Key Points
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Sterile inflammation occurs in the absence of microorganisms and is typically associated with the recognition of intracellular contents released from damaged and necrotic cells (also known as damage-associated molecular patterns) by inflammatory signalling receptors. Sterile inflammation can also be induced by exogenous material, such as silica and asbestos particles, which can injure cells.
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Host receptors used in microbial detection, specifically pattern recognition receptors such as the Toll-like receptors (TLRs) and NOD-like recpetors (NLRs), are also activated by endogenous and non-infectious stimuli and mediate sterile inflammatory responses. However, host receptors that are not necessarily involved in pathogen recognition, such as receptor for advanced glycation end products (RAGE), can also sense sterile stimuli.
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NLRP3 (NOD-, LRR- and pyrin domain-containing 3) is a member of the NLR family of receptors involved in innate immunity and has the ability to sense numerous structurally diverse stimuli. The mechanism by which NLRP3 achieves this is still not completely understood, but it may involve the sensing of reactive oxygen species, ionic changes within the cell or lysosomal membrane damage.
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Intracellular cytokines, such as interleukin-1α (IL-1α), are also important mediators of the sterile inflammatory response and can be released in their biologically active forms from necrotic cells.
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Sterile inflammation has been associated with certain disease states, such as the increased tissue damage that results from ischaemia–reperfusion in myocardial infarction, as well as atherosclerosis, silicosis and Alzheimer's disease. Furthermore, sterile inflammation may also have an important role in host immune responses against tumours.
Abstract
Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.
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Acknowledgements
We apologize to our colleagues whose work was not cited or was cited through others' review articles because of space limitations. Work in the authors' laboratories is supported by US National Institutes of Health grants CA133185 (G.C.), and DK61707, AR051790, AI06331, AR059688 and DK091191 (G.N.).
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Glossary
- Ischaemia–reperfusion injury
-
An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow further enhances inflammation, which exacerbates tissue damage.
- Reactive oxygen species
-
(ROS). Oxygen radicals that are mainly produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.
- Myocardial infarction
-
An episode of acute cardiac ischaemia that leads to death of heart muscle cells. It is usually caused by a thrombotic atherosclerotic plaque.
- Atherosclerosis
-
A chronic disorder of the arterial wall characterized by endothelial cell damage that gradually induces deposits of cholesterol, cellular debris, calcium and other substances. These deposits finally lead to plaque formation and arterial stiffness.
- Necrosis
-
A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and the release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self antigens that are released by necrosis can become immunogenic.
- Apoptosis
-
A common form of cell death that is defined by specific morphological changes and by the involvement of caspases. The morphological features include chromatin condensation, plasma membrane blebbing and DNA fragmentation into segments of ∼180 base pairs. Eventually, the cell breaks up into many membrane-bound 'apoptotic bodies', which are phagocytosed by neighbouring cells.
- High-mobility group box 1
-
(HMGB1; also known as amphoterin). A nuclear protein that binds DNA in a non-sequence-specific manner and modulates transcription and chromatin remodelling by bending DNA and facilitating the binding of transcription factors and nucleosomes, respectively.
- Adjuvant
-
A substance that stimulates the immune system to enhance the immunogenicity of antigens or vaccines and enhance antigen-specific antibody production.
- Inflammasome
-
A multiprotein complex that contains a pattern recognition receptor (PRR), typically a member of the NOD-like receptor (NLR) family, that, on sensing its cognate agonist, oligomerizes and recruits the adaptor protein ASC (apoptosis-related speck-like protein containing a CARD) through protein domain interactions. ASC can recruit caspase 1 through its CARD, thereby linking the PRR to caspase 1 activation and interleukin-1 production. There are currently four characterized inflammasomes, named by the PRRs that form them: the NRLP1 (NOD-, LRR- and pyrin domain-containing 1), NLRP3, NLRC4 (NOD-, LRR- and CARD-containing 4) and absence in melanoma 2 (AIM2) inflammasomes.
- NADPH oxidase
-
An enzyme system that consists of several cytoplasmic and membrane-bound subunits. The complex is assembled in activated phagocytic cells mainly on phagolysosomal membranes. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid, a highly toxic and microbicidal agent.
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Chen, G., Nuñez, G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol 10, 826–837 (2010). https://doi.org/10.1038/nri2873
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DOI: https://doi.org/10.1038/nri2873
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