Abstract
Damage-associated molecular patterns (DAMPs) are endogenous molecules that are released from host cells as a result of cell death or damage. The release of DAMPs in tissues is associated with loss of tissue homeostasis. Sensing of DAMPs by innate immune receptors triggers inflammation, which can be beneficial in initiating the processes that restore tissue homeostasis but can also drive inflammatory diseases. In recent years, the sensing of intracellular DAMPs has received extensive attention in the field of sterile inflammation. However, emerging studies have shown that DAMPs that originate from neighbouring cells, and even from distal tissues or organs, also mediate sterile inflammatory responses. This multi-level sensing of DAMPs is crucial for intercellular, trans-tissue and trans-organ communication. Here, we summarize how DAMP-sensing receptors detect DAMPs from intracellular, intercellular or distal tissue and organ sources to mediate sterile inflammation. We also discuss the possibility of targeting DAMPs or their corresponding receptors to treat inflammatory diseases.
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Acknowledgements
R.Z. was supported by grants from the National Key Research and Development Program of China (2019YFA0508500), the National Natural Science Foundation of China (81821001, 82130107, 82330052) and the CAS Project for Young Scientists in Basic Research (YSBR-074). W.J. was supported by the National Key Research and Development Program of China (2020YFA0509101), the National Natural Science Foundation of China (U20A20359). Y.H. was supported by the Research Start-up Fund (2024KYQD004) of the Institute of Health and Medicine, Hefei Comprehensive National Science Center, the National Natural Science Foundation of China (82202038) and the Natural Science Foundation of Jiangsu Province (BK20221085).
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Glossary
- 2′-3′-cyclic GMP–AMP
-
(2′-3′-cGAMP). An adaptor protein that is a key component of the innate cellular immune response to pathogenic cytoplasmic DNA.
- Acute kidney injury
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A common clinical syndrome characterized by rapid decline in renal function and accumulation of metabolic waste.
- Aicardi–Goutieres syndrome
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A rare inherited disease that results in severe intellectual and physical disability, usually caused by mutations in several genes associated with the innate immune response.
- Alu elements
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A scattered set of related sequences in the human genome, each about 300 bp long. This sequence is so-named because of the presence of Alu restriction enzyme cleavage sites at each end of a single member. A large number of different types of Alu element exist in the primate genome.
- Amyotrophic lateral sclerosis
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A rare progressive neurological disease. Patients lose the ability to initiate and control voluntary movements as their motor neurons degenerate and die.
- Atrophic macular degeneration
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An eye disease that results in loss of central vision. It is caused primarily by macular damage to the retina.
- Danger theory
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The danger theory was proposed by Polly Matzinger in 1994. It states that danger signals from the body’s own cells can elicit an immune response and that the immune system is more interested in the detection of, and protection from, danger than in the distinction between self and non-self.
- Exosomes
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Small vesicles with a diameter of about 30–150 nm secreted by living cells, which typically have a lipid bilayer structure. They can carry various proteins, lipids, RNA and other important information and have an important role in the transfer of material and information between cells.
- Interferon-stimulated genes
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(ISGs). A set of genes induced by interferons that fulfil a crucial role in host resistance to viral infections.
- Micronuclei
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Small nuclear structures that contain DNA. They are spatially separated from the main nucleus and usually form as a result of chromosome mis-segregation and mutagenesis.
- Multiple sclerosis
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An autoimmune disease in which the immune system mistakenly attacks healthy cells that produce myelin, causing damage to nerve fibres in the central nervous system and disrupting the transmission of nerve signals.
- Neutrophil extracellular traps
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(NETs). Reticular fibrous structures formed by the release of components from the nucleus of a neutrophil to the outside of the cell.
- Nonalcoholic fatty liver disease
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(NAFLD). A syndrome characterized by diffuse hepatocyte macrovesicular steatosis, which is not caused by ethanol and other definite liver injury factors.
- PANoptosome
-
A cytoplasmic multimeric protein complex that drives PANoptosis, a distinct form of programmed inflammatory cell death that is implicated in various human diseases, including autoinflammatory diseases, metabolic diseases, neurodegenerative diseases and cancer.
- Proteasome-associated autoinflammatory disease
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(PRAAS). An autoinflammatory disease caused by genetic mutations that result in defective proteasome activity.
- Systemic lupus erythematosus
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An autoimmune disease in which the immune system attacks its own tissues and causes widespread inflammation and tissue damage.
- Unfolded protein response
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(UPR). Cells can sense the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum and alleviate endoplasmic reticulum stress through three main signalling pathways. The signalling pathways that mediate this regulation are called the UPR.
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Huang, Y., Jiang, W. & Zhou, R. DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01027-3
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DOI: https://doi.org/10.1038/s41577-024-01027-3
