One challenge in studying chronic infectious and inflammatory disorders is understanding how host pattern recognition receptors (PRRs), specifically toll-like receptors (TLRs), sense and respond to pathogen- or damage-associated molecular patterns, their communication with each other and different components of the immune system, and their role in propagating inflammatory stages of disease. The discovery of innate immune activation through nucleic acid recognition by intracellular PRRs such as endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) and cytoplasmic proteins (absent in melanoma 2 and DNA-dependent activator of interferon regulatory factor) opened a new paradigm: Nucleic acid sensing is now implicated in multiple immune and inflammatory conditions (e.g., atherosclerosis, cancer), viral (e.g., human papillomavirus, herpes virus) and bacterial (e.g., Helicobacter pylori, pneumonia) diseases, and autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis). Clinical investigations reveal the overexpression of specific nucleic acid sensors in diseased tissues. In vivo animal models show enhanced disease progression associated with receptor activation. The involvement of nucleic acid sensors in various systemic conditions is further supported by studies reporting receptor knockout mice being either protected from or prone to disease. TLR9-mediated inflammation is also implicated in periodontal diseases. Considering that persistent inflammation in the oral cavity is associated with systemic diseases and that oral microbial DNA is isolated at distal sites, nucleic acid sensing may potentially be a link between oral and systemic diseases. In this review, we discuss recent advances in how intracellular PRRs respond to microbial nucleic acids and emerging views on the role of nucleic acid sensors in various systemic diseases. We also highlight new information on the role of intracellular PRRs in the pathogenesis of oral diseases including periodontitis and oral cavity cancer, which might offer future possibilities for disease prevention and therapy.
ArmingoharZJorgensenJJKristoffersenAKAbesha-BelayEOlsenI. 2014. Bacteria and bacterial DNA in atherosclerotic plaque and aneurysmal wall biopsies from patients with and without periodontitis. J Oral Microbiol. [epub ahead of print 2014May15]. doi:10.3402/jom.v6.23408.
BhanULukacsNWOsterholzerJJNewsteadMWZengXMooreTAMcMillanTRKriegAMAkiraSStandifordTJ. 2007. TLR9 is required for protective innate immunity in gram-negative bacterial pneumonia: role of dendritic cells. J Immunol. 179(6):3937–3946.
5.
BostanciNMeierAGuggenheimBBelibasakisGN. 2011. Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms. Cell Immunol. 270(1):88–93.
6.
BouladouxNHallJAGraingerJRdos SantosLMKannMGNagarajanVVerthelyiDBelkaidY. 2012. Regulatory role of suppressive motifs from commensal DNA. Mucosal Immunol. 5(6):623–634.
7.
ColeJENavinTJCrossAJGoddardMEAlexopoulouLMitraATDaviesAHFlavellRAFeldmannMMonacoC. 2011. Unexpected protective role for toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A. 108(6):2372–2377.
8.
ConnollyDJO’NeillLA. 2012. New developments in toll-like receptor targeted therapeutics. Curr Opin Pharmacol. 12(4):510–518.
9.
de KivitSTobinMCForsythCBKeshavarzianALandayAL. 2014. Regulation of intestinal immune responses through TLR activation: implications for pro- and prebiotics. Front Immunol. 5:60.
10.
El KebirDJozsefLPanWWangLLFilepJG. 2009. Bacterial DNA activates endothelial cells and promotes neutrophil adherence through TLR9 signaling. J Immunol. 182(7):4386–4394.
11.
ErridgeCBurdessAJacksonAJMurrayCRiggioMLappinDMilliganSSpickettCMWebbDJ. 2008. Vascular cell responsiveness to toll-like receptor ligands in carotid atheroma. Eur J Clin Invest. 38(10):713–720.
12.
FangRHaraHSakaiSHernandez-CuellarEMitsuyamaMKawamuraITsuchiyaK. 2014. Type I interferon signaling regulates activation of the absent in melanoma 2 inflammasome during Streptococcus pneumoniae infection. Infect Immun. 82(6):2310–2317.
13.
FardiniYChungPDummRJoshiNHanYW. 2010. Transmission of diverse oral bacteria to murine placenta: evidence for the oral microbiome as a potential source of intrauterine infection. Infect Immun. 78(4):1789–1796.
14.
FukuiAOhtaKNishiHShigeishiHTobiumeKTakechiMKamataN. 2013. Interleukin-8 and CXCL10 expression in oral keratinocytes and fibroblasts via toll-like receptors. Microbiol Immunol. 57(3):198–206.
15.
