MicroRNAs and immunity in periodontal health and disease

Abstract

MicroRNAs (miRNAs) are critical regulators of the host immune and inflammatory response against bacterial pathogens. In the present review, we discuss target genes, target gene functions, the potential regulatory role of miRNAs in periodontal tissues, and the potential role of miRNAs as biomarkers and therapeutics. In periodontal disease, miRNAs exert control over all aspects of innate and adaptive immunity, including the functions of neutrophils, macrophages, dendritic cells and T and B cells. Previous human studies have highlighted some key miRNAs that are dysregulated in periodontitis patients. In the present study, we mapped the major miRNAs that were altered in our reproducible periodontitis mouse model relative to control animals. The miRNAs that were upregulated as a result of periodontal disease in both human and mouse studies included miR-15a, miR-29b, miR-125a, miR-146a, miR-148/148a and miR-223, whereas miR-92 was downregulated. The association of individual miRNAs with unique aspects of periodontal disease and their stability in gingival crevicular fluid underscores their potential as markers for periodontal disease progression or healthy restitution. Moreover, miRNA therapeutics hold great promise for the future of periodontal therapy because of their ability to modulate the immune response to infection when applied in conjunction with synthetic antagomirs and/or relatively straightforward delivery strategies.

References

[1] Diekwisch TGH. Novel approaches toward managing the micromanagers: ‘non-toxic’ but effective. Gene Ther., 2016, 23: 697-698.

[2] Luan X, . MicroRNAs and periodontal homeostasis. J. Dent. Res., 2017, 96: 491-500.

[3] O’Neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat. Rev. Immunol., 2011, 11: 163-175.

[4] O’Connell RM, Zhao JL, Rao DS. MicroRNA function in myeloid biology. Blood, 2011, 118: 2960-2969.

[5] Eulalio A, Schulte L, Vogel J. The mammalian microRNA response to bacterial infections. RNA Biol., 2012, 9: 742-750.

[6] Singaravelu R, . MicroRNAs regulate the immunometabolic response to viral infection in the liver. Nat. Chem. Biol., 2015, 11: 988-993.

[7] Dix A, . Specific and novel microRNAs are regulated as response to fungal infection in human dendritic cells. Front. Microbiol., 2017, 8: 270.

[8] Britton C, Winter AD, Gillan V, Devaney E. microRNAs of parasitic helminths—identification, characterization and potential as drug targets. Int. J. Parasitol. Drugs Drug Resist., 2014, 4: 85-94.

[9] Pauley KM, Cha S, Chan EKL. MicroRNA in autoimmunity and autoimmune diseases. J. Autoimmun., 2009, 32: 189-194.

[10] Alexander M, O’Connell RM. Noncoding RNAs and chronic inflammation: micro-managing the fire within. BioEssays, 2015, 37: 1005-1015.

[11] Maegdefessel L. The emerging role of microRNAs in cardiovascular disease. J. Intern. Med., 2014, 276: 633-644.

[12] Omahen DA. MicroRNA and diseases of the nervous system. Neurosurgery, 2011, 69: 440-454.

[13] Turchinovich A, Cho WC. The origin, function and diagnostic potential of extracellular microRNA in human body fluids. Front. Genet., 2014, 5: 30.

[14] Cortez MA, . MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat. Rev. Clin. Oncol., 2011, 8: 467-477.

[15] Maudet C, Mano M, Eulalio A. MicroRNAs in the interaction between host and bacterial pathogens. FEBS Lett., 2014, 588: 4140-4147.

[16] Lee YH, . Comparison of inflammatory microRNA expression in healthy and periodontitis tissues. Biocell, 2011, 35: 43-49.

[17] Ogata Y, . MicroRNA expression in inflamed and noninflamed gingival tissues from Japanese patients. J. Oral Sci., 2014, 56: 253-260.

[18] Stoecklin-Wasmer C, . MicroRNAs and their target genes in gingival tissues. J. Dent. Res., 2012, 91: 934-940.

[19] Xie YF, Shu R, Jiang SY, Liu Dl, Zhang Xl. Comparison of microRNA profiles of human periodontal diseased and healthy gingival tissues. Int. J. Oral Sci., 2011, 3: 125-134.

[20] Perri R, Nares S, Zhang S, Barros SP, Offenbacher S. MicroRNA modulation in obesity and periodontitis. J. Dent. Res., 2011, 91: 33-38.

