TY - JOUR
T1 - Sensing of apoptotic cells through Axl causes lung basal cell proliferation in inflammatory diseases
AU - Fujino, Naoya
AU - Brand, Oliver J.
AU - Morgan, David J.
AU - Fujimori, Toshifumi
AU - Grabiec, Aleksander M.
AU - Jagger, Christopher P.
AU - Maciewicz, Rose A.
AU - Yamada, Mitsuhiro
AU - Itakura, Koji
AU - Sugiura, Hisatoshi
AU - Ichinose, Masakazu
AU - Hussell, Tracy
N1 - Funding Information:
We are grateful to Peter C. Cook and Gareth Howell (Manchester Collaborative Centre for Inflammation Research, the University of Manchester, Manchester, UK) for FACS; Takaya Suzuki, Takashi Kondo, Yoshinori Okada, and Chiharu Ota (Tohoku University, Sendai, Japan) and Satoshi Suzuki (Japanese Red Cross Ishinomaki Hospital, Miyagi, Japan) for obtaining human lung tissues. Special thanks go to Steve Mardsen for his help with the microscopy. We also thank the Biomedical Research Core of Tohoku University Graduate School of Medicine and the Biomedical Research Unit of Tohoku University Hospital for technical support. This research was supported by a precompetitive open innovation award from AstraZeneca and GlaxoSmithKline that formed the Manchester Collaborative Centre for Inflammation Research. This work was also supported by the Japan Society for the Promotion of Science KAKENHI (grant nos. JP17H04180, JP16K15453, JP26293195, JP16H05307, and JP16H06641). The Bioimaging Facility microscopes used in this study were purchased with grants from Biotechnology and Biological Sciences Research Council, Wellcome Trust (grant no. 202865/Z/16/Z), and the University of Manchester Strategic Fund. R.A. Maciewicz is an employee and shareholder of AstraZeneca. The other authors declare no competing financial interests. Author contributions: N. Fujino conceived this project, designed strategy, performed experiments, analyzed/interpreted data, and wrote the manuscript. T. Fujimori conceived this project and performed in vivo experiments. O.J. Brand, D.J. Morgan, A.M. Grabiec, C.P. Jagger, and K. Itakura performed in vitro and in vivo experiments. R.A. Maciewicz conceived this project. M. Yamada, H. Sugiura, and M. Ichinose collected human samples and interpreted the data. T. Hussell conceived this project, designed strategy, interpreted data, and wrote the manuscript.
Funding Information:
This research was supported by a precompetitive open innovation award from AstraZeneca and GlaxoSmithKline that formed the Manchester Collaborative Centre for Inflammation Research. This work was also supported by the Japan Society for the Promotion of Science KAKENHI (grant nos. JP17H04180, JP16K15453, JP26293195, JP16H05307, and JP16H06641). The Bioimaging Facility microscopes used in this study were purchased with grants from Biotechnology and Biological Sciences Research Council, Wellcome Trust (grant no. 202865/Z/16/Z), and the University of Manchester Strategic Fund.
Publisher Copyright:
© 2019 Fujino et al.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Epithelial cell proliferation, division, and differentiation are critical for barrier repair following inflammation, but the initial trigger for this process is unknown. Here we define that sensing of apoptotic cells by the TAM receptor tyrosine kinase Axl is a critical indicator for tracheal basal cell expansion, cell cycle reentry, and symmetrical cell division. Furthermore, once the pool of tracheal basal cells has expanded, silencing of Axl is required for their differentiation. Genetic depletion of Axl triggers asymmetrical cell division, leading to epithelial differentiation and ciliated cell regeneration. This discovery has implications for conditions associated with epithelial barrier dysfunction, basal cell hyperplasia, and continued turnover of dying cells in patients with chronic inflammatory pulmonary diseases.
AB - Epithelial cell proliferation, division, and differentiation are critical for barrier repair following inflammation, but the initial trigger for this process is unknown. Here we define that sensing of apoptotic cells by the TAM receptor tyrosine kinase Axl is a critical indicator for tracheal basal cell expansion, cell cycle reentry, and symmetrical cell division. Furthermore, once the pool of tracheal basal cells has expanded, silencing of Axl is required for their differentiation. Genetic depletion of Axl triggers asymmetrical cell division, leading to epithelial differentiation and ciliated cell regeneration. This discovery has implications for conditions associated with epithelial barrier dysfunction, basal cell hyperplasia, and continued turnover of dying cells in patients with chronic inflammatory pulmonary diseases.
UR - http://www.scopus.com/inward/record.url?scp=85071785867&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071785867&partnerID=8YFLogxK
U2 - 10.1084/jem.20171978
DO - 10.1084/jem.20171978
M3 - Article
C2 - 31289116
AN - SCOPUS:85071785867
VL - 216
SP - 2184
EP - 2201
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 9
ER -