Tethering of Apoptotic Cells to Phagocytes through Binding of CD47 to Src Homology 2 Domain-Bearing Protein Tyrosine Phosphatase Substrate-1
Abstract
Apoptotic cells are swiftly phagocytosed by macrophages and immature dendritic cells. In this study, we found that one mouse macrophage cell line (BAM3) engulfed apoptotic thymocytes, but not a lymphoma cell line (WR19L). mAbs that inhibited the phagocytosis of apoptotic thymocytes by BAM3 were identified. Purification of the Ag revealed that it was Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1 (SHPS-1). CD47, the ligand for SHPS-1, was expressed in mouse thymocytes, but not in WR19L. When WR19L was transformed with CD47, the transformants, after induction of apoptosis, could be phagocytosed by BAM3. The WR19L transformants expressing CD47 were more efficiently engulfed in vivo by splenic dendritic cells than the parental WR19L. Masking of the phosphatidylserine exposed on apoptotic thymocytes inhibited the engulfment, whereas the anti-SHPS-1 mAb inhibited not only the engulfment, but also the binding of apoptotic cells to phagocytes. These results indicate that macrophages require CD47 and phosphatidylserine on apoptotic cells for engulfment, and suggest that the interaction between CD47 and SHPS-1 works as a tethering step in the phagocytosis.
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CD47 is required for efficient phagocytic uptake of some murine cell lines undergoing RCD.
“That said, CD47 appears to be required for the efficient phagocytic uptake of some murine cell lines undergoing RCD [892, 893].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [892]
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Larsson, A. O., Hult, A., Nilsson, A. K., Olsson, M., & Oldenborg, P. (2016) · Transfusion · doi:10.1111/trf.13612 · Cited by 34 · see citing works
“Volume 56, July 2016 TRANSFUSION 1841 The function of CD47 as a marker of self in regulating uptake of viable host cells by macrophages and DCs is well established.25,26 This function of CD47, to inhibit phagocytosis by interacting with phagocyte SIRPa, is lost on apoptotic WBCs.30,48,49 However, recent data suggest t…”
BackgroundTarget cell CD47 regulates macrophage activation and erythrophagocytosis
Olsson, M., Nilsson, A., & Oldenborg, P. (2006) · Transfusion Clinique et Biologique · doi:10.1016/j.tracli.2006.02.013 · Cited by 33 · see citing works
SIRP-α-CD47 system functions as an intercellular signal in the renal glomerulus
Kurihara, H., Harita, Y., Ichimura, K., Hattori, S., & Sakai, T. (2010) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00571.2009 · Cited by 33 · see citing works
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“In many organs, apoptotic cells are phagocytized by macrophages in a non-immunogenic manner (Tada et al., 2003).”
Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis
Gregory, C. D. (2023) · Immunological Reviews · doi:10.1111/imr.13259 · Cited by 28 · see citing works
“15,88,96 Paradoxically, CD47 also seems able to act as a tethering receptor in efferocytosis 97 ; this is potentially due to apoptosis-induced qualitative changes in its structure or topology that may include acquisition of capacity to bind THSP1.”
BackgroundThe CD47 pathway is deregulated in human immune thrombocytopenia
Catani, L., Sollazzo, D., Ricci, F., Polverelli, N., Palandri, F., Baccarani, M., Vianelli, N., & Lemoli, R. M. (2011) · Experimental Hematology · doi:10.1016/j.exphem.2010.12.011 · Cited by 27 · see citing works
Osada, Y., Shiratsuchi, A., & Nakanishi, Y. (2006) · Experimental Cell Research · doi:10.1016/j.yexcr.2006.02.010 · Cited by 27 · see citing works
Van, V. Q., Baba, N., Rubio, M., Wakahara, K., Panzini, B., Richard, C. S., Soucy, G., Franchimont, D. P., Fortin, G., Martínez‐Torres, A. C., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041972 · Cited by 26 · see citing works
“redistribution on apoptotic cells also appear to augment phagocytosis [28,53].”
BackgroundOldenborg, P. (2012) · Transfusion Medicine and Hemotherapy · doi:10.1159/000342537 · Cited by 24 · see citing works
Expression and Role of TRIM2 in Human Diseases
Xiao, M., Li, J., Liu, Q., He, X., Yang, Z., & Wang, D. (2022) · BioMed Research International · doi:10.1155/2022/9430509 · Cited by 23 · see citing works
“…phagocytosis by incubating bone marrow-derived macrophages (BMDMs) isolated from TRIM2 knockout and wild-type mice with phrodo Red-labeled apoptotic thymocytes and found that loss of TRIM2 led to increased macrophage engulfment of apoptotic cells, a process known to be regulated by SIRPA [35, 36].”
Antigen Handling and Presentation by Mucosal Dendritic Cells and Macrophages
Kelsall, B. L., Leon, F., Smythies, L. E., & Smith, P. D. (2005) · Elsevier eBooks · doi:10.1016/b978-012491543-5/50030-9 · Cited by 17 · see citing works
Prion pathogenesis is unaltered in the absence of SIRPα-mediated "don't-eat-me" signaling
Nuvolone, M., Paolucci, M., Sorce, S., Kana, V., Moos, R., Matozaki, T., & Aguzzi, A. (2017) · PLOS ONE · doi:10.1371/journal.pone.0177876 · Cited by 13 · see citing works
“Binding of CD47 to SIRPα mediates tethering of apoptotic cells to phagocytes [21,22].”
