Migration to Apoptotic “Find-me” Signals Is Mediated via the Phagocyte Receptor G2A

Christoph Peter,Michaela Waibel,Caius G Radu,Li V Yang,Owen N Witte,Klaus Schulze-Osthoff,Sebastian Wesselborg,Kirsten Lauber

doi:10.1074/jbc.m706586200

Abstract

Phagocytosis of apoptotic cells is fundamentally important throughout life, because non-cleared cells become secondarily necrotic and release intracellular contents, thus instigating inflammatory and autoimmune responses. Secreted "find-me" and exposed "eat-me" signals displayed by the dying cell in concert with the phagocyte receptors comprise the phagocytic synapse of apoptotic cell clearance. In this scenario, lysophospholipids (lysoPLs) are assumed to act as find-me signals for the attraction of phagocytes. However, both the identity of the lyso-PLs released from apoptotic cells and the nature of the phagocyte receptor are largely unknown. By a detailed analysis of the structural requirements we show here that lysophosphatidylcholine (lysoPC), but none of the lysoPC metabolites or other lysoPLs, represents the essential apoptotic attraction signal able to trigger a phagocyte chemotactic response. Furthermore, using RNA interference and expression studies, we demonstrate that the G-protein-coupled receptor G2A, unlike its relative GPR4, is involved in the chemotaxis of monocytic cells. Thus, our study identifies lysoPC and G2A as the crucial receptor/ligand system for the attraction of phagocytes to apoptotic cells and the prevention of autoimmunity.

Highlights

Interactions between the dying cell and the phagocyte has evolved that are displayed at the phagocytic synapse
Caspase-3-mediated activation of calcium-independent phospholipase-A2 was shown to result in the release of the phospholipid lysoPC that is involved in the chemotactic response
We deliberately focused on oxidized fatty acids (oxFAs) tion assay with apoptotic culture supernatants (ACS) but could not detect any neutralizing because FA oxidation occurs during apoptosis [13] and chemo

Summary

Introduction

Interactions between the dying cell and the phagocyte has evolved that are displayed at the phagocytic synapse. We could demonstrate that lysoPC acts as a chemotactic find-me signal attracting the phagocyte to the apoptotic cell [4]. As the receptor for phagocyte recruitment remains unknown, it is unclear whether lysoPC represents the sole lipid find-me signal or whether additional phospholipids secreted during apoptosis are involved in chemotaxis.

Results

Conclusion