10.1111/prd.12326
Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40(7):1830–1835. https://doi.org/10.1002/eji.201040391
Koidou VP, Cavalli N, Hagi-Pavli E, Nibali L, Donos N (2020) Expression of inflammatory biomarkers and growth factors in gingival crevicular fluid at different healing intervals following non-surgical periodontal treatment: a systematic review. J Periodontal Res 55(6):801–809. https://doi.org/10.1111/jre.12795
Lam RS, O'Brien-Simpson NM, Holden JA, Lenzo JC, Fong SB, Reynolds EC (2016) Unprimed, M1 and M2 macrophages differentially interact with Porphyromonas gingivalis. PLoS One 11(7):e0158629. https://doi.org/10.1371/journal.pone.0158629
Li W, Zhang Z, Wang ZM (2020a) Differential immune cell infiltrations between healthy periodontal and chronic periodontitis tissues. BMC Oral Health 20(1):293. https://doi.org/10.1186/s12903-020-01287-0
Li Y, Wang X, Wang S, Zhu C, Guo J, Li K, Li A (2020b) Complement 3 mediates periodontal destruction in patients with type 2 diabetes by regulating macrophage polarization in periodontal tissues. Cell Prolif 53(10):e12886. https://doi.org/10.1111/cpr.12886
Mahanonda R, Champaiboon C, Subbalekha K, Sa-Ard-Iam N, Yongyuth A, Isaraphithakkul B, Rerkyen P, Charatkulangkun O, Pichyangkul S (2018) Memory T cell subsets in healthy gingiva and periodontitis tissues. J Periodontol 89(9):1121–1130. https://doi.org/10.1002/JPER.17-0674
Medara N, Lenzo JC, Walsh KA, Holden JA, Reynolds EC, Darby IB, O'Brien-Simpson NM (2021a) Peripheral memory T-cell profile is modified in patients undergoing periodontal management. J Clin Periodontol 48(2):249–262. https://doi.org/10.1111/jcpe.13399
Medara N, Lenzo JC, Walsh KA, O'Brien-Simpson NM, Reynolds EC, Darby IB (2021b) Peripheral T helper cell profiles during management of periodontitis. J Clin Periodontol 48(1):76–90. https://doi.org/10.1111/jcpe.13389
Miao Y, He L, Qi X, Lin X (2020) Injecting immunosuppressive M2 macrophages alleviates the symptoms of periodontitis in mice. Front Mol Biosci 7:603817. https://doi.org/10.3389/fmolb.2020.603817
Monasterio G, Budini V, Fernandez B, Castillo F, Rojas C, Alvarez C, Cafferata EA, Vicencio E, Cortes BI, Cortez C, Vernal R (2019a) IL-22-expressing CD4(+) AhR(+) T lymphocytes are associated with RANKL-mediated alveolar bone resorption during experimental periodontitis. J Periodontal Res 54(5):513–524. https://doi.org/10.1111/jre.12654
Monasterio G, Castillo F, Ibarra JP, Guevara J, Rojas L, Alvarez C, Fernandez B, Aguero A, Betancur D, Vernal R (2018) Alveolar bone resorption and Th1/Th17-associated immune response triggered during Aggregatibacter actinomycetemcomitans-induced experimental periodontitis are serotype-dependent. J Periodontol 89(10):1249–1261. https://doi.org/10.1002/JPER.17-0563
Monasterio G, Fernandez B, Castillo F, Rojas C, Cafferata EA, Rojas L, Alvarez C, Fernandez A, Hernandez M, Bravo D, Vernal R (2019b) Capsular-defective Porphyromonas gingivalis mutant strains induce less alveolar bone resorption than W50 wild-type strain due to a decreased Th1/Th17 immune response and less osteoclast activity. J Periodontol 90(5):522–534. https://doi.org/10.1002/JPER.18-0079
Nagaraj S, Youn JI, Gabrilovich DI (2013) Reciprocal relationship between myeloid-derived suppressor cells and T cells. J Immunol 191(1):17–23. https://doi.org/10.4049/jimmunol.1300654
Nibali L, Bayliss-Chapman J, Almofareh SA, Zhou Y, Divaris K, Vieira AR (2019) What is the heritability of periodontitis? A systematic review. J Dent Res 98(6):632–641. https://doi.org/10.1177/0022034519842510
Ortiz MC, Lefimil C, Rodas PI, Vernal R, Lopez M, Acuna-Castillo C, Imarai M, Escobar A (2015) Neisseria gonorrhoeae modulates immunity by polarizing human macrophages to a M2 profile. PLoS One 10(6):e0130713. https://doi.org/10.1371/journal.pone.0130713
Papadopoulos G, Shaik-Dasthagirisaheb YB, Huang N, Viglianti GA, Henderson AJ, Kantarci A, Gibson FC 3rd (2017) Immunologic environment influences macrophage response to Porphyromonas gingivalis. Mol Oral Microbiol 32(3):250–261. https://doi.org/10.1111/omi.12168
Polak D, Shapira L (2018) An update on the evidence for pathogenic mechanisms that may link periodontitis and diabetes. J Clin Periodontol 45(2):150–166. https://doi.org/10.1111/jcpe.12803
Pradeep AR, Roopa Y, Swati PP (2008) Interleukin-4, a T-helper 2 cell cytokine, is associated with the remission of periodontal disease. J Periodontal Res 43(6):712–716. https://doi.org/10.1111/j.1600-0765.2007.01079.x