[21] Van Dyke TE, Hoop GA. Neutrophil function and oral disease. Crit. Rev. Oral Biol. Med., 1990, 1: 117-133.

[22] Scott DA, Krauss J. Neutrophils in periodontal inflammation. Front. Oral Biol., 2011, 15: 56-83.

[23] Hajishengallis G, Chavakis T, Hajishengallis E, Lambris JD. Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis. J. Leukoc. Biol., 2015, 98: 539-548.

[24] Baek D, . The impact of microRNAs on protein output. Nature, 2008, 455: 64-71.

[25] Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontol. 2000., 2013, 64: 57-80.

[26] Suárez Y, Wang C, Manes TD, Pober JS. Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. J. Immunol., 2009, 184: 21-25.

[27] Zenobia C, . Commensal bacteria-dependent select expression of CXCL2 contributes to periodontal tissue homeostasis. Cell Microbiol., 2013, 15: 1419-1426.

[28] Bhattacharyya S, . Elevated miR-155 promotes inflammation in cystic fibrosis by driving hyperexpression of interleukin-8. J. Biol. Chem., 2011, 286: 11604-11615.

[29] Gantier MP. The not-so-neutral role of microRNAs in neutrophil biology. J. Leukoc. Biol., 2013, 94: 575-583.

[30] Murata K, . MicroRNA-451 down-regulates neutrophil chemotaxis via p38 MAPK. Arthritis Rheumatol., 2014, 66: 549-559.

[31] Dorhoi A, . MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. J. Clin. Invest., 2013, 123: 4836-4848.

[32] Orlowski GM, . Multiple cathepsins promote pro-IL-1β synthesis and NLRP3-mediated IL-1β activation. J. Immunol., 2015, 195: 1685-1697.

[33] Bauernfeind F, . NLRP3 inflammasome activity is negatively controlled by miR-223. J. Immunol., 2012, 189: 4175-4181.

[34] Lawrence T. The nuclear factor NF- B pathway in inflammation. Cold Spring Harb. Perspect. Biol., 2009, 1: a001651.

[35] Bazzoni F, . Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc. Natl. Acad. Sci. USA, 2009, 106: 5282-5287.

[36] Kayal RA. The role of osteoimmunology in periodontal disease. Biomed. Res. Int., 2013, 2013: 1-12.

[37] Tacke F, . Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest., 2007, 117: 185-194.

[38] Geissmann F, . Development of monocytes, macrophages, and dendritic cells. Science, 2010, 327: 656-661.

[39] Roy S. miRNA in macrophage development and function. Antioxid. Redox Signal., 2016, 25: 795-804.

[40] Zhou H, . Identification of the microRNA networks contributing to macrophage differentiation and function. Oncotarget, 2016, 7: 28806-28820.

[41] Fordham JB, Naqvi AR, Nares S. Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J. Leukoc. Biol., 2015, 98: 195-207.

[42] Naqvi AR, Fordham JB, Nares S. miR-24, miR-30b, and miR-142-3p regulate phagocytosis in myeloid inflammatory cells. J. Immunol., 2015, 194: 1916-1927.

[43] Naqvi AR, Fordham JB, Khan A, Nares S. MicroRNAs responsive to Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis LPS modulate expression of genes regulating innate immunity in human macrophages. Innate Immun., 2014, 20: 540-551.

[44] Naqvi, A. et al. Expression profiling of LPS responsive miRNA in primary human macrophages. J. Microb. Biochem. Technol. 08, 136–143 (2016).

[45] Jiang SY, . The negative feedback regulation of microRNA-146a in human periodontal ligament cells after Porphyromonas gingivalis lipopolysaccharide stimulation. Inflamm. Res., 2015, 64: 441-451.

[46] O’Connell RM, Taganov KD, Boldin MP, Cheng G, Baltimore D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. USA, 2007, 104: 1604-1609.

[47] Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF- B-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. USA, 2006, 103: 12481-12486.

[48] Pauley KM, . Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res. Ther., 2008, 10: R101.

[49] Hou J, . MicroRNA-146a feedback inhibits RIG-I-dependent type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol., 2009, 183: 2150-2158.

[50] Etzrodt M, . Regulation of monocyte functional heterogeneity by miR-146a and Relb. Cell Rep., 2012, 1: 317-324.

