Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

Abstract

Interleukin(IL)-1β, a pro-inflammatory cytokine, was elevated and participates in periodontitis. Not only the link between IL-1β and periodontitis was proved by clinical evidence, but also the increased IL-1β triggers a series of inflammatory reactions and promotes bone resorption. Currently, IL-1β blockage has been therapeutic strategies for autoimmune and autoinflammatory diseases such as rheumatoid arthritis, cryopyrin-associated periodic syndromes, gout and type II diabetes mellitus. It is speculated that IL-1β be a potential therapeutic target for periodontitis. The review focuses on the production, mechanism, present treatments and future potential strategies for IL-1β in periodontitis.

References

[1] Cheng R, Hu T, Bhowmick NA. Be resistant to apoptosis: a host factor from gingival fibroblasts. Cell Death Dis., 2015, 6

[2] 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.

[3] Cardoso EM, Reis C, Manzanares-Cespedes MC. Chronic periodontitis, inflammatory cytokines, and interrelationship with other chronic diseases. Postgrad. Med., 2018, 130: 98-104.

[4] Stashenko P, Dewhirst FE, Peros WJ, Kent RL, Ago JM. Synergistic interactions between interleukin 1, tumor necrosis factor, and lymphotoxin in bone resorption. J. Immunol., 1987, 138: 1464-1468.

[5] Rangbulla V, Nirola A, Gupta M, Batra P, Gupta M. Salivary IgA, interleukin-1beta and MMP-8 as salivary biomarkers in chronic periodontitis patients. Chin. J. Dent. Res., 2017, 20: 43-51.

[6] Kinney JS, . Crevicular fluid biomarkers and periodontal disease progression. J. Clin. Periodontol., 2014, 41: 113-120.

[7] Offenbacher S, . Periodontal disease at the biofilm-gingival interface. J. Periodontol., 2007, 78: 1911-1925.

[8] Sanchez GA, Miozza VA, Delgado A, Busch L. Salivary IL-1beta and PGE2 as biomarkers of periodontal status, before and after periodontal treatment. J. Clin. Periodontol., 2013, 40: 1112-1117.

[9] Engebretson SP, Grbic JT, Singer R, Lamster IB. GCF IL-1beta profiles in periodontal disease. J. Clin. Periodontol., 2002, 29: 48-53.

[10] Kusuhara M, Isoda K, Ohsuzu F. Interleukin-1 and occlusive arterial diseases. Cardiovasc. Hematol. Agents Med. Chem., 2006, 4: 229-235.

[11] Zhu H, Lin X, Zheng P, Chen H. Inflammatory cytokine levels in patients with periodontitis and/or coronary heart disease. Int. J. Clin. Exp. Med., 2015, 8: 2214-2220.

[12] Bostanci N, . Expression and regulation of the NALP3 inflammasome complex in periodontal diseases. Clin. Exp. Immunol., 2009, 157: 415-422.

[13] Isaza-Guzman DM, Medina-Piedrahita VM, Gutierrez-Henao C, Tobon-Arroyave SI. Salivary levels of NLRP3 inflammasome-related proteins as potential biomarkers of periodontal clinical status. J. Periodontol., 2017, 88: 1329-1338.

[14] McDevitt MJ, . Interleukin-1 genetic association with periodontitis in clinical practice. J. Periodontol., 2000, 71: 156-163.

[15] Nikolopoulos GK, Dimou NL, Hamodrakas SJ, Bagos PG. Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J. Clin. Periodontol., 2008, 35: 754-767.

[16] Deng JS, Qin P, Li XX, Du YH. Association between interleukin-1beta C (3953/4)T polymorphism and chronic periodontitis: evidence from a meta-analysis. Hum. Immunol., 2013, 74: 371-378.

[17] Ayazi G, Pirayesh M, Yari K. Analysis of interleukin-1beta gene polymorphism and its association with generalized aggressive periodontitis disease. DNA Cell Biol., 2013, 32: 409-413.

[18] Amirisetty R, . Interleukin 1beta (+3954, −511 and −31) polymorphism in chronic periodontitis patients from North India. Acta Odontol. Scand., 2015, 73: 343-347.

