Migration to Apoptotic “Find-me” Signals Is Mediated via the Phagocyte Receptor G2A
Open accessAbstract
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.
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Potential immunogenic signals from dying cells include surface-exposed proteins such as calreticulin and heat shock proteins, lipid moieties such as phosphatidylserine that flip to the outer leaflet, released proteins such as HMGB1, and extracellular nucleic acids and their degradation products (oligonucleotides, nucleotides, nucleosides, urate).
“Potential immunogenic signals emanating from dying cells include proteins that appear at the surface of stressed and dying cells (such as calreticulin and heat shock proteins, HSPs), lipid moieties that flip from the inner plasma membrane leaflet to the outer leaflet (such as phosphatidylserine) 38,60, proteins that are released into the supernatant of cells (such as HMGB1) 51, as well as nucleic”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [43]
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- Authors
- Peter, C., Waibel, M., Radu, C. G., Yang, L. V., Witte, O. N., Schulze-Osthoff, K., Wesselborg, S., & Lauber, K.
- Affiliations
- University of Tübingen (DE)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Wesselborg, Sebastian
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 283
- Issue
- 9
- Pages
- 5296-5305
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2088466646
- Cited by
- 258
- References
- 32
- Citations by year
- 2026: 7 · 2025: 19 · 2024: 14 · 2023: 11 · 2022: 9 · 2021: 20 · 2020: 16 · 2019: 9 · 2018: 13 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 10 · 2013: 14 · 2012: 12
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft (GRK 1302, SFB 685)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Keywords
- efferocytosis, find-me signals, GPR4, lysophosphatidylcholine, lysophospholipids, phagocytosis, monocytic cells, autoimmunity, secondary necrosis
- MeSH terms
- Chemotaxis, Humans, Inflammation, Lysophospholipids, Monocytes, Necrosis, Phagocytosis, Signal Transduction, Autoimmunity, Apoptosis, Cell Cycle Proteins, U937 Cells, RNA Interference, Receptors, G-Protein-Coupled
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