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Eicke Latz recalls the discovery of the inflammasome in 2002 and how it revolutionized our understanding of inflammation and is now a target of new immunotherapeutics for inflammatory disease.

On 24–27 September 2008, members of the scientific community gathered to discuss advances in innate immunity at the 'Toll meeting' in Cascais, Portugal. Before long, attendees noticed that 'Toll2008' might be a misnomer.

Leucine-rich repeat (LRR) domains are commonly present in immune regulatory proteins. Here the authors show that LRR exonic modularity and alternative splicing of an LRR-containing protein, NLRP3, modulate the ratio of functional/afunctional NLRP3 isoforms to instill a stochastic regulation of NLRP3-mediated inflammation and innate immunity.

High-density lipoprotein (HDL) has beneficial effects in coronary artery disease. Latz and colleagues show that HDL's benefits stem at least in part by activating an anti-inflammatory program dependent on the transcription factor ATF3.

Researchers gathered at the Wellcome Trust Genome Campus in Hinxton, Cambridge, for the first Innate Immune Memory Conference dedicated to the adaptive characteristics of innate immunity, to further the understanding of this newly described immunological process that probably has a central role in host defense and inflammation.

Recognition of nucleic acids is a key strategy of the innate immune system to detect infectious organisms and tissue damage. Toll-like receptor (TLR) 8 was long assumed to be a receptor for single-stranded (ss) RNA. Unexpected findings now suggest that TLR8 recognizes RNA degradation products rather than ssRNA and that synergistic binding of two uridine-containing agonists at distinct sites of the receptor leads to activation of the innate immune response.

During atherosclerosis, crystals of cholesterol accumulate in atherosclerotic plaques. But are they a consequence or a cause of the inflammation associated with the disease? Here it is shown that small cholesterol crystals appear early in the development of atherosclerosis, and that they act as an endogenous danger signal, causing inflammation by activating the NLRP3 inflammasome pathway. Cholesterol crystals thus seem to be an early cause, rather than a late consequence, of inflammation.

In the gut, cells of the immune system must tolerate commensal bacteria but also detect pathogens. To achieve this, intestinal phagocytes are hyporesponsive to Toll-like receptor stimulants released from commensals, but can detect invasion of pathogens via the intracellular NLRC4 inflammasome.

This Review describes how microbial or self DNA that enters the cytoplasm can be detected by various mechanisms and triggers a range of cellular responses. These include the induction of antiviral innate immune responses and inflammasome-dependent caspase-1 activation and pyroptotic cell death.

Inflammasomes are multiprotein signalling platforms that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and induce cell death in response to pathogens and sterile stressors. This Review provides a comprehensive overview of our rapidly evolving understanding of the regulatory mechanisms that control the activation of distinct inflammasome components, as well as the non-canonical processing of IL-1β.

Alzheimer’s-prone mice deficient in NLRP3 or caspase-1 fail to develop learning deficits and show reduced neuropathology.

Various endogenous and pathogen-derived stimuli trigger the assembly of cytosolic multimolecular 'speck' platforms coordinated by the adapter ASC. Latz and colleagues demonstrate that ASC specks have extracellular functions that can prolong inflammation.

Activation of the NALP3 inflammasome induces interleukin 1β production and inflammation. Latz and colleagues show that silica uptake followed by lysosome disruption and cathepsin B release activates the NALP3 inflammasome.

NLRP10 has been considered as an inflammasome inhibitor. Here the authors show that upon mitochondrial rupture, NLRP10 assembles a canonical inflammasome and is highly expressed in differentiated keratinocytes, possibly supporting skin homeostasis.

Lifestyle-associated pathologies have reached epidemic proportions and urgent action is needed to protect the public from unhealthy diets. Here, the authors describe how the Western diet has long-lasting effects on the immune system that promote chronic metabolic inflammatory diseases.

In this Review, the authors discuss how innate immune mechanisms can contribute to the development of neurodegenerative disease. They suggest that both local and systemic inflammation can drive pathological microglial cell activity, thereby leading to neuronal cell dysfunction and disease.

Here a group of leaders in the field define our current understanding of ‘trained immunity’, which refers to the memory-type responses that occur in the innate immune system. The authors discuss our current understanding of the key epigenetic and metabolic processes involved in trained immunity and consider its relevance in immune-mediated diseases and cancer.

The inflammasome is a key integration point for innate immunity. As such, targeting this signalling hub has the potential to be useful in numerous autoimmune and metabolic disorders. In this article, Latz and colleagues discuss the progress that has been made towards targeting the inflammasome, highlighting the therapeutic potential of some of these compounds as well as caveats for their use.

Inflammasomes are multiprotein complexes that detect and respond to foreign and endogenous danger signals by activating caspase-1; active caspase-1, in turn, matures the pro-inflammatory IL-1β family cytokines by cleaving their pro-forms into the biologically active cytokines. The upstream mechanisms leading to inflammasome activation, in particular for the NRLP3 inflammasome, remain poorly understood. Lu and colleagues identify a new function of Protein Kinase R (PKR) for activating the NLRP1, NLRP3, NLRC4 and AIM2 inflammasomes, thus identifying a potential new target for treating inflammasome-mediated diseases.