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.
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Acknowledgements
We would like to acknowledge Dr. Michael Dewaele and Dr. Tom Verfaillie (KU Leuven) for technical help; Dr. Shinjini Mukherjee (KU Leuven) for help with NMDS analysis. ADG is a recipient of European Molecular Biology Organization (EMBO) Short-term Fellowship (2012–2013); and FWO Postdoctoral Fellowship (2013–2016/2016–2019) from FWO-Vlaanderen, Belgium. MVW is supported by SBO grant (IWT-Flanders); NV is supported by FWO PhD Fellowship. This work is supported by grants from Olivia Hendrickx Research Fund to SVG, Academy of Finland and Sigrid Juselius Foundation to PS, and FWO (G0584.12N, K202313N and GA01111N), KU Leuven (C16/15/073) and Belgian State (IAP7/32) to PA.
Author contributions
ADG, LV, SF, TF performed the main experiments. SVG, JM, MVW, CK, NV provided supplementary experimental/technical support. ADG, SF, PS, PA designed the project/experiments. NG, PDW, SVG, PS provided technical/instrumental support and critically reviewed the manuscript. ADG wrote the manuscript and made the figures. PA critically revised and corrected the manuscript. PA, PDW, PS provided senior supervision/guidance.
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Garg, A., Vandenberk, L., Fang, S. et al. Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing. Cell Death Differ 24, 832–843 (2017). https://doi.org/10.1038/cdd.2017.15
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DOI: https://doi.org/10.1038/cdd.2017.15
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