Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans

Mio Yamane, Shinri Sato, Eisuke Shimizu, Shinsuke Shibata, Motoshi Hayano, Tomonori Yaguchi, Hajime Kamijuku, Mamoru Ogawa, Takanori Suzuki, Shin Mukai, Shigeto Shimmura, Hideyuki Okano, Tsutomu Takeuchi, Yutaka Kawakami, Yoko Ogawa, Kazuo Tsubota

Research output: Contribution to journalArticle

Abstract

Chronic graft-vs-host disease (cGVHD) is a multifactorial inflammatory disease that affects patients undergoing hematopoietic stem cell transplantation. Multiple organs, including the lacrimal glands (LGs), are negatively affected by cGVHD and lose function due to the resultant fibrosis. An abnormal immune response is thought to be a major factor in the development of chronic ocular GVHD, which is currently treated primarily with immunosuppressive therapies. However, all the treatments yield unsatisfactory outcomes, and additional treatment strategies are needed. To meet this unmet medical need, we aimed to elucidate an additional pathway of chronic ocular GVHD. Our findings suggest a potential association between chronic ocular GVHD pathogenesis and stress-induced cellular senescence through the senescence-associated secretory phenotype (SASP). Senescent cells produce cytokines and chemokines, such as IL-6 and CXCL9. Indeed, senescent cell accumulation was presumably associated with cGVHD development in LGs, as evidenced by the improvement in LGs after the selective elimination of senescent cells (senolysis) with ABT-263. Results in the sclerodermatous cGVHD mouse model suggest that inhibiting the major components of the SASP, including IL-6 and CXCL9, with senolytics is a potential novel strategy for treating cGVHD-affected LGs. Taken together, our results indicate a potential association between the SASP and cGVHD development in LGs and suggest that targeted senolytic treatment may be a new therapeutic option for this disease.

Original languageEnglish
JournalFASEB Journal
DOIs
Publication statusAccepted/In press - 2020

Keywords

  • chronic ocular graft-vs-host disease
  • lacrimal glands
  • senescence-associated secretory phenotype
  • senolytic treatment
  • stress-induced senescence

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Yamane, M., Sato, S., Shimizu, E., Shibata, S., Hayano, M., Yaguchi, T., Kamijuku, H., Ogawa, M., Suzuki, T., Mukai, S., Shimmura, S., Okano, H., Takeuchi, T., Kawakami, Y., Ogawa, Y., & Tsubota, K. (Accepted/In press). Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans. FASEB Journal. https://doi.org/10.1096/fj.201900218R