[51] Zhu J, . Regulation of microRNA-155 in atherosclerotic inflammatory responses by targeting MAP3K10. PLoS ONE, 2012, 7: e46551.

[52] Androulidaki A, . The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity, 2009, 31: 220-231.

[53] Wang P, . Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol., 2010, 185: 6226-6233.

[54] Nazari-Jahantigh M, . MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J. Clin. Invest., 2012, 122: 4190-4202.

[55] Cai X, . Re-polarization of tumor-associated macrophages to pro-inflammatory M1 macrophages by microRNA-155. J. Mol. Cell Biol., 2012, 4: 341-343.

[56] Martinez-Nunez RT, Louafi F, Sanchez-Elsner T. The interleukin 13 (IL-13) pathway in human macrophages is modulated by microRNA-155 via direct targeting of interleukin 13 receptoralpha1 (IL13Ralpha1). J. Biol. Chem., 2011, 286: 1786-1794.

[57] Louafi F, Martinez-Nunez RT, Sanchez-Elsner T. MicroRNA-155 targets SMAD2 and modulates the response of macrophages to transforming growth factor-β. J. Biol. Chem., 2010, 285: 41328-41336.

[58] Sierra-Filardi E, . Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood, 2011, 117: 5092-5101.

[59] Chaudhuri AA, . MicroRNA-125b potentiates macrophage activation. J. Immunol., 2011, 187: 5062-5068.

[60] Squadrito ML, Etzrodt M, De Palma M, Pittet MJ. MicroRNA-mediated control of macrophages and its implications for cancer. Trends Immunol., 2013, 34: 350-359.

[61] Banerjee S, . MicroRNA let-7c regulates macrophage polarization. J. Immunol., 2013, 190: 6542-6549.

[62] Banerjee S, . miR-125a-5p regulates differential activation of macrophages and inflammation. J. Biol. Chem., 2013, 288: 35428-35436.

[63] Wang Z, . MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation. PLoS ONE, 2015, 10: e0115855.

[64] Fordham JB, Naqvi AR, Nares S. miR-24 regulates macrophage polarization and plasticity. J. Clin. Cell. Immunol., 2015, 06: 362.

[65] Venkatesan G, Uppoor A, Naik DG. Redefining the role of dendritic cells in periodontics. J. Indian Soc. Periodontol., 2013, 17: 700-705.

[66] Wilensky A, . Dendritic cells and their role in periodontal disease. Oral Dis., 2014, 20: 119-126.

[67] Dillon S, . A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-FoS in dendritic cells. J. Immunol., 2004, 172: 4733-4743.

[68] Carotta S, . The transcription factor PU.1 controls dendritic cell development and Flt3 cytokine receptor expression in a dose-dependent manner. Immunity, 2010, 32: 628-641.

[69] Evel-Kabler K, Song XT, Aldrich M, Huang XF, Chen SY. SOCS1 restricts dendritic cells’ ability to break self tolerance and induce antitumor immunity by regulating IL-12 production and signaling. J. Clin. Invest., 2005, 116: 90-100.

[70] Luo Y, . Tsc1 expression by dendritic cells is required to preserve T-cell homeostasis and response. Cell Death Dis., 2017, 8: e2553-e2553.

[71] Martinez-Nunez RT, Louafi F, Friedmann PS, Sanchez-Elsner T. MicroRNA-155 modulates the pathogen binding ability of dendritic cells (DCs) by down-regulation of DC-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN). J. Biol. Chem., 2009, 284: 16334-16342.

[72] Smyth LA, Boardman DA, Tung SL, Lechler R, Lombardi G. MicroRNAs affect dendritic cell function and phenotype. Immunology, 2015, 144: 197-205.

[73] Dunand-Sauthier I, . Silencing of c-Fos expression by microRNA-155 is critical for dendritic cell maturation and function. Blood, 2011, 117: 4490-4500.

[74] Huffaker TB, O’Connell R. M. miR-155-SOCS1 as a functional axis: satisfying the burden of proof. Immunity, 2015, 43: 3-4.

[75] Kim SJ, Gregersen PK, Diamond B. Regulation of dendritic cell activation by microRNA let-7c and BLIMP1. J. Clin. Invest., 2013, 123: 823-833.

