NLRP3炎性小体在牙周疾病中的研究进展
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摘要
牙周病被认为是微生物感染与宿主免疫、炎症反应共同导致的结果。NLRP3炎性小体与牙周疾病的发生、发展存在关联已被证实,其在牙周疾病中出现活化与抑制两种状态也得到越来越多学者的重视。在牙周病进程中,NLRP3炎性小体活化与抑制状态的触发条件与切换过程尚未形成定论,对于NLRP3相关基因多态性与基因突变在牙周疾病中的研究也刚刚起步。本文主要对NLRP3炎性小体的活化假说、抑制机制及其在牙周疾病中的作用进行综述。
Periodontal disease is considered as the joint effort of microbial infection and immunoinflammatory responses.The association between NLRP3 inflammasome and periodontal disease has been confirmed in many experiments. The reverse states, activation and inhibition of NLRP3 inflammasome have received increasing attention. In the progress of periodontal disease, the explanations for the activation and inhibition of the NLRP3 inflammasome have not been unified with the triggering conditions and the switching process. Studies on NLRP3 inflammasome gene mutation or gene polymorphism in periodontal disease have just been initiated. This article briefly describes the NLRP3 inflammasome and highlights the currently accepted hypothesis of the activation of this oligomer and the finding regarding various inhibitory mechanisms.
Periodontal disease is considered as the joint effort of microbial infection and immunoinflammatory responses.The association between NLRP3 inflammasome and periodontal disease has been confirmed in many experiments. The reverse states, activation and inhibition of NLRP3 inflammasome have received increasing attention. In the progress of periodontal disease, the explanations for the activation and inhibition of the NLRP3 inflammasome have not been unified with the triggering conditions and the switching process. Studies on NLRP3 inflammasome gene mutation or gene polymorphism in periodontal disease have just been initiated. This article briefly describes the NLRP3 inflammasome and highlights the currently accepted hypothesis of the activation of this oligomer and the finding regarding various inhibitory mechanisms.
引文
[1]Wu YY,Xiao E,Graves DT.Diabetes mellitus related bone metabolism and periodontal disease[J].Int J Oral Sci,2015,7(2):63-72.
[2]Guo H,Callaway JB,Ting JP.Inflammasomes:mechanism of action,role in disease,and therapeutics[J].Nat Med,2015,21(7):677-687.
[3]Strowig T,Henao-Mejia J,Elinav E,et al.Inflammasomes in health and disease[J].Nature,2012,481(7381):278-286.
[4]de Zoete MR,Palm NW,Zhu S,et al.Inflammasomes[J].Cold Spring Harb Perspect Biol,2014,6(12):a016287.
[5]Bostanci N,Emingil G,Saygan B,et al.Expression and regulation of the NALP3 inflammasome complex in periodontal diseases[J].Clin Exp Immunol,2009,157(3):415-422.
[6]Chen G,Shaw MH,Kim YG,et al.NOD-like receptors:role in innate immunity and inflammatory disease[J].Annu Rev Pathol,2009,4:365-398.
[7]Schroder K,Tschopp J.The inflammasomes[J].Cell,2010,140(6):821-832.
[8]Ting JP,Lovering RC,Alnemri ES,et al.The NLRgene family:a standard nomenclature[J].Immunity,2008,28(3):285-287.
[9]吴冷,王骏,赵蕾,等.核苷酸结合寡聚化结构域样受体热蛋白结构域亚家族成员3炎性小体的活化调节与牙周疾病的关系[J].国际口腔医学杂志,2015,42(6):710-714.Wu L,Wang J,Zhao L,et al.Nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 inflammasomes and the relationship between it and periodontal diseases[J].Int J Stomatol,2015,42(6):710-714.
[10]Xue F,Shu R,Xie Y.The expression of NLRP3,NLRP1 and AIM2 in the gingival tissue of periodontitis patients:RT-PCR study and immunohistochemistry[J].Arch Oral Biol,2015,60(6):948-958.
[11]Isaza-Guzmán DM,Medina-Piedrahíta VM,Gutiérrez-Henao C,et al.Salivary levels of NLRP3 inflammasome-related proteins as potential biomarkers of periodontal clinical status[J].J Periodontol,2017,88(12):1329-1338.
[12]Olsen I,Yilmaz?.Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases[J].J Oral Microbiol,2016,8:30385.
[13]Abderrazak A,Syrovets T,Couchie D,et al.NLRP3inflammasome:from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases[J].Redox Biol,2015,4:296-307.
