Abstract
Developmental tissues go through regression, remodeling, and apoptosis. In these processes, macrophages phagocytize dead cells and induce apoptosis directly. In hyaloid vascular system (HVS), macrophages induce apoptosis of vascular endothelial cells (VECs) by cooperation between the Wnt and angiopoietin (Ang) pathways through cell–cell interaction. However, it remains unclear how macrophages are activated and interact with VECs. Here we show that Ninjurin1 (nerve injury-induced protein; Ninj1) was temporally increased in macrophages during regression of HVS and these Ninj1-expressing macrophages closely interacted with hyaloid VECs. Systemic neutralization using an anti-Ninj1 antibody resulted in the delay of HVS regression in vivo. We also found that Ninj1 increased cell–cell and cell–matrix adhesion of macrophages. Furthermore, Ninj1 stimulated the expression of Wnt7b in macrophages and the conditioned media from Ninj1-overexpressing macrophages (Ninj1-CM) decreased Ang1 and increased Ang2 in pericytes, which consequently switched hyaloid VEC fate from survival to death. Collectively, these findings suggest that macrophages express Ninj1 to increase the death signal through cell–cell interaction and raise the possibility that Ninj1 may act similarly in other developmental regression mediated by macrophages.
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Abbreviations
- Ang1/2:
-
angiopoietin-1/2
- col. I/IV:
-
type I/IV collagen
- CM:
-
conditioned media
- ECM:
-
extracellular matrix
- FN:
-
fibronectin
- h:
-
hour
- HVS:
-
hyaloid vascular system
- MMP1:
-
matrix metalloproteinase 1
- Ninjurin1 (Ninj1):
-
nerve injury-induced protein 1
- ONH:
-
optic nerve head
- P:
-
postnatal day
- R:
-
retina
- RV:
-
retinal vessel
- V:
-
vitreous
- VEC:
-
vascular endothelial cell
- VEGF:
-
vascular endothelial growth factor
- Wnt7b:
-
wingless-type MMTV integration site 7B from Drosophila melanogaster
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Acknowledgements
We thank Dr. Jeffrey Milbrandt (University of Washington, USA) and Dr. Toshiyuki Araki (National Institute of Neuroscience, Japan) for providing the Ninj1 antibody. We also thank Dr. Mi In Roh (Yonsei University, Korea) for linguistic corrections. This work was supported by the Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (MEST) through the Creative Research Initiative program (Grant R16-2004-001010010-2008).
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Edited by M Piacentini
Author contributions: H-JL planned the project, performed the experiments, analyzed the data, and wrote the article; BJA and MWS performed the experiments and analyzed the data; J-WJ contributed to the data analysis and to the writing of the article; JHK provided advice to the data analysis on the ocular experiment; K-WK planned the project, analyzed the data, and wrote the article.
Conflict of interest. The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Lee, HJ., Ahn, B., Shin, M. et al. Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development. Cell Death Differ 16, 1395–1407 (2009). https://doi.org/10.1038/cdd.2009.78
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DOI: https://doi.org/10.1038/cdd.2009.78
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