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Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans.
FASEB J. 2020 Jul 03 [Online ahead of print]FJ

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.

Authors+Show Affiliations

Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.Division of Cardiology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Center for Interdisciplinary Cardiovascular Sciences, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Department of Physiology, Keio University School of Medicine, Tokyo, Japan.Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32619061

Citation

Yamane, Mio, et al. "Senescence-associated Secretory Phenotype Promotes Chronic Ocular Graft-vs-host Disease in Mice and Humans." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 2020.
Yamane M, Sato S, Shimizu E, et al. Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans. FASEB J. 2020.
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. (2020). Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.201900218R
Yamane M, et al. Senescence-associated Secretory Phenotype Promotes Chronic Ocular Graft-vs-host Disease in Mice and Humans. FASEB J. 2020 Jul 3; PubMed PMID: 32619061.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Senescence-associated secretory phenotype promotes chronic ocular graft-vs-host disease in mice and humans. AU - Yamane,Mio, AU - Sato,Shinri, AU - Shimizu,Eisuke, AU - Shibata,Shinsuke, AU - Hayano,Motoshi, AU - Yaguchi,Tomonori, AU - Kamijuku,Hajime, AU - Ogawa,Mamoru, AU - Suzuki,Takanori, AU - Mukai,Shin, AU - Shimmura,Shigeto, AU - Okano,Hideyuki, AU - Takeuchi,Tsutomu, AU - Kawakami,Yutaka, AU - Ogawa,Yoko, AU - Tsubota,Kazuo, Y1 - 2020/07/03/ PY - 2019/01/23/received PY - 2020/04/30/revised PY - 2020/06/04/accepted PY - 2020/7/4/entrez KW - chronic ocular graft-vs-host disease KW - lacrimal glands KW - senescence-associated secretory phenotype KW - senolytic treatment KW - stress-induced senescence JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. N2 - 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/32619061/Senescence-associated_secretory_phenotype_promotes_chronic_ocular_graft-vs-host_disease_in_mice_and_humans L2 - https://doi.org/10.1096/fj.201900218R DB - PRIME DP - Unbound Medicine ER -
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