[14]Taxman DJ,Swanson KV,Broglie PM,et al.Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis[J].J Biol Chem,2012,287(39):32791-32799.
[15]Shimada K,Crother TR,Karlin J,et al.Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis[J].Immunity,2012,36(3):401-414.
[16]Almeida-da-Silva CLC,Morandini AC,Ulrich H,et al.Purinergic signaling during Porphyromonas gingivalis infection[J].Biomed J,2016,39(4):251-260.
[17]Ramos-Junior ES,Morandini AC,Almeida-da-Silva CL,et al.A dual role for P2X7 receptor during Porphyromonas gingivalis infection[J].J Dent Res,2015,94(9):1233-1242.
[18]Park E,Na HS,Song YR,et al.Activation of NLRP3and AIM2 inflammasomes by Porphyromonas gingivalis infection[J].Infect Immun,2014,82(1):112-123.
[19]Hung SC,Choi CH,Said-Sadier N,et al.P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation[J].PLoS One,2013,8(7):e70210.
[20]Morandini AC,Ramos-Junior ES,Potempa J,et al.Porphyromonas gingivalis fimbriae dampen P2X7-dependent interleukin-1βsecretion[J].J Innate Immun,2014,6(6):831-845.
[21]Guo ZL,Yu B,Ning BT,et al.Genetically modified“obligate”anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma[J].J Hematol Oncol,2015,8:99.
[22]Choi CH,Spooner R,DeGuzman J,et al.Porphyromonas gingivalis-nucleoside-diphosphate-kinase inhibits ATP-induced reactive-oxygen-species via P2X7receptor/NADPH-oxidase signalling and contributes to persistence[J].Cell Microbiol,2013,15(6):961-976.
[23]Johnson L,Atanasova KR,Bui PQ,et al.Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase[J].Microbes Infect,2015,17(5):369-377.
[24]Montenegro Raudales JL,Yoshimura A,Sm Z,et al.Dental calculus stimulates interleukin-1βsecretion by activating NLRP3 inflammasome in human and mouse phagocytes[J].PLoS One,2016,11(9):e0162865.
[25]Huang X,Yu T,Ma C,et al.Macrophages play a key role in the obesity-induced periodontal innate immune dysfunction via nucleotide-binding oligomerization domain-like receptor protein 3 pathway[J].J Periodontol,2016,87(10):1195-1205.
[26]Yilmaz O,Sater AA,Yao L,et al.ATP-dependent activation of an inflammasome in primary gingival epithelial cells infected by Porphyromonas gingivalis[J].Cell Microbiol,2010,12(2):188-198.
[27]Guo W,Wang P,Liu Z,et al.The activation of pyrin domain-containing-3 inflammasome depends on lipopolysaccharide from Porphyromonas gingivalis and extracellular adenosine triphosphate in cultured oral epithelial cells[J].BMC Oral Health,2015,15(1):133.
[28]Huck O,Elkaim R,Davideau JL,et al.Porphyromonas gingivalis-impaired innate immune response via NLRP3proteolysis in endothelial cells[J].Innate Immun,2015,21(1):65-72.
[29]Belibasakis GN,Guggenheim B,Bostanci N.Downregulation of NLRP3 inflammasome in gingival fibroblasts by subgingival biofilms:involvement of Porphyromonas gingivalis[J].Innate Immun,2013,19(1):3-9.
[30]Bostanci N,Meier A,Guggenheim B,et al.Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms[J].Cell Immunol,2011,270(1):88-93.
[31]Yamaguchi Y,Kurita-Ochiai T,Kobayashi R,et al.Activation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated atherosclerosis[J].Pathog Dis,2015,73(4).doi:10.1093/femspd/ftv011.
[32]Belibasakis GN,Johansson A.Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6inflammasome expression in human mononuclear leukocytes[J].Cytokine,2012,59(1):124-130.
[33]Hajishengallis G.Periodontitis:from microbial immune subversion to systemic inflammation[J].Nat Rev Immunol,2015,15(1):30-44.
[34]Laine ML,Crielaard W,Loos BG.Genetic susceptibility to periodontitis[J].Periodontol 2000,2012,58(1):37-68.
[35]Schoultz I,Verma D,Halfvarsson J,et al.Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men[J].Am JGastroenterol,2009,104(5):1180-1188.
