Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
Michael R. Elliott, et al. Nature. 461, 282-287 (2009)
Speaker: Chia-Yun Wu (吳佳芸) Time: 13:10~14:00, Nov. 18, 2009
Commentator: Dr. Chiou-Feng Lin (林秋烽博士) Place: Room 601
Abstract:
Most development thymocytes undergo apoptosis, however only a small percentage of cells can be detected as apoptotic cells in the steady state 1. There seems to be that apoptotic thymocytes release “find-me” signals to recruit phagocytes to promote the clearance of apoptotic cells. Nevertheless, the identity and in vivo relevance of the “find-me” signals are not well understood. In the study, the authors showed that the apoptotic supernatants from thymocytes under Fas-induced apoptosis were able to attract THP-1 monocytes. Using murine air-pouch model, thay also found that the apoptotic supernatants could attract phagocytes. Some studies suggested extracellular nucleotides as possible find-me signals. Treating the apoptotic supernatants with apyrase, which is an enzyme that hydrolyses ATP to ADP and AMP, abrogated the chemotaxis. Among the natural extracellular nucleotides, only triphosphate nucleotides were strong chemoattractants for THP-1 monocytes. Previous studies showed that leukocyte migration towards nucleotides was dependent on members of the P2Y family of G-protein-coupled receptors2. To examine the role of the P2Y receptor on monocyte migration, treating THP-1 monocytes with suramin, a non-selective inhibitor of P2Y family members induced a does-dependent inhibition of migration toward apoptotic supernatants. Varies members of P2Y family had been identified; include P2Y2, P2Y4 and P2Y6receptors. Among them, the
P2Y2 receptors had high affinity for ATP and UTP2. siRNA-mediated knockdown of the P2Y2 in THP-1 monocytes inhibited migration toward apoptotic supernatants. The apoptotic supernatants injected into the air-pouch of P2Y2-deficient mice strongly reduced the recruitment of phagocytes. Furthermore, destruction of the nucleotides by apyrase seemed to affect the phagocyte recruitment and delay the clearance in a model of dexamethasone induced apoptosis. At the same time, the P2Y-/- mice significantly impairs the clearance of apoptotic thymocytes. In summary, nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance.
References:
1. Henson, P. M. & Hume, D. A. Apoptotic cell removal in development and tissue homeostasis. Trends Immunol. 27, 244–250 (2006).
2. Burnstock, G. & Knight, G. E. Cellular distribution and functions of P2 receptor subtypes in different systems. Int. Rev. Cytol. 240, 31–304 (2004).