GonzálezOALiMTEbersoleJLHuangCB. 2010. HIV-1 reactivation induced by the periodontal pathogens Fusobacterium nucleatum and Porphyromonas gingivalis involves toll-like receptor 4 and 9 activation in monocytes/macrophages. Clin Vaccine Immunol. 17(9):1417–1427.
16.
GoulopoulouSMatsumotoTBomfimGFWebbRC. 2012. Toll-like receptor 9 activation: a novel mechanism linking placenta-derived mitochondrial DNA and vascular dysfunction in pre-eclampsia. Clin Sci (Lond). 123(7):429–435.
HakimiMPetersABeckerABocklerDDihlmannS. 2014. Inflammation-related induction of absent in melanoma 2 (AIM2) in vascular cells and atherosclerotic lesions suggests a role in vascular pathogenesis. J Vasc Surg. 59(3):794–803.
19.
HanXLaRosaKBKawaiTTaubmanMA. 2014. DNA-based adaptive immunity protect host from infection-associated periodontal bone resorption via recognition of Porphyromonas gingivalis virulence component. Vaccine. 32(2):297–303.
20.
HeZHuangXNiYShiPWangZHanWHuQ. 2014. Functional toll-like receptor 3 expressed by oral squamous cell carcinoma induced cell apoptosis and decreased migration. Oral Surg Oral Med Oral Pathol Oral Radiol. 118(1):92–100.
21.
HollaLIVokurkaJHrdlickovaBAugustinPFassmannA. 2010. Association of toll-like receptor 9 haplotypes with chronic periodontitis in Czech population. J Clin Periodontol. 37(2):152–159.
22.
KimPDXia-JuanXCrumpKEAbeTHajishengallisGSahingurSE. 2015. Toll-like receptor 9-mediated inflammation triggers alveolar bone loss in experimental murine periodontitis. Infect Immun. 83(7):2992–3002.
KnuefermannPSchwederskiMVeltenMKringsPEhrentrautHRüdigerMBoehmOFinkKDreinerUGrohéC. 2008. Bacterial DNA induces myocardial inflammation and reduces cardiomyocyte contractility: role of toll-like receptor 9. Cardiovasc Res. 78(1):26–35.
25.
KogaKCardenasIAldoPAbrahamsVMPengBFillSRomeroRMorG. 2009. Activation of TLR3 in the trophoblast is associated with preterm delivery. Am J Reprod Immunol. 61(3):196–212.
26.
KogaKIzumiGMorGFujiiTOsugaY. 2014. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications. Am J Reprod Immunol. 72(2):192–205.
27.
KotrashettiVSNayakRBhatKHosmaniJSomannavarP. 2013. Immunohistochemical expression of TLR4 and TLR9 in various grades of oral epithelial dysplasia and squamous cell carcinoma, and their roles in tumor progression: a pilot study. Biotech Histochem. 88(6):311–322.
28.
LamontRJHajishengallisG. 2015. Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med. 21(3):172–183.
29.
LankaraniKBSivandzadehGRHassanpourS. 2013. Oral manifestation in inflammatory bowel disease: a review. World J Gastroenterol. 19(46):8571–8579.
LindenGJLyonsAScannapiecoFA. 2013. Periodontal systemic associations: review of the evidence. J Clin Periodontol. 40(Suppl 14):S8–S19.
32.
LohnerRSchwederskiMNarathCKleinJDuerrGDTornoAKnuefermannPHoeftABaumgartenGMeyerR. 2013. Toll-like receptor 9 promotes cardiac inflammation and heart failure during polymicrobial sepsis. Mediators Inflamm. 2013:261049.
33.
LundbergAMKetelhuthDFJohanssonMEGerdesNLiuSYamamotoMAkiraSHanssonGK. 2013. Toll-like receptor 3 and 4 signalling through the TRIF and TRAM adaptors in haematopoietic cells promotes atherosclerosis. Cardiovasc Res. 99(2):364–373.
34.
MäkinenLKAtulaTHäyryVJouhiLDattaNLehtonenSAhmedAMäkitieAAHaglundCHagströmJ. 2015. Predictive role of toll-like receptors 2, 4, and 9 in oral tongue squamous cell carcinoma. Oral Oncol. 51(1):96–102.
MurrayLAKnightDAMcAlonanLArgentieriRJoshiAShaheenFCunninghamMAlexopolouLFlavellRASariskyRT. 2008. Deleterious role of TLR3 during hyperoxia-induced acute lung injury. Am J Respir Crit Care Med. 178(12):1227–1237.
37.
