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In Retrospect

The inflammasome turns 15


The discovery of the inflammasome protein complex in 2002 was a breakthrough in our understanding of how the immune system triggers inflammation. Now researchers are attempting to modulate its activity to treat disease.

Fifteen years ago, Martinon, Burns and Tschopp published a paper in Molecular Cell1 that solved the puzzle of how a key component of inflammation is activated. Caspase 1 is a member of an evolutionarily conserved family of protease enzymes that cleave proteins that regulate cell death and inflammation. Martinon et al. discovered that a multiprotein complex is needed to activate caspase 1, and they named this complex the inflammasome. Their study gave birth to a field of inflammation research that continues to map the regulation of inflammatory caspases and investigates their biological roles.

The inflammasome is now considered to be a central signalling hub that regulates innate immunity, the branch of the immune system that recognizes and triggers a rapid response to infections and foreign substances that might be harmful to the host. Building on the discovery of Martinon and colleagues, scientists have found various mechanisms by which inflammasomes contribute to antimicrobial host defence and chronic inflammatory diseases2.

Martinon et al. showed that several members of the NLR protein family, along with the adaptor protein ASC, form a complex that recruits and activates caspase 1. Their findings were confirmed through the analysis of NLR-deficient mice shortly afterwards, and these studies revealed2,3 that the different NLR combinations in each inflammasome are surprisingly specific in terms of the stimuli they detect. Inflammasomes composed of a particular NLR respond to certain microbe-derived molecules known as pathogen-associated molecular patterns (PAMPs), or to environmental and host-derived cellular stress signals called damage-associated molecular patterns (DAMPs).

Although the mechanisms of inflammasome activation are incompletely understood, it is known, for example, that an NLRP3-containing inflammasome responds to diverse stimuli that might damage cellular membranes, whereas the NLRP1b-containing inflammasome is selectively activated by anthrax proteins2. The identification of inflammasomes that contain the proteins AIM2 or pyrin indicated that caspase 1 can also be activated by innate-immune receptors other than NLR proteins2,3. AIM2 senses the presence of microbial DNA in the cell cytoplasm, and pyrin is activated by bacterial toxins that interfere with the activity of a particular host enzyme. Another major conceptual advance4 was the discovery that mouse caspase 11 and its human equivalents, caspase 4 and caspase 5, are activated when lipopolysaccharide molecules — components of the bacterial cell wall — enter the cytoplasm. This leads to activation of caspase 1 that depends on the protein NLRP3 and forms part of the non-canonical inflammasome pathway, in which caspase 1 requires some of these other inflammatory caspases to act upstream of inflammasome formation (Fig. 1). Because lipopolysaccharide molecules can activate other immune signalling pathways by binding to receptor proteins on the surface of immune cells, the innate immune system can initiate a different type of response depending on whether microbial products have been detected in the intracellular or extracellular space.

Figure 1: The inflammasome.

Before 2002, it was known that, in response to infection by a bacterial pathogen, the enzyme caspase 1 can promote the release of inflammatory signalling molecules5,6,7,8, such as interleukin-1β (IL-1β) and IL-18, and that caspase 1 also has a role in pyroptosis, a type of cell death that can eliminate immune cells9,10,11. However, how caspase 1 is activated and induces pyroptosis was unknown. In 2002, Martinon, Burns and Tschopp1 discovered that innate-immune receptor proteins from the NLR protein family and the adaptor protein ASC assemble into an inflammasome complex that recruits and activates caspase 1. The infection cues that trigger inflammasome activation are now known to be molecules called pathogen-associated molecular patterns (PAMPs) or cellular stress signals called damage-associated molecular patterns (DAMPs). Diverse inflammasome complexes have been identified and the innate-immune receptors in some inflammasomes are not NLRs but are instead AIM2 or pyrin proteins. The specific basis of some inflammasome-activation mechanisms are known in detail; for example, microbial DNA triggers the formation of the AIM2-containing inflammasome. Another key advance was the identification of the non-canonical inflammasome pathway, in which caspase 4, 5 or 11 act upstream of caspase 1 activation. Caspase-mediated cleavage of the protein gasdermin D is the mechanism that enables inflammatory caspase activation to induce pyroptosis14,15,16 in both the canonical and non-canonical inflammasome pathways.

