How dying cells alert the immune system to danger

Kono, Hajime; Rock, Kenneth L.

doi:10.1038/nri2215

Cited by 1,737Immune Response and InflammationCell death mechanisms and regulationPhagocytosis and Immune Regulation

How dying cells alert the immune system to danger

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Kono, Hajime, Rock, Kenneth L.·2008·Nature Reviews Immunology

DOI 10.1038/nri2215PMC PMC2763408

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Abstract

When a cell dies in vivo, the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes - that is, it is part of normal physiological processes - then there is little threat to the organism. In this situation, little else is done other than to remove the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized in the host. The importance of these processes to host defence and disease pathogenesis has only been appreciated relatively recently. This article reviews our current knowledge of these processes.

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DNA released from damaged cells can trigger sterile inflammation via TLR9.
“Therefore, DNA released from damaged cells can also trigger sterile inflammation via TLR9,315 making TLR9 an important sensor in neurodegeneration.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [315]
The paper’s table of intracellular DAMPs (indexed as Abstract; page unavailable) lists chromatin/nucleosomes/DNA as proinflammatory and TLR9 as a potential receptor, but specifies involvement with a B-cell or Fc receptor. The “Genomic dsDNA” passage (also indexed as Abstract) says mammalian DNA can stimulate immune cells, while noting that its activity was not entirely due to TLR9. Thus the paper supports a possible link, not the unqualified claim that DNA from damaged cells triggers sterile inflammation via TLR9; the citation precedes the separate neurodegeneration inference. (LLM, conf=0.86)
Experimental — accuracy not yet measured
The consequence of PRR-DAMP binding is sterile inflammation.
“The consequence of PRR-DAMP binding is sterile inflammation (Kono and Rock, 2008;Rock et al, 2010).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Kono and Rock, 2008
DAMPs have been identified by their ability to induce inflammatory responses in vitro and/or in vivo when purified and by the observed reduction in inflammation when they are selectively depleted.
“DAMPs have been identified by their ability to induce inflammatory responses in vitro and/orin vivo when purified and by the observed reduction in inflammation when they are selectively depleted17.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [17]
Several endogenous molecules released from necrotic cells or present in the extracellular matrix have been reported to activate TLRs.
“Indeed, several endogenous molecules that are released from necrotic cells or are present in the extracellular matrix have been reported to activate TLRs.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [17]

