RANK/RANKL/OPG signaling upregulates IL-10 -regulated anti-inflammatory response during Candida albicans Infection

Research Project

Project/Area Number	19K10343
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 57060:Surgical dentistry-related
Research Institution	Ohu University
Principal Investigator	Kobayashi Michiyo 奥羽大学, 歯学部, 講師 (80316265)
Co-Investigator(Kenkyū-buntansha)	坂本直哉北海道大学, 創成研究機構, 助教 (30466429) 奥村一彦北海道医療大学, 歯学部, 教授 (60194510)
Project Period (FY)	2019-04-01 – 2022-03-31
Project Status	Completed (Fiscal Year 2021)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords	Osteoprotegerin / RANKL / RANK / Candida albicans / candida albicans / osteoprotegerin
Outline of Research at the Start	高齢者に罹患率が高い内因性感染症である口腔と消化管カンジダ症の発症・増悪の機序をモデルとし、骨代謝因子の量的変化がCandida albicans感染防御に関わる免疫細胞に影響を与えている可能性の検証を目的とする。具体的には、RANK/RANKL/OPGの投与や抑制によるカンジダ症の病態変化の評価、C. albicans感染によって骨代謝因子の発現が誘導される細胞の同定、C. albicans感染おける免疫細胞の動態解析を行う。この研究により、骨代謝疾患と免疫疾患の総合的な制御機序の理解が進み、骨代謝因子を利用した内因性感染症の予防研究につながると期待される。
Outline of Final Research Achievements	Receptor activator of nuclear factor-kappa B ligand (RANKL) to RANK interactions are critical to pathogenesis in immune cells. Osteoprotegerin (OPG) prevents binding of RANKL to RANK. This study utilized a mouse model (orally inoculated) to determine if there was a correlation between superficial candidiasis, commonly caused by the opportunistic fungus Candida albicans, and RANK/RANKL/OPG. Upregulation of OPG, RANKL, and RANK mRNA expression were found in mice whose oral cavity had a superficial C. albicans infection. Moreover, administration of exogenous soluble RANKL upregulated the mRNA of RANK in the infected tissue. Exogenous soluble RANKL also upregulated the mRNA of IL-10, which prompted anti-inflammatory effects including wound healing. Therefore, our data suggested that RANK/RANKL/OPG signaling might play a role in the pathogenesis of candidiasis, making this the first study to show the relationship between this opportunistic infection and the RANK/RANKL/OPG axis.
Academic Significance and Societal Importance of the Research Achievements	カンジダ感染症は高齢者に発症率が高い内因性感染症である。高齢者は骨代謝因子Osteoprotegerin (OPG)の血清濃度が若年者、中年者に比較して高いことが報告されている。本研究結果はOPGやRANKLの局所の濃度がCandida albicans感染の発症、増悪に関与している可能性を示唆する。　これは内因性感染症であるC. albicansの発症を制御し、QOLを高かめて国民の健康寿命を延伸するうえで有益な結果であると考える。