[36]Isaza-Guzmán DM,Hernández-Viana M,BonillaLeón DM,et al.Determination of NLRP3(rs461-2666)and IL-1B(rs1143634)genetic polymorphisms in periodontally diseased and healthy subjects[J].Arch Oral Biol,2016,65:44-51.
[37]Bullón P,Castejón-Vega B,Román-Malo L,et al.Autophagic dysfunction in patients with PapillonLefèvre syndrome is restored by recombinant cathepsin C treatment[J].J Allergy Clin Immunol,2018,142(4):1131.e7-1143.e7.
[38]Miskiewicz A,Szparecki G,Durlik M,et al.The Q705K and F359L single-nucleotide polymorphisms of NOD-like receptor signaling pathway:association with chronic pancreatitis,pancreatic cancer,and periodontitis[J].Arch Immunol Ther Exp(Warsz),2015,63(6):485-494.
[2]Guo H,Callaway JB,Ting JP.Inflammasomes:mechanism of action,role in disease,and therapeutics[J].Nat Med,2015,21(7):677-687.
[3]Strowig T,Henao-Mejia J,Elinav E,et al.Inflammasomes in health and disease[J].Nature,2012,481(7381):278-286.
[4]de Zoete MR,Palm NW,Zhu S,et al.Inflammasomes[J].Cold Spring Harb Perspect Biol,2014,6(12):a016287.
[5]Bostanci N,Emingil G,Saygan B,et al.Expression and regulation of the NALP3 inflammasome complex in periodontal diseases[J].Clin Exp Immunol,2009,157(3):415-422.
[6]Chen G,Shaw MH,Kim YG,et al.NOD-like receptors:role in innate immunity and inflammatory disease[J].Annu Rev Pathol,2009,4:365-398.
[7]Schroder K,Tschopp J.The inflammasomes[J].Cell,2010,140(6):821-832.
[8]Ting JP,Lovering RC,Alnemri ES,et al.The NLRgene family:a standard nomenclature[J].Immunity,2008,28(3):285-287.
[9]吴冷,王骏,赵蕾,等.核苷酸结合寡聚化结构域样受体热蛋白结构域亚家族成员3炎性小体的活化调节与牙周疾病的关系[J].国际口腔医学杂志,2015,42(6):710-714.Wu L,Wang J,Zhao L,et al.Nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 inflammasomes and the relationship between it and periodontal diseases[J].Int J Stomatol,2015,42(6):710-714.
[10]Xue F,Shu R,Xie Y.The expression of NLRP3,NLRP1 and AIM2 in the gingival tissue of periodontitis patients:RT-PCR study and immunohistochemistry[J].Arch Oral Biol,2015,60(6):948-958.
[11]Isaza-Guzmán DM,Medina-Piedrahíta VM,Gutiérrez-Henao C,et al.Salivary levels of NLRP3 inflammasome-related proteins as potential biomarkers of periodontal clinical status[J].J Periodontol,2017,88(12):1329-1338.
[12]Olsen I,Yilmaz?.Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases[J].J Oral Microbiol,2016,8:30385.
[13]Abderrazak A,Syrovets T,Couchie D,et al.NLRP3inflammasome:from a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases[J].Redox Biol,2015,4:296-307.
[14]Taxman DJ,Swanson KV,Broglie PM,et al.Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis[J].J Biol Chem,2012,287(39):32791-32799.
[15]Shimada K,Crother TR,Karlin J,et al.Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis[J].Immunity,2012,36(3):401-414.
[16]Almeida-da-Silva CLC,Morandini AC,Ulrich H,et al.Purinergic signaling during Porphyromonas gingivalis infection[J].Biomed J,2016,39(4):251-260.
[17]Ramos-Junior ES,Morandini AC,Almeida-da-Silva CL,et al.A dual role for P2X7 receptor during Porphyromonas gingivalis infection[J].J Dent Res,2015,94(9):1233-1242.
[18]Park E,Na HS,Song YR,et al.Activation of NLRP3and AIM2 inflammasomes by Porphyromonas gingivalis infection[J].Infect Immun,2014,82(1):112-123.
[19]Hung SC,Choi CH,Said-Sadier N,et al.P2X4 assembles with P2X7 and pannexin-1 in gingival epithelial cells and modulates ATP-induced reactive oxygen species production and inflammasome activation[J].PLoS One,2013,8(7):e70210.
[20]Morandini AC,Ramos-Junior ES,Potempa J,et al.Porphyromonas gingivalis fimbriae dampen P2X7-dependent interleukin-1βsecretion[J].J Innate Immun,2014,6(6):831-845.