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Exploring the full spectrum of macrophage activation
Mosser, D. M., & Edwards, J. P. (2008) · Nature Reviews Immunology · doi:10.1038/nri2448 · Cited by 9,144 · see citing works
Sterile inflammation: sensing and reacting to damage
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Phosphorylation-Driven Assembly of the RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation
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STING-Dependent Cytosolic DNA Sensing Mediates Innate Immune Recognition of Immunogenic Tumors
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Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance
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Immune responses to implants – a review of the implications for the design of immunomodulatory biomaterials
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
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Mitochondria and the Autophagy–Inflammation–Cell Death Axis in Organismal Aging
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Intravascular Danger Signals Guide Neutrophils to Sites of Sterile Inflammation
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Astrocyte barriers to neurotoxic inflammation
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Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells
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Phagocyte partnership during the onset and resolution of inflammation
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Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis
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Towards an understanding of the adjuvant action of aluminium
Marrack, P., McKee, A. S., & Munks, M. W. (2009) · Nature Reviews Immunology · doi:10.1038/nri2510 · Cited by 887 · see citing works
The Sterile Inflammatory Response
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Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury
Lai, Y., Di Nardo, A., Nakatsuji, T., Leichtle, A., Yang, Y., Cogen, A. L., Wu, Z.-R., Hooper, L. V., Schmidt, R. R., von Aulock, S., et al. (2009) · Nature Medicine · doi:10.1038/nm.2062 · Cited by 781 · see citing works
Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome
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Para-Inflammation in the Aging Retina
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Sterile inflammation in the liver
Kubes, P., & Mehal, W. Z. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.09.008 · Cited by 666 · see citing works
Immunology of Wound Healing
Ellis, S., Lin, E. J., & Tartar, D. (2018) · Current Dermatology Reports · doi:10.1007/s13671-018-0234-9 · Cited by 625 · see citing works
An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells
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A Reservoir of Mature Cavity Macrophages that Can Rapidly Invade Visceral Organs to Affect Tissue Repair
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Triggering the succinate receptor GPR91 on dendritic cells enhances immunity
Rubic, T., Lametschwandtner, G., Jost, S., Hinteregger, S., Kund, J., Carballido-Perrig, N., Schwärzler, C., Junt, T., Voshol, H., Meingassner, J. G., et al. (2008) · Nature Immunology · doi:10.1038/ni.1657 · Cited by 525 · see citing works
Dying cells actively regulate adaptive immune responses
Yatim, N., Cullen, S., & Albert, M. L. (2017) · Nature Reviews Immunology · doi:10.1038/nri.2017.9 · Cited by 442 · see citing works
STING: a master regulator in the cancer-immunity cycle
Zhu, Y., An, X., Zhang, X., Qiao, Y., Zheng, T., & Li, X. (2019) · Molecular Cancer · doi:10.1186/s12943-019-1087-y · Cited by 431 · see citing works
Neuromodulation by the immune system: a focus on cytokines
Salvador, A. F., de Lima, K. A., & Kipnis, J. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00508-z · Cited by 389 · see citing works
Die another way – non-apoptotic mechanisms of cell death
Tait, S. W. G., Ichim, G., & Green, D. R. (2014) · Journal of Cell Science · doi:10.1242/jcs.093575 · Cited by 366 · see citing works
Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases
Belizário, J. E., Faintuch, J., & Garay-Malpartida, M. (2018) · Mediators of Inflammation · doi:10.1155/2018/2037838 · Cited by 341 · see citing works
Metal Drugs and the Anticancer Immune Response
Englinger, B., Pirker, C., Heffeter, P., Terenzi, A., Kowol, C. R., Keppler, B. K., & Berger, W. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00396 · Cited by 355 · see citing works
Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity
Andrés, C. M. C., Pérez de la Lastra, J. M., Andrés Juan, C., Plou, F. J., & Pérez-Lebeña, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031841 · Cited by 342 · see citing works
Uric acid promotes an acute inflammatory response to sterile cell death in mice
Kono, H., Chen, C.-J., Ontiveros, F., & Rock, K. L. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40124 · Cited by 337 · see citing works
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Improved implant osseointegration of a nanostructured titanium surface via mediation of macrophage polarization
Ma, Q.-L., Zhao, L.-Z., Liu, R.-R., Jin, B.-Q., Song, W., Wang, Y., Zhang, Y.-S., Chen, L.-H., & Zhang, Y.-M. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.08.025 · Cited by 319 · see citing works
Ferroptosis: bug or feature?
Dixon, S. J. (2017) · Immunological Reviews · doi:10.1111/imr.12533 · Cited by 314 · see citing works
The clearance of dying cells: table for two
Green, D. R., Oguin, T. H., & Martinez, J. (2016) · Cell Death & Differentiation · doi:10.1038/cdd.2015.172 · Cited by 314 · see citing works
Efferocytosis Is an Innate Antibacterial Mechanism
Martin, C. J., Booty, M. G., Rosebrock, T. R., Nunes-Alves, C., Desjardins, D. M., Keren, I., Fortune, S. M., Remold, H. G., & Behar, S. M. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.06.010 · Cited by 285 · see citing works
Heme oxygenase-1: from biology to therapeutic potential
Soares, M. P., & Bach, F. H. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2008.12.004 · Cited by 257 · see citing works
Danger-associated molecular patterns in Alzheimer’s disease
Venegas, C., & Heneka, M. T. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.3mr0416-204r · Cited by 236 · see citing works
Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming
Frank, M. G., Weber, M. D., Watkins, L. R., & Maier, S. F. (2015) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.03.010 · Cited by 237 · see citing works
Microglia and mast cells: two tracks on the road to neuroinflammation
Skaper, S. D., Giusti, P., & Facci, L. (2012) · The FASEB Journal · doi:10.1096/fj.11-197194 · Cited by 235 · see citing works
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Authors: Kono, H., & Rock, K. L.
Affiliations: University of Massachusetts Chan Medical School (US)
ORCID: Kono, Hajime
Rock, Kenneth L.
Venue: Nature Reviews Immunology
Publisher: Springer Science and Business Media LLC
Published: 2008-03-14
Volume: 8
Issue: 4
Pages: 279-289
ISSN: 1474-1733 (ISSN-L)
1474-1741
DOI: 10.1038/nri2215
PMC: PMC2763408
OpenAlex: W2055132644
Cited by: 1,737
References: 127
Citations by year: 2026: 51 · 2025: 55 · 2024: 74 · 2023: 68 · 2022: 81 · 2021: 81 · 2020: 84 · 2019: 82 · 2018: 109 · 2017: 115 · 2016: 117 · 2015: 129 · 2014: 135 · 2013: 120 · 2012: 140
FWCI: 7.27
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature reviews. Immunology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
Funders: Kanae Foundation for the Promotion of Medical Science
National Institutes of Health
National Institute of Allergy and Infectious Diseases (P01AI057784, R01AI043543)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords: cell death, damage-associated molecular patterns, innate immunity, inflammation, tissue repair, host defense, pathogenesis
MeSH terms: Animals, Humans, Infections, Lymphocyte Activation, Cell Death

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