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Innate immune sensing of cell death in disease and therapeutics

Nature Cell Biology volume 26, pages 1420–1433 (2024)Cite this article

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Abstract

Innate immunity, cell death and inflammation underpin many aspects of health and disease. Upon sensing pathogens, pathogen-associated molecular patterns or damage-associated molecular patterns, the innate immune system activates lytic, inflammatory cell death, such as pyroptosis and PANoptosis. These genetically defined, regulated cell death pathways not only contribute to the host defence against infectious disease, but also promote pathological manifestations leading to cancer and inflammatory diseases. Our understanding of the underlying mechanisms has grown rapidly in recent years. However, how dying cells, cell corpses and their liberated cytokines, chemokines and inflammatory signalling molecules are further sensed by innate immune cells, and their contribution to further amplify inflammation, trigger antigen presentation and activate adaptive immunity, is less clear. Here, we discuss how pattern-recognition and PANoptosome sensors in innate immune cells recognize and respond to cell-death signatures. We also highlight molecular targets of the innate immune response for potential therapeutic development.

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Fig. 1: Dying or dead cells release PAMPs, DAMPs and cytokines that contribute to innate immunity and disease pathogenesis.
Fig. 2: Necrotic cells release DAMPs that activate TLRs and inflammasomes.
Fig. 3: PAMPs, DAMPs and cytokines activate PANoptosomes.
Fig. 4: Necrotic cells release DAMPs that activate CLRs.
Fig. 5: Necrotic cells release DAMPs that activate the cytosolic DNA-sensing and RNA-sensing pathways.

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Acknowledgements

We acknowledge our colleagues whose work contributed to the advancement of immune sensing of cell death, and we apologize to those whose work could not be comprehensively cited due to space constraints. Research studies in our laboratories are supported by the US National Institutes of Health (grants AI101935, AI124346, AI160179, AR056296 and CA253095 to T.-D.K.) and the American Lebanese Syrian Associated Charities (T.-D.K.), and the National Health and Medical Research Council of Australia (Ideas Grant APP2002686 and Investigator Grant 2026910 to S.M.M.) and the CSL Centenary Fellowship (S.M.M.).

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  1. Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

    Si Ming Man

  2. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Thirumala-Devi Kanneganti

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S.M.M. and T.-D.K. researched the literature, wrote and edited the Review, and created the original figures.

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Man, S.M., Kanneganti, TD. Innate immune sensing of cell death in disease and therapeutics. Nat Cell Biol 26, 1420–1433 (2024). https://doi.org/10.1038/s41556-024-01491-y

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