In 1992, a decade before Martinon et al. discovered the inflammasome, it was already known5,6 that caspase proteolytic activity could generate the mature form of interleukin-1β (IL-1β), a potent type of fever-inducing inflammatory signalling molecule known as a cytokine. By 1997, it was found7,8 that caspase 1 could cause the maturation of IL-18, another key cytokine. At around this time, caspase 1 was shown9,10,11 to trigger the death of immune cells called macrophages after they have been infected with bacteria. In this caspase-1-induced cell death, the cell breaks apart and spills IL-1β and IL-18 into the extracellular milieu. This type of cell death was named pyroptosis (from the Greek word pyro meaning fire and ptosis denoting a falling) to highlight its intrinsically inflammatory nature. In addition to being a conduit for the release of IL-1β and IL-18, pyroptosis is considered to be a mechanism to release DAMP molecules, such as IL-1α, HMGB1 proteins and ATP, that alert the body's defence mechanisms to an imminent threat12,13.

It wasn't until 2015 that the mechanism by which inflammatory caspases activate pyroptosis was revealed, with the discovery that caspase 1, 4, 5 and 11 mediate the cleavage of the protein gasdermin D to release the protein's amino-terminal domain, which generates pores in cellular membranes that break the cell apart14,15,16.

The discovery of the inflammasome sparked intense research to clarify which biochemical mechanisms control the activation of inflammatory caspases, the production of inflammatory cytokines, and pyroptosis, but it also attracted investigators from across many biomedical disciplines to characterize the role of these immune mechanisms in human disease. Many studies have shown that inflammasome activation generally promotes protective antimicrobial defences and tissue repair. It has even been proposed that inflammasomes can alter the host's immune status by shaping the composition of the gut microbial ecosystem. This latter assumption has recently been disproved17, but nevertheless, inflammasome activation is increasingly considered to be a major culprit of tissue damage and pathology in the context of severe, life-threatening systemic infections, as well as in chronic inflammatory, metabolic, cardiovascular and neurodegenerative diseases.

The discovery of the inflammasome led Martinon et al. to speculate that aberrant inflammasome activation was the underlying cause of the periodic fever syndromes that occur in people who have NLRP3 mutations. This idea was confirmed by the remarkable efficacy of IL-1-blocking agents (for example, agents that target IL-1β or IL-1α or their receptor protein) for the treatment of several autoinflammatory diseases. Blocking IL-1β has also proved to be an effective way to treat gout and several other rheumatic diseases that affect the joints and muscles. A large placebo-controlled phase 3 trial18 has enrolled more than 10,000 individuals who have coronary artery disease and inflammatory atherosclerosis to test whether treatment with an IL-1β-blocking antibody in addition to the standard therapy reduces the risk of cardiovascular damage. It has been reported19 that the antibody treatment had a protective effect.

IL-1-neutralizing treatments currently dominate this field, but as our understanding of the mechanisms that regulate caspase-1 activation becomes increasingly sophisticated, researchers are exploring other treatment approaches. Previous efforts to block capase-1 enzymatic activity directly have mainly failed, so researchers are now trying to intervene pharmacologically at points further upstream in the caspase-activation pathway. Selective inflammasome inhibition might well be within reach — the drug glyburide, which is used to treat diabetes, has been found to selectively block activation of the NLRP3-containing inflammasome, thus setting the stage for the identification of additional anti-inflammatory agents20. As the biopharmaceutical industry seeks to develop inflammasome-modulating agents that might boost cancer immunotherapy and dampen inflammation in other diseases, it is possible that the next 15 years of inflammasome research might deliver additional therapeutic options.Footnote 1


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Correspondence to Mohamed Lamkanfi or Vishva M. Dixit.

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Lamkanfi, M., Dixit, V. The inflammasome turns 15. Nature 548, 534–535 (2017).

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