[19] Ribeiro MS, Pacheco RB, Fischer RG, Macedo JM. Interaction of IL1B and IL1RN polymorphisms, smoking habit, gender, and ethnicity with aggressive and chronic periodontitis susceptibility. Contemp. Clin. Dent., 2016, 7: 349-356.

[20] Kornman KS, . The interleukin-1 genotype as a severity factor in adult periodontal disease. J. Clin. Periodontol., 1997, 24: 72-77.

[21] Isaza-Guzman DM, Hernandez-Viana M, Bonilla-Leon DM, Hurtado-Cadavid MC, Tobon-Arroyave SI. Determination of NLRP3 (rs4612666) and IL-1B (rs1143634) genetic polymorphisms in periodontally diseased and healthy subjects. Arch. Oral Biol., 2016, 65: 44-51.

[22] Chen YJ, . Interleukin-1beta rs1143634 polymorphism and aggressive periodontitis susceptibility: a meta-analysis. Int. J. Clin. Exp. Med., 2015, 8: 2308-2316.

[23] Yin, W. T., Pan, Y. P. & Lin, L. Association between IL-1alpha rs17561 and IL-1beta rs1143634 polymorphisms and periodontitis: a meta-analysis. Genet. Mol. Res. https://doi.org/10.4238/gmr.15017325 (2016).

[24] da Silva FRP, . Association between the rs1143634 polymorphism in interleukin-1B and chronic periodontitis: results from a meta-analysis composed by 54 case/control studies. Gene, 2018, 668: 97-106.

[25] Lavu V, . Clinical relevance of cytokines gene polymorphisms and protein levels in gingival cervical fluid from chronic periodontitis patients. Iran. J. Immunol., 2017, 14: 51-58.

[26] Wang HF, . Association between the interleukin-1beta C-511T polymorphism and periodontitis: a meta-analysis in the Chinese population. Genet. Mol. Res., 2017, 16: gmr16019315.

[27] Zeng XT, . Meta-analysis of association between interleukin-1beta C-511T polymorphism and chronic periodontitis susceptibility. J. Periodontol., 2015, 86: 812-819.

[28] Huang W, He BY, Shao J, Jia XW, Yuan YD. Interleukin-1beta rs1143627 polymorphism with susceptibility to periodontal disease. Oncotarget, 2017, 8: 31406-31414.

[29] Liu YC, Lerner UH, Teng YT. Cytokine responses against periodontal infection: protective and destructive roles. Periodontol 2000, 2010, 52: 163-206.

[30] Bent R, Moll L, Grabbe S, Bros M. Interleukin-1 beta-A friend or foe in malignancies?. Int. J. Mol. Sci., 2018, 19: E2155.

[31] Kwak A, Lee Y, Kim H, Kim S. Intracellular interleukin (IL)-1 family cytokine processing enzyme. Arch. Pharm. Res., 2016, 39: 1556-1564.

[32] He Y, Hara H, Nunez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci., 2016, 41: 1012-1021.

[33] Lamkanfi M, Dixit VM. Mechanisms and functions of inflammasomes. Cell, 2014, 157: 1013-1022.

[34] Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting to microbes through the inflammasomes. Nat. Immunol., 2012, 13: 325-332.

[35] Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature, 2012, 481: 278-286.

[36] Hajishengallis G, . Differential interactions of fimbriae and lipopolysaccharide from Porphyromonas gingivalis with the toll-like receptor 2-centred pattern recognition apparatus. Cell. Microbiol., 2006, 8: 1557-1570.

[37] Park E, . Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect. Immun., 2014, 82: 112-123.

[38] Ramos-Junior ES, . A dual role for P2X7 receptor during Porphyromonas gingivalis infection. J. Dent. Res., 2015, 94: 1233-1242.

[39] Yilmaz O, . ATP-dependent activation of an inflammasome in primary gingival epithelial cells infected by Porphyromonas gingivalis. Cell. Microbiol., 2010, 12: 188-198.

