Bacterial-induced maternal interleukin 17A pathway promotes autistic-like behaviors in mouse offspring

• Project/Area Number: 18K19657
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: Fukuoka Dental College
• Principal Investigator: Tanaka Yoshihiko 福岡歯科大学, 口腔歯学部, 教授 (00398083)
• Co-Investigator(Kenkyū-buntansha): 永尾 潤一 福岡歯科大学, 口腔歯学部, 講師 (30509047) ; 成田 由香 福岡歯科大学, 口腔歯学部, 助教 (50758050) ; 長 環 福岡歯科大学, 口腔歯学部, 客員教授 (90131870) ; 有田 健一 福岡歯科大学, 口腔歯学部, 助教 (90780205)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 自閉スペクトラム症 / 脳神経系 / 免疫系 / 細菌感染

Outline of Final Research Achievements

Maternal immune activation (MIA) by an infection is considered to be an important environmental factor of fetal brain development. Recent animal model on MIA induced by a mimic of viral infection, demonstrates that maternal interleukin-17A (IL-17A) signaling is required for the development of autism spectrum disorder (ASD)-like behaviors of offspring. However, there is little information on bacterial infection. In this study, we demonstrated that lipopolysaccharide (LPS)-induced MIA promoted ASD-like behaviors in mouse offspring. We further found that LPS exposure induced acute phase immune response: elevation of serum IL-17A levels in MIA mothers and upregulation of IL-17R mRNA expression in the fetal brain. Blocking of IL-17A in LPS-induced MIA ameliorated ASD-like behaviors in offspring. Our data suggest that bacterial-induced maternal IL-17A pathway promotes ASD-like behaviors in offspring.

Academic Significance and Societal Importance of the Research Achievements

母体マウスに細菌抽出物で擬似感染させたところ、仔マウスが自閉症様行動を示すようになりました。母体ではインターロイキン-17Aが上昇しており、中和抗体で除去すると健常な仔マウスが誕生することが分かりました。母体の細菌感染による免疫応答が胎児の脳神経発達に関連することを意味します。本研究によって、自閉症の原因の一つが妊娠中の細菌感染であることが動物実験で明らかになりました。

Research Products

• [Journal Article] Bacterial-induced maternal interleukin-17A pathway promotes autistic-like behaviors in mouse offspring (2020)
  • Author(s): Yasumatsu K, Nagao J, Arita-Morioka K, Narita Y, Tasaki S, Toyoda K, Ito S, Kido H, Tanaka Y.
  • Journal Title: Experimental Animals Volume: 69 Issue: 2 Pages: 250-260
  • DOI: 10.1538/expanim.19-0156
  • NAID: 130007835083
  • ISSN: 0007-5124, 1341-1357, 1881-7122
  • Peer Reviewed / Open Access
• [Journal Article] Th17 cells differentiated with mycelial membranes of Candida albicans prevent oral candidiasis. (2018)
  • Author(s): Tasaki S, Cho T, Nagao JI, Ikezaki S, Narita Y, Arita-Morioka KI, Yasumatsu K, Toyoda K, Kojima H, Tanaka Y.
  • Journal Title: FEMS Yeast Res.2018 May 1;18(3). Volume: 18 Issue: 3 Pages: 1-10
  • DOI: 10.1093/femsyr/foy018
  • Peer Reviewed / Open Access
• [Journal Article] Inhibitory effects of Myricetin derivatives on curli-dependent biofilm formation in Escherichia coli. (2018)
  • Author(s): Arita-Morioka, K., Yamanaka, K., Mizunoe, Y., Tanaka, Y., Ogura, T. and Sugimoto, S.
  • Journal Title: Sci. Rep. Volume: 8 Issue: 1 Pages: 8432-8432
  • DOI: 10.1038/s41598-018-26748-z
  • Peer Reviewed / Open Access
• [Presentation] 胎児脳システム発達に関わる母体免疫活性化の重要性について (2019)
  • Author(s): 安松香奈江, 城戸寛史, 田中芳彦
  • Organizer: 第62回秋季日本歯周病学会学術大会
• [Presentation] 母体の病原性細菌感染が仔の行動異常に与える影響について (2019)
  • Author(s): 安松香奈江, 永尾潤一、成田由香, 有田（森岡）健一,長環, 城戸寛史, 田中芳彦
  • Organizer: 第61回歯科基礎医学会学術大会・総会
• [Presentation] 細菌感染による母体環境変化が引き起こす仔マウスの行動異常について (2019)
  • Author(s): 安松香奈江, 田中芳彦, 城戸寛史
  • Organizer: 第49回日本口腔インプラント学会学術大会
• [Presentation] A novel alternatively spliced SWAP-70-like adapter of T cells in differentiated Th2 cells. (2018)
  • Author(s): Tanaka, Y.
  • Organizer: The 91th Annual Meeting of the Japanese Biochemical Society.
  • Invited
• [Presentation] The influence of maternal inflammation by bacterial infection on fetal brain development. (2018)
  • Author(s): Yasumatsu, K., Nagao, J., Narita, Y., Arita-Morioka, K, Ikezaki, S., Tasaki, S., Toyoda, K., Cho, T., Kido, H., Tanaka Y.
  • Organizer: The 48th Annual Meeting of The Japanese Society for Immunology.
• [Presentation] 母体の細菌感染が胎児脳システム発達に及ぼす影響 (2018)
  • Author(s): 安松香奈江, 永尾潤一, 成田由香, 有田（森岡）健一,池崎晶二郎, 長環, 城戸寛史, 田中芳彦.
  • Organizer: 第４５回福岡歯科大学学会総会
• [Presentation] 細菌感染による母体免疫活性化と胎児脳システム発達の関連性 (2018)
  • Author(s): 安松香奈江, 城戸寛史, 田中芳彦.
  • Organizer: 第61回秋季日本歯周病学会学術大会
• [Presentation] 細菌感染がもたらす母体免疫活性化が胎児脳システムへ与える影響について (2018)
  • Author(s): 安松香奈江, 永尾潤一、豊田馨太, 成田由香, 有田（森岡）健一,池崎晶二郎、田﨑園子, 長環, 城戸寛史, 田中芳彦.
  • Organizer: 第60回歯科基礎医学会学術大会・総会
• [Remarks] 研究者HP
  • URL: https://www.fdcnet.ac.jp/col/info/teacher/teacher_info_tanaka
• [Remarks] 所属研究機関研究分野HP
  • URL: https://www.fdcnet.ac.jp/col/department_graduate_school/div_info/div_info_kinou#sec02