NgMTVan’t HofRCrockettJCHopeMEBerrySThomsonJMcLeanMHMcCollKEEl-OmarEMHoldGL. 2010. Increase in NF-kappaB binding affinity of the variant C allele of the toll-like receptor 9 -1237T/C polymorphism is associated with Helicobacter pylori-induced gastric disease. Infect Immun. 78(3):1345–1352.
38.
ObermeierFDungerNDemlLHerfarthHScholmerichJFalkW. 2002. CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. Eur J Immunol. 32(7):2084–2092.
39.
OkaTHikosoSYamaguchiOTaneikeMTakedaTTamaiTOyabuJMurakawaTNakayamaHNishidaK. 2012. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature. 485(7397):251–255.
40.
PandaBPandaAUedaIAbrahamsVMNorwitzERStanicAKYoungBCEckerJLAltfeldMShawAC. 2012. Dendritic cells in the circulation of women with preeclampsia demonstrate a pro-inflammatory bias secondary to dysregulation of TLR receptors. J Reprod Immunol. 94(2):210–215.
41.
PandeySKawaiTAkiraS. 2015. Microbial sensing by toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb Perspect Med. 5(1):a016246.
42.
ParkENaHSSongYRShinSYKimYMChungJ. 2014. Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect Immun. 82(1):112–123.
43.
ParkerDPrinceA. 2012. Staphylococcus aureus induces type I IFN signaling in dendritic cells via TLR9. J Immunol. 189(8):4040–4046.
44.
Rojo-BotelloNRGarcia-HernandezALMoreno-FierrosL. 2012. Expression of toll-like receptors 2, 4 and 9 is increased in gingival tissue from patients with type 2 diabetes and chronic periodontitis. J Periodontal Res. 47(1):62–73.
45.
RuanMThornKLiuSLiSYangWZhangCZhangC. 2014. The secretion of IL-6 by CpG-ODN-treated cancer cells promotes T-cell immune responses partly through the TLR-9/AP-1 pathway in oral squamous cell carcinoma. Int J Oncol. 44(6):2103–2110.
46.
RuanMZhangZLiSYanMLiuSYangWWangLZhangC. 2014. Activation of toll-like receptor-9 promotes cellular migration via up-regulating MMP-2 expression in oral squamous cell carcinoma. PLoS One. 9(3):e92748.
47.
SahingurSEXiaXJAlamgirSHonmaKSharmaASchenkeinHA. 2010. DNA from Porphyromonas gingivalis and Tannerella forsythia induce cytokine production in human monocytic cell lines. Mol Oral Microbiol. 25(2):123–135.
48.
SahingurSEXiaXJGunsolleyJSchenkeinHAGencoRJDe NardinE. 2011. Single nucleotide polymorphisms of pattern recognition receptors and chronic periodontitis. J Periodontal Res. 46(2):184–192.
49.
SahingurSEXiaXJSchifferleRE. 2012. Oral bacterial DNA differ in their ability to induce inflammatory responses in human monocytic cell lines. J Periodontol. 83(8):1069–1077.
SahingurSEYeudallWA. 2015. Chemokine function in periodontal disease and oral cavity cancer. Front Immunol. 6:214.
52.
SalagianniMGalaniIELundbergAMDavosCHVarelaAGavriilALyytikäinenLPLehtimäkiTSigalaFFolkersenL. 2012. Toll-like receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation. 126(8):952–962.
53.
Scharfe-NugentACorrSCCarpenterSBKeoghLDoyleBMartinCFitzgeraldKADalySO’LearyJJO’NeillLA. 2012. TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. J Immunol. 188(11):5706–5712.
54.
SlotsJ. 2005. Herpesviruses in periodontal diseases. Periodontol2000. 38:33–62.
55.
UeharaATakadaH. 2008. Synergism between TLRs and NOD1/2 in oral epithelial cells. J Dent Res. 87(7):682–686.
56.
WuJChenZJ. 2014. Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol. 32:461–488.
57.
XueFShuRXieY. 2015. The expression of NLRP3, NLRP1 and AIM2 in the gingival tissue of periodontitis patients: RT-PCR study and immunohistochemistry. Arch Oral Biol. 60(6):948–958.
58.
YamamotoSYamamotoTKataokaTKuramotoEYanoOTokunagaT. 1992. Unique palindromic sequences in synthetic oligonucleotides are required to induce INF and augment INF-mediated natural-killer activity. J Immunol. 148(12):4072–4076.
59.
ZhanYBZhangRMLvHCSongXJXuXMChaiLLvWHShangZWJiangYSZhangRJ. 2014. Prioritization of candidate genes for periodontitis using multiple computational tools. J Periodontol. 85(8):1059–1069.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