[40] Pelegrin P, Barroso-Gutierrez C, Surprenant A. P2X7 receptor differentially couples to distinct release pathways for IL-1beta in mouse macrophage. J. Immunol., 2008, 180: 7147-7157.

[41] Netea MG, . Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood, 2009, 113: 2324-2335.

[42] Bostanci N, Meier A, Guggenheim B, Belibasakis GN. Regulation of NLRP3 and AIM2 inflammasome gene expression levels in gingival fibroblasts by oral biofilms. Cell. Immunol., 2011, 270: 88-93.

[43] Belibasakis GN, Guggenheim B, Bostanci N. Downregulation of NLRP3 inflammasome in gingival fibroblasts by subgingival biofilms: involvement of Porphyromonas gingivalis. Innate Immun., 2013, 19: 3-9.

[44] Cheng R, . Porphyromonas gingivalis-derived lipopolysaccharide combines hypoxia to induce caspase-1 activation in periodontitis. Front. Cell. Infect. Microbiol., 2017, 7: 474.

[45] Belibasakis GN, Johansson A. Aggregatibacter actinomycetemcomitans targets NLRP3 and NLRP6 inflammasome expression in human mononuclear leukocytes. Cytokine, 2012, 59: 124-130.

[46] Kelk P, Claesson R, Chen C, Sjostedt A, Johansson A. IL-1beta secretion induced by Aggregatibacter (Actinobacillus) actinomycetemcomitans is mainly caused by the leukotoxin. Int. J. Clin. Exp. Med., 2008, 298: 529-541.

[47] Kelk P, Johansson A, Claesson R, Hanstrom L, Kalfas S. Caspase 1 involvement in human monocyte lysis induced by Actinobacillus actinomycetemcomitans leukotoxin. Infect. Immun., 2003, 71: 4448-4455.

[48] Kelk P, . Abundant secretion of bioactive interleukin-1beta by human macrophages induced by Actinobacillus actinomycetemcomitans leukotoxin. Infect. Immun., 2005, 73: 453-458.

[49] Zhao P, Liu J, Pan C, Pan Y. NLRP3 inflammasome is required for apoptosis of Aggregatibacter actinomycetemcomitans-infected human osteoblastic MG63 cells. Acta Histochem., 2014, 116: 1119-1124.

[50] Kim S, Park MH, Song YR, Na HS, Chung J. Aggregatibacter actinomycetemcomitans-induced AIM2 inflammasome activation is suppressed by xylitol in differentiated THP-1 macrophages. J. Periodontol., 2016, 87: e116-e126.

[51] Okinaga T, Ariyoshi W, Nishihara T. Aggregatibacter actinomycetemcomitans invasion induces interleukin-1beta production through reactive oxygen species and cathepsin B. J. Interferon Cytokine Res., 2015, 35: 431-440.

[52] Faizuddin M, Bharathi SH, Rohini NV. Estimation of interleukin-1beta levels in the gingival crevicular fluid in health and in inflammatory periodontal disease. J. Periodontal Res., 2003, 38: 111-114.

[53] Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat. Rev. Immunol., 2016, 12: 14-24.

[54] Kobayashi M, . Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum., 2005, 52: 128-135.

[55] Makela M, Salo T, Uitto VJ, Larjava H. Matrix metalloproteinases (MMP-2 and MMP-9) of the oral cavity: cellular origin and relationship to periodontal status. J. Dent. Res., 1994, 73: 1397-1406.

[56] Salo T, Makela M, Kylmaniemi M, Autio-Harmainen H, Larjava H. Expression of matrix metalloproteinase-2 and -9 during early human wound healing. Lab. Invest., 1994, 70: 176-182.

[57] Rai B, Kaur J, Jain R, Anand SC. Levels of gingival crevicular metalloproteinases-8 and -9 in periodontitis. Saudi Dent. J., 2010, 22: 129-131.

[58] Rai B, Kharb S, Jain R, Anand SC. Biomarkers of periodontitis in oral fluids. J. Oral Sci., 2008, 50: 53-56.

[59] Kusano K, . Regulation of matrix metalloproteinases (MMP-2, -3, -9, and -13) by interleukin-1 and interleukin-6 in mouse calvaria: association of MMP induction with bone resorption. Endocrinology, 1998, 139: 1338-1345.

