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DAMP-sensing receptors in sterile inflammation and inflammatory diseases

Abstract

The innate immune system has the capacity to detect ‘non-self’ molecules derived from pathogens, known as pathogen-associated molecular patterns, via pattern recognition receptors. In addition, an increasing number of endogenous host-derived molecules, termed damage-associated molecular patterns (DAMPs), have been found to be sensed by various innate immune receptors. The recognition of DAMPs, which are produced or released by damaged and dying cells, promotes sterile inflammation, which is important for tissue repair and regeneration, but can also lead to the development of numerous inflammatory diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases and cancer. Here we examine recent discoveries concerning the roles of DAMP-sensing receptors in sterile inflammation and in diseases resulting from dysregulated sterile inflammation, and then discuss insights into the cross-regulation of these receptors and their ligands.

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Fig. 1: Different types of cells involved in DAMP-sensing and sterile inflammation.
Fig. 2: DAMP sensing and signalling transduction cascades of PRRs.
Fig. 3: DAMP sensing and signal transduction cascades of multiple transmembrane receptors.
Fig. 4: Crosstalk between different DAMP-sensing receptors.

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Acknowledgements

This work was supported by the National Key research and development program of China (grant 2019YFA0508503), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB29030102), the National Natural Science Foundation of China (grants 31770991, 91742202, 81525013, 81722022, 81788101, 81821001) and the Young Talent Support Program and Fundamental Research Funds for the Central Universities.

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All authors contributed to writing and editing the review. T.G. and L.L. share first authorship.

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Correspondence to Wei Jiang or Rongbin Zhou.

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Nature Reviews Immunology thanks Michael Lotze and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Pattern recognition receptors

(PRRs). A group of germ-line-encoded innate immune sensors that can initiate an innate immune response by detecting highly conserved molecules typical of pathogens. In addition to their well-established roles in pathogen recognition, several PRRs can also recognize endogenous ligands released by distressed or damaged cells and initiate sterile immune responses.

Ischaemia–reperfusion injury

(IRI). Tissue injury that occurs when blood flow returns to tissue after a period of ischaemia, which is accompanied by inflammatory cell infiltration, ROS production and cytokine release. It can occur in various organ systems, including the brain, heart and kidneys, leading to stroke, myocardial infarction and acute kidney injury, respectively.

β2-Glycoprotein I

An abundant plasma glycoprotein, also known as apolipoprotein H, that can bind to negatively charged molecules, including phospholipids, DNA and lipoproteins. It plays an important role in a variety of physiological processes, such as coagulation, apoptosis, lipid metabolism, angiogenesis and the production of antiphospholipid autoantibodies.

Pyroptosis

An inflammatory form of programmed cell death initiated by inflammasome assembly and caspase-1 or caspase-11 (in humans, caspase-1, caspase-4 or caspase-5) activation. The activated caspases cleave gasdermin D (GSDMD), generating an N-terminal GSDMD fragment that can form pores on lipid membranes and induce cell death directly.

Inflammasome

A cytosolic multiprotein complex consisting of a sensor molecule, the adaptor protein ASC and cysteine protease pro-caspase-1. To date, several pattern recognition receptors, including NLRP1, NLRP3, NLRP6, NLRC4, AIM2, IFI16 and pyrin, have been found to act as sensor molecules to trigger the assembly of inflammasomes in response to microbial infection or noninfectious agonists.

Alu-RNA

RNA transcripts that are transcribed from Alu elements, the most abundant repetitive elements in primate genomes. Alu-RNA can exist in two forms: free Alu-RNA is synthesized by RNA polymerase III, whereas embedded Alu-RNA is synthesized by RNA polymerase II and can be embedded in mRNAs. Both of these forms play an important role in the post-transcriptional regulation of gene expression. In addition, the level of free Alu-RNA can increase dramatically under cell stress conditions, which may be sensed by innate immune sensors.

Non-canonical NLRP3 inflammasome

In contrast to canonical inflammasome assembly, the NLRP3 inflammasome can also be activated through a non-canonical pathway that requires mouse caspase 11 (the human counterparts are caspase 4 and 5).

Aicardi–Goutières syndrome

(AGS). An inheritable neuroinflammatory disease that leads to microcephaly and intellectual disability with extraneurological vasculitic skin lesions. This condition is driven by chronic IFN signalling caused by mutations in genes involved in DNA degradation and metabolism or RNA editing and recognition.

Exosomes

Small extracellular vesicles (with a diameter between 30 nm and 100 nm) that are produced by various types of cells, such as mesenchymal stem cells, tumour cells and dendritic cells. Several endogenous molecules, including DNA, RNA, lipids and proteins, are sorted to exosomes and are delivered from donor cells to recipient cells, a process that plays a critical role in both healthy and diseased conditions.

5-AZA-2′deoxycytidine

A deoxycytidine analogue that can incorporate into DNA strands and inhibit DNA methyltransferase activity, resulting in global DNA demethylation. It can reactivate tumour suppressor genes silenced by aberrant DNA methylation and is used in the treatment of malignancies.

Ataxia telangiectasia

(AT). An autosomal recessive disease caused by mutations of ataxia telangiectasia mutated (ATM), a kinase that plays a central role in the DNA repair pathway. It affects several body systems, including the nervous system and the immune system, and leads to susceptibility to various types of cancer.

Senescence-associated secretory phenotype

(SASP). A characteristic feature of senescent cells, which refers to the secretion of inflammatory cytokines, chemokines, extracellular matrix proteins and growth factors. It not only serves as a marker of senescence but also participates in the senescence process.

Advanced glycation end products

(AGEs). A heterogeneous group of compounds, including proteins, lipids and nucleic acids, that are formed with reducing sugars via a non-enzymatic glycosylation reaction. AGEs play crucial roles in ageing and in the pathogenesis of various chronic and degenerative diseases, such as diabetes, chronic kidney disease, atherosclerosis and Alzheimer disease.

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Gong, T., Liu, L., Jiang, W. et al. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 20, 95–112 (2020). https://doi.org/10.1038/s41577-019-0215-7

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