[76] Mescher MF, . Signals required for programming effector and memory development by CD8 + T cells. Immunol. Rev., 2006, 211: 81-92.

[77] Lu C, . miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1. Blood, 2011, 117: 4293-4303.

[78] Zhang Y, . Cross-talk between programmed death-1 and suppressor of cytokine signaling-1 in inhibition of il-12 production by monocytes/macrophages in hepatitis C virus infection. J. Immunol., 2011, 186: 3093-3103.

[79] Agudo J, . The miR-126–VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nat. Immunol., 2014, 15: 54-62.

[80] Kubach J, . Dendritic cells: sentinels of immunity and tolerance. Int. J. Hematol., 2005, 81: 197-203.

[81] Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol., 2008, 8: 958-969.

[82] Naqvi AR, Fordham JB, Ganesh B, Nares S. miR-24, miR-30b and miR-142-3p interfere with antigen processing and presentation by primary macrophages and dendritic cells. Sci. Rep., 2016, 6

[83] Cooper MD, Alder MN. The evolution of adaptive immune systems. Cell, 2006, 124: 815-822.

[84] Buchmann K. Evolution of innate immunity: clues from invertebrates via fish to mammals. Front. Immunol., 2014, 5: 459.

[85] Taubman MA, Kawai T. Involvement of T-lymphocytes in periodontal disease and in direct and indirect induction of bone resorption. Crit. Rev. Oral Biol. Med., 2001, 12: 125-135.

[86] Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T cells: differentiation and functions. Clin. Dev. Immunol., 2012, 2012: 925135.

[87] Teteloshvili N, . T-cell activation induces dynamic changes in miRNA expression patterns in CD4 and CD8 T-cell subsets. MicroRNA, 2015, 4: 117-122.

[88] Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science, 2004, 303: 83-86.

[89] Li QJ, . miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell, 2007, 129: 147-161.

[90] Zimmerman EI, . Lyn kinase-dependent regulation of miR181 and myeloid cell leukemia-1 expression: implications for drug resistance in myelogenous leukemia. Mol. Pharmacol., 2010, 78: 811-817.

[91] Baumjohann D, Ansel KM. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat. Rev. Immunol., 2013, 13: 666-678.

[92] Fu G, . Fine-tuning T cell receptor signaling to control T cell development. Trends Immunol., 2014, 35: 311-318.

[93] Jindra PT, Bagley J, Godwin JG, Iacomini J. Costimulation-dependent expression of microRNA-214 increases the ability of T cells to proliferate by targeting Pten. J. Immunol., 2010, 185: 990-997.

[94] Liu SQ, Jiang S, Li C, Li QJ. miR-17-92 cluster targets phosphatase and tensin homology and ikaros family zinc finger 4 to promote TH17-mediated inflammation. J. Biol. Chem., 2014, 289: 12446-12456.

[95] Yang L, . miR-146a controls the resolution of T cell responses in mice. J. Exp. Med., 2012, 209: 1655-1670.

[96] Crane IJ, Forrester JV. Th1 and Th2 lymphocytes in autoimmune disease. Crit. Rev. Immunol., 2005, 25: 75-102.

[97] Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine, 2014, 74: 5-17.

[98] Gaffen SL, Hajishengallis G. A new inflammatory cytokine on the block: re-thinking periodontal disease and the Th1/Th2 paradigm in the context of Th17 cells and IL-17. J. Dent. Res., 2008, 87: 817-828.

[99] Arun KV, Talwar A, Kumar TSS. T-helper cells in the etiopathogenesis of periodontal disease: a mini review. J. Indian Soc. Periodontol., 2011, 15: 4-10.

[100] Garlet GP. Destructive and protective roles of cytokines in periodontitis: a re-appraisal from host defense and tissue destruction viewpoints. J. Dent. Res., 2010, 89: 1349-1363.

[101] Yücel OumlOuml, Berker E, Gariboğlu S, Otlu H. Interleukin-11, interleukin-1β, interleukin-12 and the pathogenesis of inflammatory periodontal diseases. J. Clin. Periodontol., 2008, 35: 365-370.

[102] Steiner DF, . MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity, 2011, 35: 169-181.

[103] Jiang S, . Molecular dissection of the miR-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood, 2011, 118: 5487-5497.

[104] Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL. Micro-RNA-155 inhibits IFN-γ signaling in CD4+ T cells. Eur. J. Immunol., 2010, 40: 225-231.