[60] Du M, . Effects of IL-1beta on MMP-9 expression in cementoblast-derived cell line and MMP-mediated degradation of type I collagen. Inflammation, 2019, 42: 413-425.

[61] Murayama R, Kobayashi M, Takeshita A, Yasui T, Yamamoto M. MAPKs, activator protein-1 and nuclear factor-kappaB mediate production of interleukin-1beta-stimulated cytokines, prostaglandin E(2) and MMP-1 in human periodontal ligament cells. J. Periodontal Res., 2011, 46: 568-575.

[62] Nakaya H, Oates TW, Hoang AM, Kamoi K, Cochran DL. Effects of interleukin-1 beta on matrix metalloproteinase-3 levels in human periodontal ligament cells. J. Periodontol., 1997, 68: 517-523.

[63] Kida Y, . Interleukin-1 stimulates cytokines, prostaglandin E2 and matrix metalloproteinase-1 production via activation of MAPK/AP-1 and NF-kappaB in human gingival fibroblasts. Cytokine, 2005, 29: 159-168.

[64] Belibasakis GN, Bostanci N. The RANKL-OPG system in clinical periodontology. J. Clin. Periodontol., 2012, 39: 239-248.

[65] Huynh NC, Everts V, Pavasant P, Ampornaramveth RS. Interleukin-1beta induces human cementoblasts to support osteoclastogenesis. Int. J. Oral Sci., 2017, 9

[66] Nakamura I, Jimi E. Regulation of osteoclast differentiation and function by interleukin-1. Vitam. Horm., 2006, 74: 357-370.

[67] Bloemen V, Schoenmaker T, de Vries TJ, Everts V. IL-1beta favors osteoclastogenesis via supporting human periodontal ligament fibroblasts. J. Cell. Biochem., 2011, 112: 1890-1897.

[68] Diercke K, Kohl A, Lux CJ, Erber R. IL-1beta and compressive forces lead to a significant induction of RANKL-expression in primary human cementoblasts. J. Orofac. Orthop., 2012, 73: 397-412.

[69] Yang CY, . RANKL deletion in periodontal ligament and bone lining cells blocks orthodontic tooth movement. Int. J. Oral Sci., 2018, 10: 3.

[70] Ruscitti P, . The role of IL-1beta in the bone loss during rheumatic diseases. Mediat. Inflamm., 2015, 2015: 782382.

[71] Belibasakis GN, . Gene expression of transcription factor NFATc1 in periodontal diseases. APMIS, 2011, 119: 167-172.

[72] Birkedal-Hansen H. Role of cytokines and inflammatory mediators in tissue destruction. J. Periodontal Res., 1993, 28: 500-510.

[73] Corrado A, Neve A, Maruotti N, Cantatore FP. Bone effects of biologic drugs in rheumatoid arthritis. Clin. Dev. Immunol., 2013, 2013: 945945.

[74] Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG system in immunity, bone, and beyond. Front. Immunol., 2014, 5: 511.

[75] Sakata M, . Osteoprotegerin levels increased by interleukin-1beta in human periodontal ligament cells are suppressed through prostaglandin E(2) synthesized de novo. Cytokine, 2002, 18: 133-139.

[76] Wada N, Maeda H, Yoshimine Y, Akamine A. Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-alpha. Bone, 2004, 35: 629-635.

[77] Takegami N, . RANK/RANKL/OPG system in the intervertebral disc. Arthritis Res. Ther., 2017, 19: 121.

[78] Suda T, . Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev., 1999, 20: 345-357.

[79] Matsuura T, . Involvement of CX3CL1 in the migration of osteoclast precursors across osteoblast layer stimulated by interleukin-1ss. J. Cell. Physiol., 2017, 232: 1739-1745.

[80] Cheng R, . The extent of pyroptosis varies in different stages of apical periodontitis. Biochim. Biophys. Acta, 2018, 1864: 226-237.

