Elucidation of NASH progression mechanism of red complex dental infection via TLR2 pathway

• Project/Area Number: 16K20437
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Hiroshima University
• Principal Investigator: Furusho Hisako 広島大学, 医歯薬保健学研究科(歯), 助教 (00634461)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: red complex / TLR2 / NASH / 歯性感染 / Red complex / 炎症

Outline of Final Research Achievements

In vivo experiment, crown-like structure (CLS) number and fibrosis were increased in high-fat-diet induced wild type mice groups (WT-HFD), excluding 1 group, and they were decreased in high-fat-diet induced TLR2 (TLR2KO-HFD) groups ultimately. Similarly, IL-1β mRNA expression, upregulated in WT-HFD groups, were restrained in TLR2KO-HFD groups. In vitro experiment, IL-1β and IL-6 mRNA expression were upregulated in the steatotic hepatocyte, stimulated by each red complex (Pg, Td, Tf) dead body stimulation. After the dosage of the TLR2 inhibitor, the mRNA upregulation were suppressed. It was revealed that the TLR2 pathway participated in NASH progression by the red complex odontogenic infection.

Academic Significance and Societal Importance of the Research Achievements

本研究は顎骨における歯周病原細菌感染と肝疾患の関連性を課題としている。今回の研究において作成する歯性感染モデルでは、歯周病原細菌の中のred complexを使用し、各菌単独およびその組み合わせにおいてより患者の病態を模倣したnaturalな状態を観察している。red complex歯性感染によるNASH病態増悪の機序についてTLR2の役割を明らかにしたことは、脂肪肝患者におけるTLR2を標的とした新たな治療法開発につながり、社会に還元できる有意義な研究であると考える。

Research Products

• [Journal Article] Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice. (2016)
  • Author(s): Rider D, Furusho H, Xu S, Trachtenberg AJ, Kuo WP, Hirai K, Susa M, Bahammam L, Stashenko P, Fujimura A, Sasaki H,
  • Journal Title: Anatomical record Volume: Sep;299(9) Issue: 9 Pages: 1281-1292
  • DOI: 10.1002/ar.23383
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Interrelationship Between Periapical Lesion and Systemic Metabolic Disorders. (2016)
  • Author(s): Sasaki H, Hirai K, Martins CM, Furusho H, Battaglino R, Hashimoto K.
  • Journal Title: Current pharmaceutical design Volume: 22(15) Pages: 2204-2215
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phospholipase C-related catalytically inactive protein is a new modulator of thermogenesis promoted by β-adrenergic receptors in brown adipocytes (2015)
  • Author(s): Kana Oue, Jun Zhang, Kae Harada-Hada, Satoshi Asano, Yosuke Yamawaki, Masaki Hayashiuchi, Hisako Furusho, Takashi Takata, Masahiro Irifune, Masato Hirata, Takashi Kanematsu
  • Journal Title: Journal of Biological Chemistry Volume: 291 Issue: 8 Pages: 4185-96
  • DOI: 10.1074/jbc.m115.705723
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced Expression of Contractile-Associated Proteins and Ion Channels in Preterm Delivery Model Mice With Chronic Odontogenic Porphyromonas Gingivalis Infection (2015)
  • Author(s): Miyoshi H, Konishi H, Teraoka Y, Urabe S, Furusho H, Miyauchi M, Takata T, Kudo Y.
  • Journal Title: Reprod Sci. Volume: なし Issue: 7 Pages: 838-846
  • DOI: 10.1177/1933719115620497
  • Peer Reviewed
• [Presentation] Porphyromonas gingivalisの歯性感染は非アルコール性脂肪性肝炎の病態を増悪する (2018)
  • Author(s): 宮内睦美，古庄寿子，坂本真一，高田 隆
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] Porphyromonas gingivalis 歯性感染は肝星細胞を活性化し、非アルコール性脂肪性肝炎の病態を増悪する (2017)
  • Author(s): 宮内睦美，長﨑敦洋，坂本真一，古庄寿子，髙田 隆
  • Organizer: 第60回 春季日本歯周病学会学術大会
• [Presentation] Porphyromonas gingivalis の歯性感染は非アルコール性脂肪性肝炎(NASH)の病態を増悪する (2017)
  • Author(s): 宮内睦美,古庄寿子, 坂本真一, 應原和久, 栗原英見, 高田 隆
  • Organizer: 日本歯周病学会60周年記念京都大会
  • Invited
• [Presentation] Key roles of TLR2 in NASH progression by P.g.-odontogenic infection. (2016)
  • Author(s): Furusho H, Miyauchi M, Takata T.
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 北海道（札幌）
  • Year and Date: 2016-08-24
• [Presentation] Key roles of TLR2 in NASH progression by P.g.-odontogenic infection. Furusho H, Nagasaki A, Sakamoto S, Miyauchi M, Takata T. (2016)
  • Author(s): Furusho H, Nagasaki A, Sakamoto S, Miyauchi M, Takata T.
  • Organizer: 第64回 JADR総会・学術大会(IADR共同開催）
  • Place of Presentation: 大韓民国（ソウル）
  • Year and Date: 2016-06-22
  • Int'l Joint Research