Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance

Area of Science:

• Immunology
• Cell Biology
• Biochemistry

Background:

• Efficient phagocytic clearance of apoptotic cells is essential for tissue homeostasis.
• Apoptotic cells release 'find-me' signals to recruit phagocytes, but these signals are poorly understood.
• Monocytes, macrophages, and dendritic cells are key phagocytes involved in clearing dying cells.

Purpose of the Study:

• To identify the molecular signals released by apoptotic cells that recruit phagocytes.
• To elucidate the role of these signals and their receptors in vivo apoptotic cell clearance.
• To establish the link between specific 'find-me' signals and efficient corpse removal.

Main Methods:

• Caspase-dependent release of nucleotides (ATP, UTP) from apoptotic thymocytes and cell lines was measured.
• Monocyte recruitment assays were performed using purified nucleotides and apoptotic cell supernatants.
• Nucleotide receptors (P2Y2) were studied using RNA interference and knockout mice (P2Y2-/-).
• In vivo studies utilized a murine air-pouch model and assessed apoptotic thymocyte clearance.

Main Results:

• Apoptotic cells release equimolar quantities of ATP and UTP.
• Extracellular nucleotides at these concentrations effectively recruit monocytes.
• Enzymatic removal of nucleotides or P2Y2 receptor deficiency abrogated phagocyte recruitment and apoptotic cell clearance.
• In vivo experiments confirmed the role of nucleotides and P2Y2 in monocyte/macrophage recruitment and corpse clearance.

Conclusions:

• Extracellular nucleotides (ATP and UTP) are critical 'find-me' signals released by apoptotic cells.
• The P2Y2 receptor is essential for sensing these nucleotide signals and mediating phagocyte recruitment.
• This nucleotide-P2Y2 axis plays a vital role in the in vivo clearance of apoptotic cells.