[105] Kumar M, . Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J. Allergy Clin. Immunol., 2011, 128: 1077-1085.e1010.

[106] Mattes J, Collison A, Plank M, Phipps S, Foster PS. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc. Natl. Acad. Sci. USA, 2009, 106: 18704-18709.

[107] Dezerega A, Maggiolo S, Garrido M, Dutzan N. The TH17 vs. TREG imbalance in the pathogenesis of periodontitis: new approach for dichotomy TH1 vs. TH2. Rev. Clín. Period. Implantol. Rehabil. Oral, 2008, 1: 70-72.

[108] Rouas R, . Human natural Treg microRNA signature: role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur. J. Immunol., 2009, 39: 1608-1618.

[109] Sethi A, Kulkarni N, Sonar S, Lal G. Role of miRNAs in CD4 T cell plasticity during inflammation and tolerance. Front. Genet., 2013, 4: 8.

[110] Lu LF, . Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity, 2009, 30: 80-91.

[111] Lu LF, . Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell, 2010, 142: 914-929.

[112] Fayyad-Kazan H, . MicroRNA profile of circulating CD4-positive regulatory T cells in human adults and impact of differentially expressed microRNAs on expression of two genes essential to their function. J. Biol. Chem., 2012, 287: 9910-9922.

[113] Zhang L, . MicroRNA-31 negatively regulates peripherally derived regulatory T-cell generation by repressing retinoic acid-inducible protein 3. Nat. Commun., 2015, 6

[114] Pan W, . MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis. Nat. Commun., 2015, 6

[115] Allam JP, . IL-23-producing CD68+ macrophage-like cells predominate within an IL-17-polarized infiltrate in chronic periodontitis lesions. J. Clin. Periodontol., 2011, 38: 879-886.

[116] Zhao L, . 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., 2011, 38: 509-516.

[117] Laurence A, O’Shea JJ. TH-17 differentiation: of mice and men. Nat. Immunol., 2007, 8: 903-905.

[118] Mycko MP, . microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc. Natl. Acad. Sci. USA, 2012, 109: E1248-E1257.

[119] Escobar TM, . miR-155 activates cytokine gene expression in Th17 cells by regulating the DNA-binding protein Jarid2 to relieve polycomb-mediated repression. Immunity, 2014, 40: 865-879.

[120] Seymour GJ, . Experimental gingivitis in humans. A histochemical and immunological characterization of the lymphoid cell subpopulations. J. Periodontal Res., 1983, 18: 375-385.

[121] Stoufi ED, Taubman MA, Ebersole JL, Smith DJ. Preparation and characterization of human gingival cells. J. Periodontal Res., 1987, 22: 144-149.

[122] Gururajan M, . MicroRNA 125b inhibition of B cell differentiation in germinal centers. Int. Immunol., 2010, 22: 583-592.

[123] Porstner M, . miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur. J. Immunol., 2015, 45: 1206-1215.

[124] Gonzalez-Martin A, . The microRNA miR-148a functions as a critical regulator of B cell tolerance and autoimmunity. Nat. Immunol., 2016, 17: 433-440.

[125] de Yebenes VG, . miR-217 is an oncogene that enhances the germinal center reaction. Blood, 2014, 124: 229-239.

[126] Teng G, . MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity, 2008, 28: 621-629.

[127] de Yébenes VG, . miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J. Exp. Med., 2008, 205: 2199-2206.

[128] Cafiero C, . Periodontal care as a fundamental step for an active and healthy ageing. Scientific World J., 2013, 2013: 127905.

[129] Giannobile WV. C-Telopeptide pyridinoline cross-links: sensitive indicators of periodontal tissue destruction. Ann. NY Acad. Sci., 1999, 878: 404-412.

[130] Kinney JS, . Crevicular fluid biomarkers and periodontal disease progression. J. Clin. Periodontol., 2013, 41: 113-120.

[131] Syndergaard B, . Salivary biomarkers associated with gingivitis and response to therapy. J. Periodontol., 2014, 85: e295-e303.

[132] Li Y, Kowdley KV. MicroRNAs in common human diseases. Genom. Proteom. Bioinform., 2012, 10: 246-253.

[133] Cheng L, Sharples RA, Scicluna BJ, Hill AF. Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J. Extracell. Vesicles, 2014, 3: 23743.

