title: Telomerase Deficiency Causes Alveolar Stem Cell Senescence-associated Low-grade Inflammation in Lungs.
abstract: Mutations of human telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) are associated with a subset of lung aging diseases, but the mechanisms by which TERC and TERT participate in lung diseases remain unclear. In this report, we show that knock-out (KO) of the mouse gene Terc or Tert causes pulmonary alveolar stem cell replicative senescence, epithelial impairment, formation of alveolar sacs, and characteristic inflammatory phenotype. Deficiency in TERC or TERT causes a remarkable elevation in various proinflammatory cytokines, including IL-1, IL-6, CXCL15 (human IL-8 homolog), IL-10, TNF-α, and monocyte chemotactic protein 1 (chemokine ligand 2 (CCL2)); decrease in TGF-β1 and TGFβRI receptor in the lungs; and spillover of IL-6 and CXCL15 into the bronchoalveolar lavage fluids. In addition to increased gene expressions of α-smooth muscle actin and collagen 1α1, suggesting myofibroblast differentiation, TERC deficiency also leads to marked cellular infiltrations of a mononuclear cell population positive for the leukocyte common antigen CD45, low-affinity Fc receptor CD16/CD32, and pattern recognition receptor CD11b in the lungs. Our data demonstrate for the first time that telomerase deficiency triggers alveolar stem cell replicative senescence-associated low-grade inflammation, thereby driving pulmonary premature aging, alveolar sac formation, and fibrotic lesion.
authors.affiliation: From the Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, Shandong Province 250012, China, the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Ruping
authors.initials: R
authors.lastname: Chen
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Kexiong
authors.initials: K
authors.lastname: Zhang
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Xiaoyin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Jianqiu
authors.initials: J
authors.lastname: Wang
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Cong
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.affiliation: the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China, the Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, the Department of Molecular and Translational Science, Faculty of Medicine, Monash University, Clayton, Victoria 3168, Australia, and.
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
authors.affiliation: the Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, the Department of Molecular and Translational Science, Faculty of Medicine, Monash University, Clayton, Victoria 3168, Australia, and.
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.affiliation: From the Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, Shandong Province 250012, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Jia
authors.affiliation: From the Department of Microbiology/Key Laboratory for Experimental Teratology of Chinese Ministry of Education, School of Medicine, Shandong University, Jinan, Shandong Province 250012, China, the Institute of Aging Research, Hangzhou Normal University, School of Medicine, Hangzhou, Zhejiang Province 311121, China, the Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia, the Department of Molecular and Translational Science, Faculty of Medicine, Monash University, Clayton, Victoria 3168, Australia, and the Department of Immunology, Faculty of Medicine, Central Clinical School, Monash University, Prahran, Victoria 3018, Australia jun-ping.liu@monash.edu.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology; D008171:Lung Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D012313:RNA / Q000235:genetics; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; C509187:Tert protein, mouse
keywords: alveolar senescence; chronic obstructive pulmonary disease (COPD); lung aging; proinflammatory cytokines; pulmonary fibrosis; telomerase; telomerase reverse transcriptase (TERT); telomere; telomeres