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Cited by 1,473Phagocytosis and Immune RegulationCell death mechanisms and regulationBiomarkers in Disease Mechanisms

Cell-Surface Calreticulin Initiates Clearance of Viable or Apoptotic Cells through trans-Activation of LRP on the Phagocyte

Open access
Gardai, Shyra J., McPhillips, Kathleen A., Frasch, S. Courtney, Janssen, William J., Starefeldt, Anna, Murphy-Ullrich, Joanne E., Bratton, Donna L., Oldenborg, Per-Arne +2 more·2005·Cell
DOI 10.1016/j.cell.2005.08.032
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Abstract

Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

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Crossref · 10.1016/j.cell.2005.08.032

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  • 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 [866]

  • During ICD, CALR translocates from ER to outer leaflet of plasma membrane.

    “In the course of ICD, CALR translocates from the ER, where it is involved in the maintenance of Ca2+ homeostasis [877], to the outer leaflet of the plasma membrane [865, 866].”

    From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [866]

  • Detection of apoptosis using the phosphatidylserine probe Annexin V is a useful marker when paired with agents that detect loss of plasma membrane integrity.

    “Nevertheless, detection of apoptosis using the PS probe Annexin V 119 is a useful marker when paired with agents to detect loss of plasma membrane integrity.”

    From Immunogenic and tolerogenic cell death (2009) · cites this paper as [119]

  • Calreticulin is a principal ligand required for engulfment activation via binding and activating LRP on macrophages.

    “which is a principal ligand required for engulfment activation via binding and activating LDL-receptor-related protein (LRP) on macrophages [150].”

    From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [150]

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Authors
Gardai, S. J., McPhillips, K. A., Frasch, S. C., Janssen, W. J., Starefeldt, A., Murphy-Ullrich, J. E., Bratton, D. L., Oldenborg, P.-A., Michalak, M., & Henson, P. M.
Affiliations
  • National Jewish Health (US)
  • University of Colorado Health (US)
  • Umeå University (SE)
  • University of Alabama at Birmingham (US)
  • University of Alberta (CA)
Corresponding author
Henson, Peter M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2005-10
Volume
123
Issue
2
Pages
321-334
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2005.08.032
OpenAlex
W2095472825
Cited by
1,473
References
43
Citations by year
2026: 50 · 2025: 77 · 2024: 74 · 2023: 97 · 2022: 77 · 2021: 98 · 2020: 84 · 2019: 73 · 2018: 83 · 2017: 84 · 2016: 88 · 2015: 86 · 2014: 64 · 2013: 64 · 2012: 77
FWCI
15.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Public Health Service (A1058228)
  • National Heart, Lung, and Blood Institute (HL068864, R01HL068864, HL34303, R01HL079644, P01HL034303, HL079644)
  • National Institute of General Medical Sciences (GM57573-006, GM48211, R01GM057573, R01GM061031, R01GM048211, GM61031)
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 › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
calreticulin, efferocytosis, LRP, LDL receptor-related protein, CD47, SIRPα, phagocytosis, phosphatidylserine, transcriptional activation, don't eat me signal, eat-me signals, inflammation resolution
MeSH terms
Animals, Antibodies, Monoclonal, Cell Line, Embryo, Mammalian, Fibroblasts, Heterozygote, Humans, Macrophages, Models, Biological, Neutrophils, Phagocytes, Phagocytosis, Receptors, Immunologic, Transcriptional Activation, Apoptosis, Mice, Knockout, Microscopy, Video, Jurkat Cells, Calreticulin, Mice, CD47 Antigen

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