Decreases in CD31 and CD47 Levels on the Cell Surface during Etoposide-Induced Jurkat Cell Apoptosis
Azuma, Y., Nakagawa, H., Dote, K., Higai, K., & Matsumoto, K. (2011) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.34.1828 · Cited by 13 · see citing works
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Ikeda, H., Okazawa, H., Ohnishi, H., Murata, Y., Oldenborg, P., & Matozaki, T. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.5.3123 · Cited by 12 · see citing works
“We also examined the effects of various mAbs to mouse SHPS-1 (p84, 15D9, or FG2) on Fc R-mediated phagocytosis of RBCs by RAW264.”
BackgroundMethodInfluentialde Almeida, A. C., Barbosa, S. M., Barjas‐Castro, M. L., Olalla-Saad, S. T., & Condino‐Neto, A. (2012) · Immunopharmacology and Immunotoxicology · doi:10.3109/08923973.2012.697470 · Cited by 11 · see citing works
“From evidence showing that the CD47–SIRP-α interaction can also promote phagocytosis of apoptotic cells,((39,40)) the authors showed that after the conformational change, TSP-1 binds to CD47 and creates a new binding site for SIRP-α, which recognizes CD47 as an “eat me” signal instead of a “don’t eat me” signal.”
BackgroundCD47 functions as a removal marker on aged erythrocytes
van Bruggen, R. (2013) · ISBT Science Series · doi:10.1111/voxs.12038 · Cited by 10 · see citing works
Denervation Enhances the Expression of SHPS-1 in Rat Skeletal Muscle
Mitsuhashi, H. (2005) · The Journal of Biochemistry · doi:10.1093/jb/mvi058 · Cited by 6 · see citing works
Eryptosis (quasi-apoptosis) the human red blood cells. Its role in medicinal therapy
Vaschenko, V. I., & Николаевич, В. В. (2019) · Reviews on Clinical Pharmacology and Drug Therapy · doi:10.17816/rcf1735-38 · Cited by 6 · see citing works
“Профагоцитозная сигнализация во время фагоцитоза, опосредованного ре- цептором FcyR, или фагоцитоза oпсонизированных эритроцитов опосредованного рецептором CR уравновешиваются блокирующим сигналом посредством CD47-SIRP-взаимодействия, следовательно, суммарное взаимодействие этих сигналов детерминирует интенсивность фа…”
InfluentialBlinova, G. A., Yarygin, K. N., & Kholodenko, I. V. (2024) · Biomedical Chemistry Research and Methods · doi:10.18097/bmcrm00221 · Cited by 5 · see citing works
Molecules Involved in Recognition and Clearance of Apoptotic/Necrotic Cells and Cell Debris
Napirei, M., & Mannherz, H. G. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9293-0_4 · Cited by 5 · see citing works
Apoptotic cell clearance by phagocytes
Tanaka, M. (2005) · International Congress Series · doi:10.1016/j.ics.2005.07.080 · Cited by 4 · see citing works
Self-citationAutoimmune Diseases and the Role of MFG-E8
Hanayama, R. (2014) · Springer eBooks · doi:10.1007/978-94-017-8765-9_6 · Cited by 2 · see citing works
Self-citationFadeel, B. (2005) · Springer eBooks · doi:10.1007/1-4020-3302-8_3 · Cited by 2 · see citing works
Apoptotic Cell Clearance by Macrophages: Relevance to Tumor Pathogenesis
Debatin, K., & Fulda, P. D. S. (2006) · doi:10.1002/9783527619665.ch25 · Cited by 2 · see citing works
Lauber, K., & Wesselborg, S. (2006) · Wiley eBooks · doi:10.1002/9783527619665.ch24
Mechanisms involved in macrophage phagocytosis of apoptotic cells
Nilsson, A. K. (2009) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Hindi, Z., Gad, A., Jarvis, C., Zahoor, T. A., Spellman, C., & Filleur, S. (2019) · Medical science monitor basic research/Medical science monitor. Basic research · doi:10.12659/msmbr.912946
“, revealed that apoptotic cells are engulfed by macrophages via CD 47/ SIRP-a interaction, which is mediated by phosphatidylserine [19].”
BackgroundKyewski, B. (2009) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.1158208.605087
If Plan A Does Not Work: The CD47 Ectodomain as a Target for Immune Tolerance
Montero, E., & Isenberg, J. S. (2025) · Cells · doi:10.3390/cells15010071
“Again, removing the CD47 ECD on murine lymphoma cells rendered them protected from phagocytosis, while replacing the CD47 ECD on the cells led to their engulfment [146].”
SIRPA suppresses integrin-dependent virus endocytosisPreprint
Yan, Z., Iyer, K. R., Li, M., Jung, K., Hu, C. T., Ansin, N., Sarute, N., Gowen, B. B., & Ross, S. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.17.719277
- Authors
- Tada, K., Tanaka, M., Hanayama, R., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S.
- Affiliations
- The University of Osaka (JP)
- RIKEN (JP)
- Japan Science and Technology Agency (JP)
- Kirin (Japan) (JP)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-12-01
- Volume
- 171
- Issue
- 11
- Pages
- 5718-5726
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1874248542
- Cited by
- 70
- References
- 52
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 7
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- 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 › Cell Biology › Cellular transport and secretion
- Keywords
- phagocytosis of apoptotic cells, CD47, SIRPα, SH2D1A, macrophages, dendritic cells, phosphatidylserine exposure
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigens, Differentiation, Carrier Proteins, Cell Line, Cricetulus, Female, Cricetinae, Humans, Macrophages, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Phagocytes, Phagocytosis, Phosphatidylserines, Protein Binding, Receptors, Immunologic, Substrate Specificity, Antigens, CD, Protein Tyrosine Phosphatases, Apoptosis, src Homology Domains, Neural Cell Adhesion Molecule L1, NIH 3T3 Cells, Cell Line, Tumor, Mice, CD47 Antigen
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