PUBLICATION

Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing

Authors
Garg, A.D., Vandenberk, L., Fang, S., Fasche, T., Van Eygen, S., Maes, J., Van Woensel, M., Koks, C., Vanthillo, N., Graf, N., de Witte, P., Van Gool, S., Salven, P., Agostinis, P.
ID
ZDB-PUB-170227-6
Date
2017
Source
Cell death and differentiation   24: 832-843 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cell Line, Tumor
  • Chemokine CCL2/genetics*
  • Chemokine CCL2/immunology
  • Chemokine CXCL1/genetics*
  • Chemokine CXCL1/immunology
  • Chemokine CXCL10/genetics*
  • Chemokine CXCL10/immunology
  • Chemokines, CC/genetics*
  • Chemokines, CC/immunology
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Epithelial Cells/immunology
  • Epithelial Cells/pathology
  • Female
  • Gene Expression Regulation/immunology
  • Humans
  • Male
  • Melanocytes/immunology
  • Melanocytes/pathology
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Differentiation Factor 88/genetics
  • Myeloid Differentiation Factor 88/immunology
  • Neuroglia/immunology
  • Neuroglia/pathology
  • Neutrophils/cytology
  • Neutrophils/immunology*
  • Signal Transduction
  • Toll-Like Receptor 7/genetics
  • Toll-Like Receptor 7/immunology
  • Zebrafish
(all 34)
PubMed
28234357 Full text @ Cell Death Differ.
Abstract
Innate immune sensing of dying cells is modulated by several signals. Inflammatory chemokines-guided early recruitment, and pathogen-associated molecular patterns-triggered activation, of major anti-pathogenic innate immune cells like neutrophils distinguishes pathogen-infected stressed/dying cells from sterile dying cells. However, whether certain sterile dying cells stimulate innate immunity by partially mimicking pathogen response-like recruitment/activation of neutrophils remains poorly understood. We reveal that sterile immunogenic dying cancer cells trigger (a cell autonomous) pathogen response-like chemokine (PARC) signature, hallmarked by co-release of CXCL1, CCL2 and CXCL10 (similar to cells infected with bacteria or viruses). This PARC signature recruits preferentially neutrophils as first innate immune responders in vivo (in a cross-species, evolutionarily conserved manner; in mice and zebrafish). Furthermore, key danger signals emanating from these dying cells, that is, surface calreticulin, ATP and nucleic acids stimulate phagocytosis, purinergic receptors and toll-like receptors (TLR) i.e. TLR7/8/9-MyD88 signaling on neutrophil level, respectively. Engagement of purinergic receptors and TLR7/8/9-MyD88 signaling evokes neutrophil activation, which culminates into H2O2 and NO-driven respiratory burst-mediated killing of viable residual cancer cells. Thus sterile immunogenic dying cells perform 'altered-self mimicry' in certain contexts to exploit neutrophils for phagocytic targeting of dead/dying cancer cells and cytotoxic targeting of residual cancer cells.
Genes / Markers
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Expression
Phenotype
No data available
Mutations / Transgenics
Human Disease / Model
No data available
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Marker Marker Type Name
GAL4EFGGAL4
GFPEFGGFP
mCherryEFGmCherry
NTREFGNTR
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Citation
Garg, A.D., Vandenberk, L., Fang, S., Fasche, T., Van Eygen, S., Maes, J., Van Woensel, M., Koks, C., Vanthillo, N., Graf, N., de Witte, P., Van Gool, S., Salven, P., Agostinis, P. (2017) Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing. Cell death and differentiation. 24:832-843.