Elucidation of epigenetic mechanism required for chronic inflammatory phenotype in conjunctival fibroblasts derived from severe allergic conjunctivitis

• Project/Area Number: 17K11500
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Ophthalmology
• Research Institution: Nihon Pharmaceutical University (2018-2019); National Center for Child Health and Development (2017)
• Principal Investigator: OKADA NAOKO 日本薬科大学, 薬学部, 助教 (50636165)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エピジェネティクス / ペリオスチン / 重症アレルギー性結膜炎 / 線維芽細胞 / アレルギー性結膜炎

Outline of Final Research Achievements

Atopic keratoconjunctivitis (AKC) represents severe forms of ocular allergies. It is characterized by chronically relapsing ocular inflammatory diseases that cause intense inflammation and fibrosis in conjunctiva. However, the precise mechanisms by which the diseases are resistant to treatment remains unknown. We previously focused on conjunctival fibroblasts derived from severe ocular allergic conjunctivitis patients and compared the gene expression patterns. It was found that the expression of periostin was significantly enhanced in the conjunctival fibroblasts derived from patients in the unstimulated state, and this expression was maintained even after the subculture. In this study, we found that epigenetic induction by enzymes involved in histone methylation status play an important role in periostin high expression in conjunctival fibroblasts. Furthermore, it was revealed that high expression of periostin in conjunctival fibroblasts can be suppressed by controlling the enzymes.

Academic Significance and Societal Importance of the Research Achievements

線維芽細胞はがんや関節リウマチなど様々な慢性炎症疾患において、炎症局所の微小環境中での様々なストレスに応答し、細胞のエピジェネティック変化が誘導されることで、慢性炎症を引き起こすことが数多く報告されている。一方、アレルギー疾患においては、炎症組織中の細胞を採取・評価できる疾患が少なく、検討が進んでいない。本研究では結膜線維芽細胞を用いて、慢性炎症型の表現型獲得とその維持のために重要なエピジェネティクスのメカニズムとその制御法を初めて解明した。またエピジェネティクス制御化合物は、眼アレルギーに限らず、炎症メカニズムが類似した疾患における治癒困難な線維化に対し、新たな治療法となる可能性がある。