[81] Nakashyan V, Tipton DA, Karydis A, Livada R, Stein SH. Effect of 1,25(OH)2 D3 and 20(OH)D3 on interleukin-1beta-stimulated interleukin-6 and -8 production by human gingival fibroblasts. J. Periodontal Res., 2017, 52: 832-841.

[82] Bhawal UK, . Micromolar sodium fluoride mediates anti-osteoclastogenesis in Porphyromonas gingivalis-induced alveolar bone loss. Int. J. Oral Sci., 2015, 7: 242-249.

[83] Hienz SA, Paliwal S, Ivanovski S. Mechanisms of bone resorption in periodontitis. J. Immunol. Res., 2015, 2015: 615486.

[84] Slots J. Periodontitis: facts, fallacies and the future. Periodontol 2000, 2017, 75: 7-23.

[85] Fleischer HC, Mellonig JT, Brayer WK, Gray JL, Barnett JD. Scaling and root planing efficacy in multirooted teeth. J. Periodontol., 1989, 60: 402-409.

[86] Brayer WK, Mellonig JT, Dunlap RM, Marinak KW, Carson RE. Scaling and root planing effectiveness: the effect of root surface access and operator experience. J. Periodontol., 1989, 60: 67-72.

[87] Al-Shammari KF, . Effect of non-surgical periodontal therapy on C-telopeptide pyridinoline cross-links (ICTP) and interleukin-1 levels. J. Periodontol., 2001, 72: 1045-1051.

[88] Aljateeli M, . Surgical periodontal therapy with and without initial scaling and root planing in the management of chronic periodontitis: a randomized clinical trial. J. Clin. Periodontol., 2014, 41: 693-700.

[89] Saglam M, . Combined application of Er:YAG and Nd:YAG lasers in treatment of chronic periodontitis. A split-mouth, single-blind, randomized controlled trial. J. Periodontal Res., 2017, 52: 853-862.

[90] Tsang YC, Corbet EF, Jin LJ. Subgingival glycine powder air-polishing as an additional approach to nonsurgical periodontal therapy in subjects with untreated chronic periodontitis. J. Periodontal Res., 2018, 53: 440-445.

[91] Konopka L, Pietrzak A, Brzezinska-Blaszczyk E. Effect of scaling and root planing on interleukin-1beta, interleukin-8 and MMP-8 levels in gingival crevicular fluid from chronic periodontitis patients. J. Periodontal Res., 2012, 47: 681-688.

[92] Kaushik R, Yeltiwar RK, Pushpanshu K. Salivary interleukin-1beta levels in patients with chronic periodontitis before and after periodontal phase I therapy and healthy controls: a case-control study. J. Periodontol., 2011, 82: 1353-1359.

[93] Reinhardt RA, . IL-1 in gingival crevicular fluid following closed root planing and papillary flap debridement. J. Clin. Periodontol., 1993, 20: 514-519.

[94] Killeen AC, Harn JA, Erickson LM, Yu F, Reinhardt RA. Local minocycline effect on inflammation and clinical attachment during periodontal maintenance: randomized clinical trial. J. Periodontol., 2016, 87: 1149-1157.

[95] Killeen AC, . Two-year randomized clinical trial of adjunctive minocycline microspheres in periodontal maintenance. J. Dent. Hyg., 2018, 92: 51-58.

[96] Machtei EE, Younis MN. The use of 2 antibiotic regimens in aggressive periodontitis: comparison of changes in clinical parameters and gingival crevicular fluid biomarkers. Quintessence Int., 2008, 39: 811-819.

[97] Aral K, Aral CA, Kapila Y. Six-month clinical outcomes of non-surgical periodontal treatment with antibiotics on apoptosis markers in aggressive periodontitis. Oral Dis., 2019, 25: 839-847.

[98] Casarin RC, . The combination of amoxicillin and metronidazole improves clinical and microbiologic results of one-stage, full-mouth, ultrasonic debridement in aggressive periodontitis treatment. J. Periodontol., 2012, 83: 988-998.

[99] Gong Y, Lu J, Ding X, Yu Y. Effect of adjunctive roxithromycin therapy on interleukin-1beta, transforming growth factor-beta1 and vascular endothelial growth factor in gingival crevicular fluid of cyclosporine a-treated patients with gingival overgrowth. J. Periodontal Res., 2014, 49: 448-457.

