The production of inflammatory interleukin 1beta after uptake of silica crystals and alum salt or amyloid-beta occurs by a process that involves lysosomal destabilization and release of cathepsin B that activates the NLRP3 inflammasome.

Aluminium adjuvants, typically referred to as 'alum', are the most commonly used adjuvants in human and animal vaccines worldwide, yet the mechanism underlying the stimulation of the immune system by alum remains unknown. Toll-like receptors are critical in sensing infections and are therefore common targets of various adjuvants used in immunological studies. Although alum is known to induce the production of proinflammatory cytokines in vitro, it has been repeatedly demonstrated that alum does not require intact Toll-like receptor signalling to activate the immune system1, 2. Here we show that aluminium adjuvants activate an intracellular innate immune response system called the Nalp3 (also known as cryopyrin, CIAS1 or NLRP3) inflammasome. Production of the pro-inflammatory cytokines interleukin-1beta and interleukin-18 by macrophages in response to alum in vitro required intact inflammasome signalling. Furthermore, in vivo, mice deficient in Nalp3, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) or caspase-1 failed to mount a significant antibody response to an antigen administered with aluminium adjuvants, whereas the response to complete Freund's adjuvant remained intact. We identify the Nalp3 inflammasome as a crucial element in the adjuvant effect of aluminium adjuvants; in addition, we show that the innate inflammasome pathway can direct a humoral adaptive immune response. This is likely to affect how we design effective, but safe, adjuvants in the future.

For decades, scientists have known that they can make vaccines much more efficacious by adding aluminum compounds, but they never knew why. Now, a study reveals how, on a molecular level, these helpers spur the production of antibodies. The finding may help researchers develop better vaccines. Many vaccines contain adjuvants, nonspecific agents that help jolt the immune system into action. "Alum," a term referring broadly to aluminum hydroxide and several aluminum salts, has this effect, as was accidentally discovered in the 1920s. It has been widely used in human vaccines since the 1950s, and it's still the only adjuvant allowed in the United States. "But we didn't really have a clue about how it worked," says immunologist Harm HogenEsch of Purdue University's School of Veterinary Medicine in West Lafayette, Indiana. The dominant theory held that alum particles bind the antigen--the vaccine's main ingredient--on their surfaces, presenting them more slowly to the immune system and thus ensuring a more thorough response. But the situation is more complicated than that. Last year, HogenEsch's team and a group led by Fabio Re at the University of Tennessee Health Science Center in Memphis showed that in macrophages--white blood cells that gobble up pathogens and cellular detritus--alum triggers the production of interleukin 1β and interleukin 18, two key signaling molecules, or cytokines, known to stimulate the production of antibodies. Researchers knew that this duo is often released after the activation of so-called NOD-like receptors. "So then the race was on," says Re, to pinpoint which NOD-like receptor was involved.

Our bodies are constantly assaulted by infectious agents, noxious chemicals, or physical trauma. Fortunately, we have evolved a complex process--the inflammatory response--to help fight and clear the infection, remove damaging chemicals, and repair damaged tissue. The mechanisms underlying inflammation are of major interest because, as noted by British surgeon John Hunter in 1794, "when inflammation cannot accomplish that salutary purpose, it does mischief " (1). The harmful effects of inflammation can be seen in many infectious diseases, in autoinflammatory diseases such as rheumatoid arthritis, or during chronic exposure to chemicals. At worst, inflammation can provoke cancer. The mechanism by which the body senses the diverse molecular factors that cause inflammation has, until recently, been poorly understood. On page 674 in this issue, Dostert et al. (2) provide key molecular insights into how airborne pollutants, including asbestos and silica, and probably other noxious inhaled particles, lead to inflammation, pulmonary diseases, and potentially lung cancer and fibrosis.

Researchers may have cracked the mystery of how asbestos causes life-threatening lung damage and cancer. A new study shows that the material triggers key immune system proteins that set off chronic inflammation. As a result, a commonly used arthritis drug might ward off the lung problems induced by exposure. Over decades, asbestos fibers inhaled into the lungs can lead to cancer and scarring that interferes with breathing. Although these risks have been known for more than 100 years, researchers have been unable to uncover how the fibers, which are found in building materials and other products, trigger damage. Gout, a seemingly unrelated disease caused by the buildup of uric acid, may have provided a vital clue. Two years ago, a team led by biologist Jürg Tschopp of the University of Lausanne in Switzerland showed that uric acid causes gout by overactivating inflammasomes, immune proteins that spark inflammation to help wipe out germs. Might asbestos have a similar effect on the body? Tschopp and colleagues exposed to asbestos human and mouse immune cells that lurk in the lungs. They found that the material stimulated an inflammasome called Nalp3 to release interleukin-1β (IL-1β), a chemical that incites inflammation. But the real proof came from mice that were bred to lack Nalp3. When these mice were exposed to asbestos for 9 days, they produced lower levels of IL-1β and less lung inflammation than did mice with Nalp3, confirming that the inflammasome is key to triggering at least some of the negative effects of the fiber, the researchers report online today in Science. Tschopp speculates that because asbestos fibers lodge in the body, prolonged exposure causes chronic inflammation that over time could result in lung scarring and cancer. The details still need to be worked out, but the researchers note that IL-1β has been linked to other cancers.

The inhalation of airborne pollutants, such as asbestos or silica, is linked to inflammation of the lung, fibrosis, and lung cancer. How the presence of pathogenic dust is recognized and how chronic inflammatory diseases are triggered are poorly understood. Here, we show that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to interleukin 1{beta} secretion. Inflammasome activation is triggered by reactive oxygen species, which are generated by a NADPH oxidase upon particle phagocytosis (NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate). In a model of asbestos inhalation, Nalp3–/– mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production. Our findings implicate the Nalp3 inflammasome in particulate matter–related pulmonary diseases and support its role as a major proinflammatory "danger" receptor.

The innate immune system recognizes nucleic acids during infection and tissue damage. Whereas viral RNA is detected by endosomal toll-like receptors (TLR3, TLR7, TLR8) and cytoplasmic RIG-I and MDA5, endosomal TLR9 and cytoplasmic DAI bind DNA1, resulting in the activation of nuclear factor-kappaB and interferon regulatory factor transcription factors. However, viruses also trigger pro-inflammatory responses2, which remain poorly defined. Here we show that internalized adenoviral DNA induces maturation of pro-interleukin-1beta in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, NALP3- and ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurs as a result of transfected cytosolic bacterial, viral and mammalian (host) DNA, but in this case sensing is dependent on ASC but not NALP3. The DNA-sensing pro-inflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.

The innate immune system comprises several classes of pattern-recognition receptors, including Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain-like receptors (NLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs sense microbial molecules in the cytosol. In this review, we focus on the role of NLRs in host defence against bacterial pathogens. Nod1 and Nod2 sense the cytosolic presence of molecules containing meso-diaminopimelic acid and muramyl dipeptide respectively, and drive the activation of mitogen-activated protein kinase and NF-κB. In contrast, Ipaf, Nalp1b and Cryopyrin/Nalp3 promote the assembly of inflammasomes that are required for the activation of caspase-1. Mutation in several NLR members, including NOD2 and Cryopyrin, is associated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defence and the pathogenesis of inflammatory diseases.