[21]Guo ZL,Yu B,Ning BT,et al.Genetically modified“obligate”anaerobic Salmonella typhimurium as a therapeutic strategy for neuroblastoma[J].J Hematol Oncol,2015,8:99.
[22]Choi CH,Spooner R,DeGuzman J,et al.Porphyromonas gingivalis-nucleoside-diphosphate-kinase inhibits ATP-induced reactive-oxygen-species via P2X7receptor/NADPH-oxidase signalling and contributes to persistence[J].Cell Microbiol,2013,15(6):961-976.
[23]Johnson L,Atanasova KR,Bui PQ,et al.Porphyromonas gingivalis attenuates ATP-mediated inflammasome activation and HMGB1 release through expression of a nucleoside-diphosphate kinase[J].Microbes Infect,2015,17(5):369-377.
[24]Montenegro Raudales JL,Yoshimura A,Sm Z,et al.Dental calculus stimulates interleukin-1βsecretion by activating NLRP3 inflammasome in human and mouse phagocytes[J].PLoS One,2016,11(9):e0162865.
[25]Huang X,Yu T,Ma C,et al.Macrophages play a key role in the obesity-induced periodontal innate immune dysfunction via nucleotide-binding oligomerization domain-like receptor protein 3 pathway[J].J Periodontol,2016,87(10):1195-1205.
[26]Yilmaz O,Sater AA,Yao L,et al.ATP-dependent activation of an inflammasome in primary gingival epithelial cells infected by Porphyromonas gingivalis[J].Cell Microbiol,2010,12(2):188-198.
[27]Guo W,Wang P,Liu Z,et al.The activation of pyrin domain-containing-3 inflammasome depends on lipopolysaccharide from Porphyromonas gingivalis and extracellular adenosine triphosphate in cultured oral epithelial cells[J].BMC Oral Health,2015,15(1):133.
[28]Huck O,Elkaim R,Davideau JL,et al.Porphyromonas gingivalis-impaired innate immune response via NLRP3proteolysis in endothelial cells[J].Innate Immun,2015,21(1):65-72.
[29]Belibasakis GN,Guggenheim B,Bostanci N.Downregulation of NLRP3 inflammasome in gingival fibroblasts by subgingival biofilms:involvement of Porphyromonas gingivalis[J].Innate Immun,2013,19(1):3-9.
[30]Bostanci N,Meier A,Guggenheim B,et al.Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms[J].Cell Immunol,2011,270(1):88-93.
[31]Yamaguchi Y,Kurita-Ochiai T,Kobayashi R,et al.Activation of the NLRP3 inflammasome in Porphyromonas gingivalis-accelerated atherosclerosis[J].Pathog Dis,2015,73(4).doi:10.1093/femspd/ftv011.
[32]Belibasakis GN,Johansson A.Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6inflammasome expression in human mononuclear leukocytes[J].Cytokine,2012,59(1):124-130.
[33]Hajishengallis G.Periodontitis:from microbial immune subversion to systemic inflammation[J].Nat Rev Immunol,2015,15(1):30-44.
[34]Laine ML,Crielaard W,Loos BG.Genetic susceptibility to periodontitis[J].Periodontol 2000,2012,58(1):37-68.
[35]Schoultz I,Verma D,Halfvarsson J,et al.Combined polymorphisms in genes encoding the inflammasome components NALP3 and CARD8 confer susceptibility to Crohn’s disease in Swedish men[J].Am JGastroenterol,2009,104(5):1180-1188.
[36]Isaza-Guzmán DM,Hernández-Viana M,BonillaLeón DM,et al.Determination of NLRP3(rs461-2666)and IL-1B(rs1143634)genetic polymorphisms in periodontally diseased and healthy subjects[J].Arch Oral Biol,2016,65:44-51.
[37]Bullón P,Castejón-Vega B,Román-Malo L,et al.Autophagic dysfunction in patients with PapillonLefèvre syndrome is restored by recombinant cathepsin C treatment[J].J Allergy Clin Immunol,2018,142(4):1131.e7-1143.e7.
[38]Miskiewicz A,Szparecki G,Durlik M,et al.The Q705K and F359L single-nucleotide polymorphisms of NOD-like receptor signaling pathway:association with chronic pancreatitis,pancreatic cancer,and periodontitis[J].Arch Immunol Ther Exp(Warsz),2015,63(6):485-494.