[100] Tanabe S, Yoshioka M, Hinode D, Grenier D. Subinhibitory concentrations of tetracyclines induce lipopolysaccharide shedding by Porphyromonas gingivalis and modulate the host inflammatory response. J. Periodontal Res., 2014, 49: 603-608.

[101] Cobb CM. Lasers and the treatment of periodontitis: the essence and the noise. Periodontol 2000, 2017, 75: 205-295.

[102] Ishikawa I, . Application of lasers in periodontics: true innovation or myth?. Periodontol 2000, 2009, 50: 90-126.

[103] Cheng Y, . Efficacy of adjunctive laser in non-surgical periodontal treatment: a systematic review and meta-analysis. Lasers Med. Sci., 2016, 31: 151-163.

[104] Qadri T, Poddani P, Javed F, Tuner J, Gustafsson A. A short-term evaluation of Nd:YAG laser as an adjunct to scaling and root planing in the treatment of periodontal inflammation. J. Periodontol., 2010, 81: 1161-1166.

[105] Abduljabbar T, Vohra F, Kellesarian SV, Javed F. Efficacy of scaling and root planning with and without adjunct Nd:YAG laser therapy on clinical periodontal parameters and gingival crevicular fluid interleukin 1-beta and tumor necrosis factor-alpha levels among patients with periodontal disease: a prospective randomized split-mouth clinical study. J. Photochem. Photobiol. B, 2017, 169: 70-74.

[106] Javed F, . Effect of Nd:YAG laser-assisted non-surgical periodontal therapy on clinical periodontal and serum biomarkers in patients with and without coronary artery disease: a short-term pilot study. Lasers Surg. Med., 2016, 48: 929-935.

[107] Ertugrul AS, Tekin Y, Talmac AC. Comparing the efficiency of Er,Cr:YSGG laser and diode laser on human beta-defensin-1 and IL-1beta levels during the treatment of generalized aggressive periodontitis and chronic periodontitis. J. Cosmet. Laser Ther., 2017, 19: 409-417.

[108] Saglam M, Kantarci A, Dundar N, Hakki SS. Clinical and biochemical effects of diode laser as an adjunct to nonsurgical treatment of chronic periodontitis: a randomized, controlled clinical trial. Lasers Med. Sci., 2014, 29: 37-46.

[109] Nguyen NT, . Adjunctive non-surgical therapy of inflamed periodontal pockets during maintenance therapy using diode laser: a randomized clinical trial. J. Periodontol., 2015, 86: 1133-1140.

[110] Lopes BM, Marcantonio RA, Thompson GM, Neves LH, Theodoro LH. Short-term clinical and immunologic effects of scaling and root planing with Er:YAG laser in chronic periodontitis. J. Periodontol., 2008, 79: 1158-1167.

[111] Ting M, Huynh BH, Devine SM, Braid SM, Suzuki JB. Laser treatment of periodontal disease: a systematic review of histological outcomes. EC Dent. Sci., 2018, 178: 1344-1367.

[112] Rajesh S, Koshi E, Philip K, Mohan A. Antimicrobial photodynamic therapy: an overview. J. Indian Soc. Periodontol., 2011, 15: 323-327.

[113] Joseph B, Janam P, Narayanan S, Anil S. Is antimicrobial photodynamic therapy effective as an adjunct to scaling and root planing in patients with chronic periodontitis? A systematic review. Biomolecules, 2017, 7: E79.

[114] Queiroz AC, . Adjunctive effect of antimicrobial photodynamic therapy to nonsurgical periodontal treatment in smokers: a randomized clinical trial. Lasers Med. Sci., 2015, 30: 617-625.

[115] Moreira AL, . Antimicrobial photodynamic therapy as an adjunct to non-surgical treatment of aggressive periodontitis: a split-mouth randomized controlled trial. J. Periodontol., 2015, 86: 376-386.

[116] Zhang J, . Photodynamic therapy versus systemic antibiotic for the treatment of periodontitis in a rat model. J. Periodontol., 2019, 90: 798-807.