Raffin C, Vo LT, Bluestone JA (2020) Treg cell-based therapies: challenges and perspectives. Nat Rev Immunol 20(3):158–172. https://doi.org/10.1038/s41577-019-0232-6
Sanz M, Marco Del Castillo A, Jepsen S, Gonzalez-Juanatey JR, D'Aiuto F, Bouchard P, Chapple I, Dietrich T, Gotsman I, Graziani F, Herrera D, Loos B, Madianos P, Michel JB, Perel P, Pieske B, Shapira L, Shechter M, Tonetti M, Vlachopoulos C, Wimmer G (2020) Periodontitis and cardiovascular diseases: consensus report. J Clin Periodontol 47(3):268–288. https://doi.org/10.1111/jcpe.13189
Sima C, Glogauer M (2013) Macrophage subsets and osteoimmunology: tuning of the immunological recognition and effector systems that maintain alveolar bone. Periodontology 2000 63(1):80–101. https://doi.org/10.1111/prd.12032
Sobacchi C, Menale C, Villa A (2019) The RANKL-RANK Axis: a bone to thymus round trip. Front Immunol 10:629. https://doi.org/10.3389/fimmu.2019.00629
Su L, Xu Q, Zhang P, Michalek SM, Katz J (2017) Phenotype and function of myeloid-derived suppressor cells induced by Porphyromonas gingivalis infection. Infect Immun 85(8). https://doi.org/10.1128/IAI.00213-17
Tonetti MS, Van Dyke TE, working group 1 of the joint EFPAAPW (2013) Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Periodontol 84(Suppl 4S):S24–S29. https://doi.org/10.1902/jop.2013.1340019
Valero-Monroy O, Garcia-Cervantes G, Marquez-Corrales LF, Leija-Montoya AG, Sandoval-Basilio J, Martinez-Coronilla G, Isiordia-Espinoza MA, Serafin-Higuera N (2016) Myeloid derived suppressor cell: a new player in periodontal disease? Med Hypotheses 95:35–38. https://doi.org/10.1016/j.mehy.2016.08.010
Veloso P, Fernandez A, Terraza-Aguirre C, Alvarez C, Vernal R, Escobar A, Hernandez M (2020) Macrophages skew towards M1 profile through reduced CD163 expression in symptomatic apical periodontitis. Clin Oral Investig 24(12):4571–4581. https://doi.org/10.1007/s00784-020-03324-2
Vernal R, Diaz-Zuniga J, Melgar-Rodriguez S, Pujol M, Diaz-Guerra E, Silva A, Sanz M, Garcia-Sanz JA (2014) Activation of RANKL-induced osteoclasts and memory T lymphocytes by Porphyromonas gingivalis is serotype dependant. J Clin Periodontol 41(5):451–459. https://doi.org/10.1111/jcpe.12236
Yamaguchi T, Movila A, Kataoka S, Wisitrasameewong W, Ruiz Torruella M, Murakoshi M, Murakami S, Kawai T (2016) Proinflammatory M1 macrophages inhibit RANKL-induced osteoclastogenesis. Infect Immun 84(10):2802–2812. https://doi.org/10.1128/IAI.00461-16
Yan X, Yuan Z, Bian Y, Jin L, Mao Z, Lei J, Chen N (2020) Uncoupling protein-2 regulates M1 macrophage infiltration of gingiva with periodontitis. Cent Eur J Immunol 45(1):9–21. https://doi.org/10.5114/ceji.2020.94664
Yang J, Park OJ, Kim J, Kwon Y, Yun CH, Han SH (2019) Modulation of macrophage subtypes by IRF5 determines osteoclastogenic potential. J Cell Physiol 234(12):23033–23042. https://doi.org/10.1002/jcp.28863
Yu S, Ding L, Liang D, Luo L (2018) Porphyromonas gingivalis inhibits M2 activation of macrophages by suppressing alpha-ketoglutarate production in mice. Mol Oral Microbiol 33(5):388–395. https://doi.org/10.1111/omi.12241
Zhao L, Zhou Y, Xu Y, Sun Y, Li L, Chen W (2011) Effect of non-surgical periodontal therapy on the levels of Th17/Th1/Th2 cytokines and their transcription factors in Chinese chronic periodontitis patients. J Clin Periodontol 38(6):509–516. https://doi.org/10.1111/j.1600-051X.2011.01712.x
Zhu LF, Li L, Wang XQ, Pan L, Mei YM, Fu YW, Xu Y (2019) M1 macrophages regulate TLR4/AP1 via paracrine to promote alveolar bone destruction in periodontitis. Oral Dis 25(8):1972–1982. https://doi.org/10.1111/odi.13167
Zhu X, Zhu J (2020) CD4 T helper cell subsets and related human immunological disorders. Int J Mol Sci 21(21):doi:10.3390/ijms21218011
Zhuang Z, Yoshizawa-Smith S, Glowacki A, Maltos K, Pacheco C, Shehabeldin M, Mulkeen M, Myers N, Chong R, Verdelis K, Garlet GP, Little S, Sfeir C (2019) Induction of M2 macrophages prevents bone loss in murine periodontitis models. J Dent Res 98(2):200–208. https://doi.org/10.1177/0022034518805984
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Cavalla, F., Hernández, M. (2022). Polarization Profiles of T Lymphocytes and Macrophages Responses in Periodontitis. In: Santi-Rocca, J. (eds) Periodontitis. Advances in Experimental Medicine and Biology, vol 1373. Springer, Cham. https://doi.org/10.1007/978-3-030-96881-6_10
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