Sterile inflammation: sensing and reacting to damage

Key Points 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. 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. 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. 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. 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. Our understanding of the triggers and mediators of sterile inflammation has advanced greatly in recent years. Here, Chen and Nuñez provide us with an up-to-date overview of these advances and discuss their therapeutic implications. 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 e