[117] Dinarello CA. An expanding role for interleukin-1 blockade from gout to cancer. Mol. Med., 2014, 20: S43-S58.

[118] Joosten LA, . Engagement of fatty acids with toll-like receptor 2 drives interleukin-1beta production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum., 2010, 62: 3237-3248.

[119] Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol., 2011, 11: 98-107.

[120] Wu YY, Xiao E, Graves DT. Diabetes mellitus related bone metabolism and periodontal disease. Int. J. Oral Sci., 2015, 7: 63-72.

[121] Lust JA, Donovan KA. The role of interleukin-1 beta in the pathogenesis of multiple myeloma. Hematol. Oncol. Clin. N. Am., 1999, 13: 1117-1125.

[122] Assuma R, Oates T, Cochran D, Amar S, Graves DT. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J. Immunol., 1998, 160: 403-409.

[123] Graves DT, . Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. J. Periodontol., 1998, 69: 1419-1425.

[124] Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov., 2012, 11: 633-652.

[125] Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin. Immunol., 2013, 25: 469-484.

[126] Arranz L, Arriero MDM, Villatoro A. Interleukin-1beta as emerging therapeutic target in hematological malignancies and potentially in their complications. Blood Rev., 2017, 31: 306-317.

[127] Grom AA, Horne A, De Benedetti F. Macrophage activation syndrome in the era of biologic therapy. Nat. Rev. Immunol., 2016, 12: 259-268.

[128] Ilowite NT, . Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol., 2014, 66: 2570-2579.

[129] Fenini G, Contassot E, French LE. Potential of IL-1, IL-18 and inflammasome inhibition for the treatment of inflammatory skin diseases. Front. Pharmacol., 2017, 8: 278.

[130] Zhang Y, Zheng Y. Effects and mechanisms of potent caspase-1 inhibitor VX765 treatment on collagen-induced arthritis in mice. Clin. Exp. Immunol., 2016, 34: 111-118.

[131] Li F, . Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema. Respir. Res., 2018, 19: 230.

[132] Audia JP, . Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. Basic Res. Cardiol., 2018, 113: 32.

[133] Vertex. Vertex announces completion of phase 2 study of VX-765 in people with epilepsy who did not respond to previous treatment. https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-completion-phase-2-study-vx-765-people-epilepsy (2011).

[134] Bassil F, . Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy. Proc. Natl Acad. Sci. USA, 2016, 113: 9593-9598.

[135] Coll RC, . A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med., 2015, 21: 248-255.

[136] Perera AP, Kunde D, Eri R. NLRP3 inhibitors as potential therapeutic agents for treatment of inflammatory bowel disease. Curr. Pharm. Des., 2017, 23: 2321-2327.

[137] Dolunay A, . Inhibition of NLRP3 inflammasome prevents LPS-induced inflammatory hyperalgesia in mice: contribution of NF-kappaB, caspase-1/11, ASC, NOX, and NOS isoforms. Inflammation, 2017, 40: 366-386.

[138] Mridha AR, . NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J. Hepatol., 2017, 66: 1037-1046.

[139] van der Heijden T, . NLRP3 inflammasome inhibition by MCC950 reduces atherosclerotic lesion development in apolipoprotein E-deficient mice-brief report. Arterioscler. Thromb. Vasc. Biol., 2017, 37: 1457-1461.

[140] van Hout GP, . The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. Eur. Heart J., 2017, 38: 828-836.

[141] Ren H, . Selective NLRP3 (pyrin domain-containing protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage. Stroke, 2018, 49: 184-192.

[142] Deora V, Albornoz EA, Zhu K, Woodruff TM, Gordon R. The ketone body beta-hydroxybutyrate does not inhibit synuclein mediated inflammasome activation in microglia. J. Neuroimmune Pharmacol., 2017, 12: 568-574.

[143] Youm YH, . The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med., 2015, 21: 263-269.

[144] Goldberg EL, . β-hydroxybutyrate deactivates neutrophil NLRP3 inflammasome to relieve gout flares. Cell Rep., 2017, 18: 2077-2087.