[134] Chen X, . Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res., 2008, 18: 997-1006.

[135] Mitchell PS, . Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl. Acad. Sci. USA, 2008, 105: 10513-10518.

[136] Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol., 2014, 14: 195-208.

[137] Fernández-Messina L, Gutiérrez-Vázquez C, Rivas-García E, Sánchez-Madrid F, de la Fuente H. Immunomodulatory role of microRNAs transferred by extracellular vesicles. Biol. Cell, 2015, 107: 61-77.

[138] de Candia P, De Rosa V, Casiraghi M, Matarese G. Extracellular RNAs: a secret arm of immune system regulation. J. Biol. Chem., 2016, 291: 7221-7228.

[139] Correia CN, . Circulating microRNAs as potential biomarkers of infectious disease. Front. Immunol., 2017, 8: 118.

[140] Schmalz G, . MicroRNAs as salivary markers for periodontal diseases: a new diagnostic approach?. Biomed. Res. Int., 2016, 2016: 1027525.

[141] Gupta G. Gingival crevicular fluid as a periodontal diagnostic indicator--I: host derived enzymes and tissue breakdown products. J. Med. Life, 2012, 5: 390-397.

[142] Gupta G. Gingival crevicular fluid as a periodontal diagnostic indicator—II: inflammatory mediators, host–response modifiers and chair side diagnostic aids. J. Med. Life, 2013, 6: 7-13.

[143] Saito A, . MicroRNA profiling in gingival crevicular fluid of periodontitis—a pilot study. FEBS Open Bio, 2017, 7: 981-994.

[144] Wong DTW. Salivaomics. J. Am. Dent. Assoc., 2012, 143: 19S-24S.

[145] Zhang Y, . The emerging landscape of salivary diagnostics. Periodontol. 2000., 2016, 70: 38-52.

[146] Byun JS, Hong SH, Choi JK, Jung JK, Lee HJ. Diagnostic profiling of salivary exosomal microRNAs in oral lichen planus patients. Oral Dis., 2015, 21: 987-993.

[147] Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov., 2017, 16: 203-222.

[148] Plaza JJP. Current roles of microRNAs in infectious diseases—advancing into healthcare. Croat. J. Infect., 2016, 36: 5-15.

[149] Wang Z. The guideline of the design and validation of MiRNA mimics. Methods Mol. Biol., 2011, 676: 211-223.

[150] Goldgraben MA, Russell R, Rueda OM, Caldas C, Git A. Double-stranded microRNA mimics can induce length- and passenger strand-dependent effects in a cell type-specific manner. RNA, 2015, 22: 193-203.

[151] Robertson B, . Specificity and functionality of microRNA inhibitors. Silence, 2010, 1

[152] Stenvang J, Petri A, Lindow M, Obad S, Kauppinen S. Inhibition of microRNA function by antimiR oligonucleotides. Silence, 2012, 3

[153] Staedel C, Darfeuille F. MicroRNAs and bacterial infection. Cell Microbiol., 2013, 15: 1496-1507.

[154] Siddle KJ, . Bacterial infection drives the expression dynamics of microRNAs and their isomiRs. PLoS Genet., 2015, 11: e1005064.

[155] Wan J, Xia L, Xu W, Lu N. Expression and function of miR-155 in diseases of the gastrointestinal tract. Int. J. Mol. Sci., 2016, 17: 709.

[156] Skapenko A, Leipe J, Lipsky PE, Schulze-Koops H. The role of the T cell in autoimmune inflammation. Arthritis Res. Ther., 2005, 7: S4-S14.

[157] Collison A, . Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm. Med., 2011, 11: 29.

[158] Sharma A, . Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model. J. Appl. Physiol., 2012, 113: 459-464.

[159] Du C, . MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol., 2009, 10: 1252-1259.

[160] Luck ME, Muljo SA, Collins CB. Prospects for therapeutic targeting of microRNAs in human immunological diseases. J. Immunol., 2015, 194: 5047-5052.

[161] Takahashi H, . TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat. Immunol., 2012, 13: 587-595.

[162] Wei J, . MiR-138 exerts anti-glioma efficacy by targeting immune checkpoints. Neuro Oncol., 2015, 18: 639-648.

[163] Cubillos-Ruiz JR, . Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res., 2012, 72: 1683-1693.