Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
Open accessAbstract
Phagocytic removal of apoptotic cells occurs efficiently in vivo such that even in tissues with significant apoptosis, very few apoptotic cells are detectable. This is thought to be due to the release of 'find-me' signals by apoptotic cells that recruit motile phagocytes such as monocytes, macrophages and dendritic cells, leading to the prompt clearance of the dying cells. However, the identity and in vivo relevance of such find-me signals are not well understood. Here, through several lines of evidence, we identify extracellular nucleotides as a critical apoptotic cell find-me signal. We demonstrate the caspase-dependent release of ATP and UTP (in equimolar quantities) during the early stages of apoptosis by primary thymocytes and cell lines. Purified nucleotides at these concentrations were sufficient to induce monocyte recruitment comparable to that of apoptotic cell supernatants. Enzymatic removal of ATP and UTP (by apyrase or the expression of ectopic CD39) abrogated the ability of apoptotic cell supernatants to recruit monocytes in vitro and in vivo. We then identified the ATP/UTP receptor P2Y(2) as a critical sensor of nucleotides released by apoptotic cells using RNA interference-mediated depletion studies in monocytes, and macrophages from P2Y(2)-null mice. The relevance of nucleotides in apoptotic cell clearance in vivo was revealed by two approaches. First, in a murine air-pouch model, apoptotic cell supernatants induced a threefold greater recruitment of monocytes and macrophages than supernatants from healthy cells did; this recruitment was abolished by depletion of nucleotides and was significantly decreased in P2Y(2)(-/-) (also known as P2ry2(-/-)) mice. Second, clearance of apoptotic thymocytes was significantly impaired by either depletion of nucleotides or interference with P2Y receptor function (by pharmacological inhibition or in P2Y(2)(-/-) mice). These results identify nucleotides as a critical find-me cue released by apoptotic cells to promote P2Y(2)-dependent recruitment of phagocytes, and provide evidence for a clear relationship between a find-me signal and efficient corpse clearance in vivo.
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Since the release of ATP from apoptotic cells functions as a specific find me message for phagocytic cells, ATP release during osteocyte apoptosis might be a specific find me signal directed to neighboring osteocytes.
“Since the release of ATP from apoptotic cells functions as a specific “find me” message for phagocytic cells,69 ATP release during osteocyte apoptosis might be a specific “find me” signal directed to neighboring osteocytes.”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [69]
Six DAMPs have been mechanistically linked to perception of RCD as immunogenic: CALR, ATP, HMGB1, type I IFN, cancer cell-derived nucleic acids, and ANXA1.
“So far, six DAMPs have been mechanistically linked to the perception of RCD as immunogenic: (1) calreticulin (CALR) [865, 866], (2) ATP [867–869], (3) high-mobility group box 1 (HMGB1) [870–872], (4) type I IFN [854, 873, 874], (5) cancer cell-derived nucleic acids [864, 875], and (6) annexin A1 (ANXA1) [876].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [868]
Extracellular ATP binds purinergic P2 receptors on several cell types including macrophages and promotes chemotaxis and phagocytosis.
“Extracellular ATP binds to purinergic P2 receptors that are present on several cell types, including macrophages, and promotes chemotaxis and phagocytosis206.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [206]
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“The function of ATP is to recruit monocytes and macrophages to the dying tumor cells and stimulate secretion of IL-1β, a key cytokine to polarize interferon-gamma-producing CD8+ T cells [38].”
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Adenosine receptor neurobiology: overview
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- Authors
- Elliott, M. R., Chekeni, F. B., Trampont, P. C., Lazarowski, E. R., Kadl, A., Walk, S. F., Park, D., Woodson, R. I., Ostankovich, M., Sharma, P., Lysiak, J. J., Harden, T. K., Leitinger, N., & Ravichandran, K. S.
- Affiliations
- University of Virginia (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Ravichandran, Kodi S.
- ORCID
- Venue
- Nature
- Published
- 2009-09
- Volume
- 461
- Issue
- 7261
- Pages
- 282-286
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2851546
- OpenAlex
- W1965130745
- Cited by
- 1,654
- References
- 31
- Citations by year
- 2026: 81 · 2025: 100 · 2024: 100 · 2023: 123 · 2022: 125 · 2021: 120 · 2020: 102 · 2019: 105 · 2018: 95 · 2017: 98 · 2016: 91 · 2015: 72 · 2014: 106 · 2013: 89 · 2012: 92
- FWCI
- 35.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Virginia
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM069998, R01GM064709)
- National Institute of Allergy and Infectious Diseases (T32AI055432)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK067629)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- efferocytosis, find-me signals, extracellular nucleotides, ATP, UTP, P2Y2 receptor, monocyte recruitment, phagocytes, CD39, purinergic signaling, thymocytes, macrophages, monocytes, dendritic cells, tissue homeostasis, autoimmunity
- MeSH terms
- Adenosine Triphosphate, Animals, Cell Line, Cells, Cultured, Chemotactic Factors, Chemotaxis, Humans, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Monocytes, Phagocytes, Phagocytosis, Thymus Gland, Uridine Triphosphate, Signal Transduction, Culture Media, Conditioned, Apoptosis, Receptors, Purinergic P2, Jurkat Cells, Mice, Receptors, Purinergic P2Y2, Purinergic P2 Receptor Antagonists
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