[145] Trotta MC, . The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome. PLoS ONE, 2019, 14

[146] Gross CJ, Gross O. The Nlrp3 inflammasome admits defeat. Trends Immunol., 2015, 36: 323-324.

[147] Mariathasan S, . Cryopyrin activates the inflammasome in response to toxins and ATP. Nature, 2006, 440: 228-232.

[148] Giuliani AL, Sarti AC, Falzoni S, Di Virgilio F. The P2X7 receptor-interleukin-1 liaison. Front. Pharmacol., 2017, 8: 123.

[149] Park JH, Kim YC. P2X7 receptor antagonists: a patent review (2010–2015). Expert Opin. Ther. Pat., 2017, 27: 257-267.

[150] Burnstock G, Knight GE. The potential of P2X7 receptors as a therapeutic target, including inflammation and tumour progression. Purinergic Signal., 2018, 14: 1-18.

[151] Mishra A, . A critical role for P2X7 receptor-induced VCAM-1 shedding and neutrophil infiltration during acute lung injury. J. Immunol., 2016, 197: 2828-2837.

[152] Correa MG, . Systemic treatment with resveratrol and/or curcumin reduces the progression of experimental periodontitis in rats. J. Periodontal Res., 2017, 52: 201-209.

[153] Pulikkotil SJ, Nath S. Effects of curcumin on crevicular levels of IL-1beta and CCL28 in experimental gingivitis. Aust. Dent. J., 2015, 60: 317-327.

[154] Xiao CJ, Yu XJ, Xie JL, Liu S, Li S. Protective effect and related mechanisms of curcumin in rat experimental periodontitis. Head Face Med., 2018, 14: 12.

[155] Dong Y, Huihui Z, Li C. Piperine inhibit inflammation, alveolar bone loss and collagen fibers breakdown in a rat periodontitis model. J. Periodontal Res., 2015, 50: 758-765.

[156] Zheng XY, . Plumbagin suppresses chronic periodontitis in rats via down-regulation of TNF-alpha, IL-1beta and IL-6 expression. Acta Pharmacol. Sin., 2017, 38: 1150-1160.

[157] Saquib SA, . Evaluation and comparison of antibacterial efficacy of herbal extracts in combination with antibiotics on periodontal pathobionts: an in vitro microbiological study. Antibiotics, 2019, 8: E89.

[158] Koychev S, Dommisch H, Chen H, Pischon N. Antimicrobial effects of mastic extract against oral and periodontal pathogens. J. Periodontol., 2017, 88: 511-517.

[159] Hawley SA, Gadalla AE, Olsen GS, Hardie DG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes, 2002, 51: 2420-2425.

[160] Salt IP, Palmer TM. Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation. Expert Opin. Investig. Drugs, 2012, 21: 1155-1167.

[161] Araujo AA, . Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis. PLoS ONE, 2017, 12

[162] Kang W, . Metformin inhibits Porphyromonas gingivalis lipopolysaccharide-influenced inflammatory response in human gingival fibroblasts via regulating activating transcription factor-3 expression. J. Periodontol., 2017, 88: e169-e178.

[163] Puertollano MA, Puertollano E, de Cienfuegos GA, de Pablo MA. Dietary antioxidants: immunity and host defense. Curr. Top. Med. Chem., 2011, 11: 1752-1766.

[164] Derradjia A, . alpha-tocopherol decreases interleukin-1beta and -6 and increases human beta-defensin-1 and -2 secretion in human gingival fibroblasts stimulated with Porphyromonas gingivalis lipopolysaccharide. J. Periodontal Res., 2016, 51: 295-303.

[165] Goncalves DC, . Infliximab attenuates inflammatory osteolysis in a model of periodontitis in wistar rats. Exp. Biol. Med., 2014, 239: 442-453.

[166] Jiang L, . The proteasome inhibitor bortezomib inhibits inflammatory response of periodontal ligament cells and ameliorates experimental periodontitis in rats. J. Periodontol., 2017, 88: 473-483.

Funding

the Innovation Spark Project of Sichuan University (2018SCUH0054)

Sichuan Provincial Natural Science Foundation of China(2018SZ0139)