Research Products

• [Journal Article] Effects of Docosahexaenoic Acid on Chemokine Expression in Human Conjunctival Fibroblasts (2019)
  • Author(s): Yazu Hiroyuki、Fukagawa Kazumi、Okada Naoko、Fujishima Hiroshi
  • Journal Title: Current Eye Research Volume: 45 Issue: 1 Pages: 81-86
  • DOI: 10.1080/02713683.2019.1648832
  • Peer Reviewed
• [Journal Article] The Effect of Cytokine-Stimulation and Pharmacologic Intervention on PGE2 Production in Primary Human Conjunctival and Corneal Cells (2019)
  • Author(s): Shimizu Eisuke、Yazu Hiroyuki、Satake Yoshiyuki、Fukagawa Kazumi、Aketa Naohiko、Murat Dogru、Okada Naoko、Fujishima Hiroshi
  • Journal Title: Ocular Immunology and Inflammation Volume: 28 Issue: 3 Pages: 384-390
  • DOI: 10.1080/09273948.2019.1595669
  • Peer Reviewed
• [Journal Article] Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid (2019)
  • Author(s): Morita H, Kubo T, Ruckert B, Ravindran A, Soyka M, Rinaldi A, Sugita K, Wawrzyniak M, Wawrzyniak P, Motomura K, Tamari M, Orimo K, Okada N, Arae K, Saito K, Altunbulakli C, Castro-Giner F, Tan G, Neumann A, Sudo K, O’Mahony L, Honda K, Nakae S, Saito H, Mjösberg J, Nilsson G, Matsumoto K, Akdis M, Akdis CA
  • Journal Title: J Allergy Clin Immunol. Volume: in press Issue: 6 Pages: 2190-2201
  • DOI: 10.1016/j.jaci.2018.12.1018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The efficacy of 0.1% tacrolimus ophthalmic suspension in the treatment of severe atopic keratoconjunctivitis (2019)
  • Author(s): Yazu Hiroyuki、Shimizu Eisuke、Aketa Naohiko、Dogru Murat、Okada Naoko、Fukagawa Kazumi、Fujishima Hiroshi
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: 122 Issue: 4 Pages: 387-392.e1
  • DOI: 10.1016/j.anai.2019.01.004
  • Peer Reviewed
• [Journal Article] JESREC score and mucosal eosinophilia can predict entnotypes of chronic rhinosinusitis with nasal polyps (2019)
  • Author(s): Nakayama T, Haruna S
  • Journal Title: Auris Nasus Larynx Volume: 46 Issue: 3 Pages: 374-383
  • DOI: 10.1016/j.anl.2018.09.004
  • Peer Reviewed / Open Access
• [Journal Article] Chitin promotes antigen-specific Th2 cell-mediated murine asthma through induction of IL-33-mediated IL-1β production by DCs (2018)
  • Author(s): Arae Ken、Morita Hideaki、Unno Hirotoshi、Motomura Kenichiro、Toyama Sumika、Okada Naoko、Ohno Tatsukuni、Tamari Masato、Orimo Keisuke、Mishima Yuko、Suto Hajime、Okumura Ko、Sudo Katsuko、Miyazawa Hiroshi、Taguchi Haruhiko、Saito Hirohisa、Matsumoto Kenji、Nakae Susumu
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11721-11721
  • DOI: 10.1038/s41598-018-30259-2
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of suitable reference genes for RT-qPCR studies in chronic rhinosinusitis. (2018)
  • Author(s): Nakayama T, Okada N, Yoshikawa M, Asaka D, Kuboki A, Kojima H, Tanaka Y, Haruna SI.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 1568-1568
  • DOI: 10.1038/s41598-018-19834-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct gene expression profiles and regulation networks of nasal polyps in eosinophilic and non-eosinophilic chronic rhinosinusitis. (2018)
  • Author(s): Okada N, Nakayama T, Asaka D, Inoue N, Tsurumoto T, Takaishi S, Otori N, Kojima H, Matsuda A, Oboki K, Saito H, Matsumoto K, Yoshikawa M.
  • Journal Title: Int Forum Allergy Rhinol. Volume: 8 Issue: 5 Pages: 592-604
  • DOI: 10.1002/alr.22083
  • Peer Reviewed
• [Journal Article] A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro (2017)
  • Author(s): Kenichiro Motomura, Naoko Okada, Hideaki Morita, Mariko Hara, Masato Tamari, Keisuke Orimo, Go Matsuda, Ken-Ichi Imadome, Akio Matsuda, Takeshi Nagamatsu, Mikiya Fujieda, Haruhiko Sago, Hirohisa Saito, and Kenji Matsumoto
  • Journal Title: PLOS ONE Volume: in press Issue: 5 Pages: e0177994-e0177994
  • DOI: 10.1371/journal.pone.0177994
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gene expression profiling of acute type A aortic dissection combined with in vitro assessment. (2017)
  • Author(s): Kimura N, Futamura K, Arakawa M, Okada N, Emrich F, Okamura H, Sato T, Shudo Y, Koyano TK, Yamaguchi A, Adachi H, Matsuda A, Kawahito K, Matsumoto K, Fischbein MP.
  • Journal Title: European Journal of Cardio-Thoracic Surgery Volume: 52 Issue: 4 Pages: 810-817
  • DOI: 10.1093/ejcts/ezx095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Restoration of Tear Secretion in a Murine Dry Eye Model by Oral Administration of Palmitoleic Acid (2017)
  • Author(s): Nakamura Shigeru、Kimura Yuki、Mori Daisuke、Imada Toshihiro、Izuta Yusuke、Shibuya Michiko、Sakaguchi Hisayo、Oonishi Erina、Okada Naoko、Matsumoto Kenji、Tsubota Kazuo
  • Journal Title: Nutrients Volume: 9 Issue: 4 Pages: 364-364
  • DOI: 10.3390/nu9040364
  • Peer Reviewed / Open Access
• [Journal Article] Eosinophilic esophagitis versus proton pump inhibitor-responsive esophageal eosinophilia: Transcriptome analysis (2017)
  • Author(s): Shoda T, Matsuda A, Nomura I, Okada N, Orihara K, Mikami H, Ishimura N, Ishihara S, Matsumoto K, Kinoshita Y
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 6 Pages: 2010-2013
  • DOI: 10.1016/j.jaci.2016.11.028
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human eosinophils constitutively express a unique serine protease, PRSS33 (2017)
  • Author(s): Toyama S, Okada N, Matsuda A, Morita H, Saito H, Fujisawa T, Nakae S, Karasuyama H, Matsumoto K.
  • Journal Title: Allergology International Volume: 66 Issue: 3 Pages: 463-471
  • DOI: 10.1016/j.alit.2017.01.001
  • NAID: 130005858869
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Up-regulation of periostin production in tears of allergic ocular disease patients (2019)
  • Author(s): Okada N., Fujishima H., Fukagawa K., Ono J., Matsuda A., Saito H., Matsumoto K., Izuhara K.
  • Organizer: KAAACI-KAPARD-WPAS-INTERASMA Joint Congress
  • Int'l Joint Research
• [Presentation] アレルギー性結膜炎の診断における涙液ペリオスチン測定の有用性 (2018)
  • Author(s): 岡田直子
  • Organizer: 第1回日本眼科アレルギー学会学術集会
• [Presentation] 好酸球性副鼻腔炎における遺伝子発現プロファイル解析 (2018)
  • Author(s): 岡田直子、中山次久、浅香大也、井上なつき、松本健治、吉川 衛
  • Organizer: 第36回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] 涙液中ぺリオスチンについて (2017)
  • Author(s): 岡田直子
  • Organizer: 第4回総合アレルギー講習会
  • Invited
• [Presentation] 涙液中のペリオスチンについて (2017)
  • Author(s): 岡田直子
  • Organizer: 第121回日本眼科学会総会
  • Invited