Migration to apoptotic "find-me" signals is mediated via the phagocyte receptor G2A.
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.
Peter
Christoph
C
Department of Internal Medicine I, University of Tuebingen, 72076 Tuebingen, Germany.
Waibel
Michaela
M
Radu
Caius G
CG
Yang
Li V
LV
Witte
Owen N
ON
Schulze-Osthoff
Klaus
K
Wesselborg
Sebastian
S
Lauber
Kirsten
K
D017209:Apoptosis / Q000502:physiology*; D015551:Autoimmunity / Q000502:physiology; D018797:Cell Cycle Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D002633:Chemotaxis / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D009336:Necrosis / Q000276:immunology / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D020298:U937 Cells
D018797:Cell Cycle Proteins; C115270:G2A receptor; C091670:GPR4 protein, human; D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled