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Cited by 92Phagocytosis and Immune RegulationCell death mechanisms and regulationIon Channels and Receptors

An essential role for calcium flux in phagocytes for apoptotic cell engulfment and the anti-inflammatory response

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Gronski, M A, Kinchen, J M, Juncadella, I J, Franc, N C, Ravichandran, K S·2009·Cell Death & Differentiation
DOI 10.1038/cdd.2009.55PMC PMC2856475
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Abstract

Cells undergo programmed cell death/apoptosis throughout the lifespan of an organism. The subsequent immunologically silent removal of apoptotic cells plays a role in the maintenance of tolerance; defects in corpse clearance have been associated with autoimmune disease. A number of receptors and signaling molecules involved in this process have been identified, but intracellular signaling downstream of corpse recognition is only now being defined. Calcium plays a key role as a second messenger in many cell types, leading to the activation of downstream molecules and eventual transcription of effector genes; however, the role of calcium signaling during apoptotic cell removal is unclear. Here, using studies in cell lines and in the context of a whole organism, we show that apoptotic cell recognition induces both an acute and sustained calcium flux within phagocytes and that the genes required for calcium flux are essential for engulfment. Furthermore, we provide evidence that both the release of calcium from the endoplasmic reticulum and the entry of extracellular calcium through CRAC channels into the phagocytes are important during engulfment. Moreover, knockdown in Caenorhabditis elegans of stim-1 and jph-1, two genes linked to the entry of extracellular calcium into cells, led to increased persistence of apoptotic cells in the nematode. Loss of these genes seemed to affect early signaling events, leading to a decreased enrichment of actin adjacent to the apoptotic cell during corpse removal. We also show that calcium is crucial for the secretion of TGF-beta by the phagocytes during the engulfment of apoptotic cells. Taken together, these data point to an earlier unappreciated and evolutionarily conserved role for calcium flux at two distinguishable steps: the formation of the phagocytic cup and the internalization of the apoptotic cell, and the anti-inflammatory signaling induced in phagocytes by contact with apoptotic cells.

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  • After engulfing apoptotic cells, macrophages secrete anti-inflammatory cytokines such as IL-10 and TGF-β to suppress immune responses.

    “After engulfing ACs, macrophages secrete a range of anti-inflammatory cytokines, such as IL-10 and TGF-β, to suppress immune responses.24,25”

    From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [24]

    The Results (page unavailable) report that macrophages exposed to apoptotic cells secrete TGF-β, and the Introduction links this response to immunological tolerance. The paper does not identify IL-10 as one of the secreted cytokines. It also finds that recognition of apoptotic cells can induce TGF-β without physical engulfment, so engulfment is not required for the response described. (LLM, conf=0.88)

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References 41 · Cited by 92

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  1. [1]Erwig LP Henson PM Immunological consequences of apoptotic cell phagocytosis Am J Pathol 2007 171 1 2 8 17591947 PMC1941587
  2. [2]Monks J Smith-Steinhart C Kruk ER Fadok VA Henson PM Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland Biol Reprod 2008 78 4 586 594 18057312
  3. [3]Savill J Dransfield I Gregory C Haslett C A blast from the past: clearance of apoptotic cells regulates immune responses Nat Rev Immunol 2002 2 12 965 975 12461569
  4. [4]Erwig LP Henson PM Clearance of apoptotic cells by phagocytes Cell Death Differ 2008 15 2 243 250 17571081
  5. [5]Cvetanovic M Ucker DS Innate immune discrimination of apoptotic cells: repression of proinflammatory macrophage transcription is coupled directly to specific recognition J Immunol 2004 172 2 880 889 14707059
  6. [6]Lewis RS Calcium signaling mechanisms in T lymphocytes Annu Rev Immunol 2001 19 497 521 11244045
  7. [7]Watanabe N Suzuki J Kobayashi Y Role of calcium in tumor necrosis factor-alpha production by activated macrophages J Biochem 1996 120 6 1190 1195 9010769
  8. [8]Cuttell L Vaughan A Silva E Escaron CJ Lavine M Van Goethem E Undertaker, a Drosophila Junctophilin, links Draper-mediated phagocytosis and calcium homeostasis Cell 2008 135 3 524 534 18984163
  9. [9]Oh-Hora M Rao A Calcium signaling in lymphocytes Curr Opin Immunol 2008 20 3 250 258 18515054 PMC2574011
  10. [10]Feske S Calcium signalling in lymphocyte activation and disease Nat Rev Immunol 2007 7 9 690 702 17703229
  11. [11]Hynes RO Integrins: bidirectional, allosteric signaling machines Cell 2002 110 6 673 687 12297042
  12. [12]Dransfield I Cabanas C Craig A Hogg N Divalent cation regulation of the function of the leukocyte integrin LFA-1 J Cell Biol 1992 116 1 219 226 1346139 PMC2289255
  13. [13]Tosello-Trampont AC Brugnera E Ravichandran KS Evidence for a conserved role for CRKII and Rac in engulfment of apoptotic cells J Biol Chem 2001 276 17 13797 13802 11297528
  14. [14]Hajnoczky G Csordas G Das S Garcia-Perez C Saotome M Sinha RS Mitochondrial calcium signalling and cell death: approaches for assessing the role of mitochondrial Ca2+ uptake in apoptosis Cell Calcium 2006 40 5–6 553 560 17074387 PMC2692319
  15. [15]Kang HW Park JY Jeong SW Kim JA Moon HJ Perez-Reyes E A molecular determinant of nickel inhibition in Cav3.2 T-type calcium channels J Biol Chem 2006 281 8 4823 4830 16377633
  16. [16]Kimura J Miyamae S Noma A Identification of sodium-calcium exchange current in single ventricular cells of guinea-pig J Physiol 1987 384 199 222 2443659 PMC1192258
  17. [17]Yoshino T Ishikawa J Ohga K Morokata T Takezawa R Morio H YM-58483, a selective CRAC channel inhibitor, prevents antigen-induced airway eosinophilia and late phase asthmatic responses via Th2 cytokine inhibition in animal models Eur J Pharmacol 2007 560 2–3 225 233 17307161
  18. [18]Zitt C Strauss B Schwarz EC Spaeth N Rast G Hatzelmann A Potent inhibition of Ca2+ release-activated Ca2+ channels and T-lymphocyte activation by the pyrazole derivative BTP2 J Biol Chem 2004 279 13 12427 12437 14718545
  19. [19]Penna A Demuro A Yeromin AV Zhang SL Safrina O Parker I The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers Nature 2008 456 7218 116 120 18820677 PMC2597643
  20. [21]Roos J DiGregorio PJ Yeromin AV Ohlsen K Lioudyno M Zhang S STIM1, an essential and conserved component of store-operated Ca2+ channel function J Cell Biol 2005 169 3 435 445 15866891 PMC2171946
  21. [22]Liou J Kim ML Heo WD Jones JT Myers JW Ferrell JE Jr STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx Curr Biol 2005 15 13 1235 1241 16005298 PMC3186072
  22. [23]Kinchen JM Cabello J Klingele D Wong K Feichtinger R Schnabel H Two pathways converge at CED-10 to mediate actin rearrangement and corpse removal in C. elegans Nature 2005 434 7029 93 99 15744306
  23. [24]Takeshima H Komazaki S Nishi M Iino M Kangawa K Junctophilins: a novel family of junctional membrane complex proteins Mol Cell 2000 6 1 11 22 10949023
  24. [26]Kim S Elkon KB Ma X Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells Immunity 2004 21 5 643 653 15539151
  25. [27]Casella JF Flanagan MD Lin S Cytochalasin D inhibits actin polymerization and induces depolymerization of actin filaments formed during platelet shape change Nature 1981 293 5830 302 305 7196996
  26. [28]Park D Hochreiter-Hufford A Ravichandran KS The phosphatidylserine receptor TIM-4 does not mediate direct signaling Curr Biol 2009 19 4 346 351 19217291
  27. [29]Park D Tosello-Trampont AC Elliott MR Lu M Haney LB Ma Z BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module Nature 2007 450 7168 430 434 17960134
  28. [31]Park SY Jung MY Kim HJ Lee SJ Kim SY Lee BH Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor Cell Death Differ 2008 15 1 192 201 17962816
  29. [32]Gardai SJ Bratton DL Ogden CA Henson PM Recognition ligands on apoptotic cells: a perspective J Leukoc Biol 2006 79 5 896 903 16641135
  30. [33]Oh-Hora M Yamashita M Hogan PG Sharma S Lamperti E Chung W Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance Nat Immunol 2008 9 4 432 443 18327260 PMC2737533
  31. [34]Rogers TB Inesi G Wade R Lederer WJ Use of thapsigargin to study Ca2+ homeostasis in cardiac cells Biosci Rep 1995 15 5 341 349 8825036
  32. [35]Kijima Y Ogunbunmi E Fleischer S Drug action of thapsigargin on the Ca2+ pump protein of sarcoplasmic reticulum J Biol Chem 1991 266 34 22912 22918 1835973
  33. [36]Lytton J Westlin M Hanley MR Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps J Biol Chem 1991 266 26 17067 17071 1832668
  34. [37]Toyoshima C Nomura H Structural changes in the calcium pump accompanying the dissociation of calcium Nature 2002 418 6898 605 611 12167852
  35. [39]Tosello-Trampont AC Kinchen JM Brugnera E Haney LB Hengartner MO Ravichandran KS Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells Cell Death Differ 2007 14 5 963 972 17304244
  36. [40]Kamath RS Fraser AG Dong Y Poulin G Durbin R Gotta M Systematic functional analysis of the Caenorhabditis elegans genome using RNAi Nature 2003 421 6920 231 237 12529635
  37. [41]Grimsley CM Lu M Haney LB Kinchen JM Ravichandran KS Characterization of a novel interaction between ELMO1 and ERM proteins J Biol Chem 2006 281 9 5928 5937 16377631

Authors
Gronski, M. A., Kinchen, J. M., Juncadella, I. J., Franc, N. C., & Ravichandran, K. S.
Affiliations
  • University of Virginia (US)
  • Scripps Research Institute (US)
Corresponding author
Ravichandran, K S
ORCID
Venue
Cell Death & Differentiation
Publisher
Springer Science and Business Media LLC
Published
2009-05-22
Volume
16
Issue
10
Pages
1323-1331
ISSN
  • 1350-9047 (ISSN-L)
  • 1476-5403
DOI
10.1038/cdd.2009.55
PMC
PMC2856475
OpenAlex
W2001695277
Cited by
92
References
41
Citations by year
2026: 7 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 12 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 4 · 2012: 4
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cell Death and Differentiation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Arthritis Foundation
  • American Asthma Foundation
  • National Institutes of Health
  • Natural Sciences and Engineering Research Council of Canada
  • National Institute of General Medical Sciences (R01GM069998, R01GM064709)
  • National Institute of Allergy and Infectious Diseases
  • 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 › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Keywords
apoptotic cell engulfment, calcium signaling, phagocytes, endoplasmic reticulum calcium release, CRAC channels, TGF-beta secretion, anti-inflammatory response, Caenorhabditis elegans
MeSH terms
Stromal Interaction Molecule 1, ORAI1 Protein, Animals, Calcium, Cell Line, Humans, Membrane Proteins, Phagocytes, Phagocytosis, Calcium Channels, Transforming Growth Factor beta, Caenorhabditis elegans, Apoptosis, Jurkat Cells, Calcium Signaling, Caenorhabditis elegans Proteins, RNA, Small Interfering, Mice

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