REVIEW Apoptosis is a cell suicide mechanism that enables metazoans to control cell number in tissues and to eliminate individual cells that threaten the animal's survival. Certain cells have unique sensors, termed death receptors, on their surface. Death receptors detect the presence of extracellular death signals and, in response, they rapidly ignite the cell's intrinsic apoptosis machinery.

The inflammasome is a complex of proteins involved in the activation of the innate immune system, an evolutionarily ancient antimicrobial defence found in most multicelled animals. When activated the inflammasome sets in motion a cascade of events that leads to the production of active molecules including interleukins. Three papers in this issue report the identification of endogenous danger signals and bacterial components that activate inflammasomes containing cryopyrin (also known as NALP3). Mariathasan et al. show that cryopyrin activates the inflammasome in response to bacterial toxins and to ATP. Kanneganti et al. show that cryopyrin is activated by bacterial RNA and by the immune response modifiers R837 and R848. And Martinon et al. show that gout-associated uric acid crystals have a similar effect. In sum these results show that cryopyrin has a vital role in host antibacterial defences and may act as a sensor of cellular stress. In addition, this work provides insight into the mechanisms of autoinflammatory disorders in which abnormalities in the innate immune system have been implicated. A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1β and IL-18. The adaptor protein ASC is essential for inflammasome function1,2, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1)5,6. Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1β5,7. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels8,9. The release of IL-1β in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1β and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1β. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

Move Over, TLR4: The innate immune system senses bacterial lipopolysaccharide (LPS) through Toll-like receptor 4 (TLR4) (see the Perspective by Kagan ). However, Kayagaki et al. (p 1246 , published online 25 July) and Hagar et al. (p. 1250 ) report that the hexa-acyl lipid A component of LPS from Gramnegative bacteria is able to access the cytoplasm and activate caspase-11 to signal immune responses independently of TLR4. Mice that lack caspase-11 are resistant to LPS-induced lethality, even in the presence of TLR4.

Inflammation is triggered when innate immune cells detect infection or tissue injury. Surveillance mechanisms involve pattern recognition receptors (PRRs) on the cell surface and in the cytoplasm. Most PRRs respond to pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) by triggering activation of NF-κB, AP1, CREB, c/EBP, and IRF transcription factors. Induction of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the recruitment and activation of leukocytes, which are critical for eliminating foreign particles and host debris. A subset of PRRs activates the protease caspase-1, which causes maturation of the cytokines IL1β and IL18. Cell adhesion molecules and chemokines facilitate leukocyte extravasation from the circulation to the affected site, the chemokines stimulating G-protein-coupled receptors (GPCRs). Binding initiates signals that regulate leukocyte motility and effector functions. Other triggers of inflammation include allergens, which form antibody complexes that stimulate Fc receptors on mast cells. Although the role of inflammation is to resolve infection and injury, increasing evidence indicates that chronic inflammation is a risk factor for cancer.

Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.