Review Article. Absent in melanoma 2 (AIM2) in the intestine: diverging actions with converging consequences

The intestinal mucosa is a difficult environment to maintain homeostasis as it is constantly challenged by microbial and food antigens. Maintaining an intact epithelial barrier, a continuous turnover of intestinal epithelial cells and normobiosis of the gut microbiota are essential components to prevent intestinal diseases such as inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Inflammasomes are critical immune regulators that are involved in all of these processes. They are multiprotein complexes able to assemble upon interaction with a noxious stimulus that will subsequently lead to caspase-1 activation. Activated caspase-1 will orchestrate the maturation and release of proinflammatory cytokines IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. Both cytokine release and pyroptosis are initiated after detection of molecular patterns by a distinct inflammasome sensor protein. Absent in melanoma 2 (AIM2) is such an inflammasome sensor that specifically responds to the presence of double stranded DNA (dsDNA) in the cytoplasm, leading to the recruitment and activation of caspase-1. Recent studies revealed additional roles of AIM2 in controlling epithelial cell proliferation, tight junction expression and the microbiome. Therefore, AIM2 plays a significant role in maintaining intestinal homeostasis. This review focuses on the multifunctional role of AIM2 in intestinal homeostasis by regulating intestinal immunity and preventing colorectal cancer development.

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasome-independent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

Vitamin C inhibits the activation of the NLRP3 inflammasome by scavenging mitochondrial ROS

Inflammasomes are intracellular protein complexes that mediate maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Inflammasomes have been connected with various diseases, therefore the regulation of inflammasome activation is important for the development of novel therapies for many inflammatory syndromes. Vitamin C is an essential nutrient and has regulatory effects on immune cells. Here we report that vitamin C has an inhibitory effect on the activation of the NLRP3 inflammasome in vitro and in vivo. Mechanistically, this inhibition is through scavenging mitochondrial ROS but not through NF-κB inhibition. Moreover, specificity tests show that the AIM2 inflammasome and the NLRC4 inflammasome can also be inhibited by vitamin C. Our results have thus identified a new inflammasome regulator and provide therapeutic potential for inflammasome-associated diseases.

Burn the house, save the day: pyroptosis in pathogen restriction

Many programmed cell death pathways are essential for organogenesis, development, immunity and the maintenance of homeostasis in multicellular organisms. Pyroptosis, a highly proinflammatory form of cell death, is a critical innate immune response to prevent intracellular infection. Pyroptosis is induced upon the activation of proinflammatory caspases within macromolecular signalling platforms called inflammasomes. This article reviews our understanding of pyroptosis induction, the function of inflammatory caspases in pyroptosis execution, and the importance of pyroptosis for pathogen clearance. It also highlights the situations in which extensive pyroptosis may in fact be detrimental to the host, leading to immune cell depletion or cytokine storm. Current efforts to understand the beneficial and pathological roles of pyroptosis bring the promise of new approaches to fight infectious diseases.

Signaling cascades and inflammasome activation in microbial infections

Recognition of extracellular pathogenassociated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) results in activation of host defense signaling pathways. Some virulent microbes can attenuate and escape antimicrobial immunity by manipulating these signaling pathways. However, impairment of the primary innate response may potentiate the activation of secondary defense program, centered around Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLRs) for inflammasome formation and IL-1β production. This review analyzes the current knowledge regarding association of innate immune signaling pathways with inflammasome activation in response to bacterial infection.

Insights into assembly of the macromolecular inflammasome complex

Dramatic advances in our understanding of the ultrastructure of the inflammasome and the molecular interactions involved in its assembly have recently been made. The adaptor protein ASC has been proposed to display prion-like activity that results in the formation of filamentous structures in the cell. These filamentouos structures can subsequently become inflammatory themselves if released into the extracellular space and then phagocytosed. Various groups have now utilised a variety of microscopy and structural approaches in order to visualise components of, and indeed the entire, inflammasome in both endogenous and overexpression systems. In this brief review we draw upon these new pieces of work to describe how our understanding of the global structure of the inflammasome has progressed in light of these new observations. In particular we begin by providing an initial perspective on the possible formation of small circular, wheel-like, oligomers resembling apoptosomes. We then address the current view that inflammasomes result from the formation of a much larger complex which may involve polymeric filaments. We discuss how these developments fit with recent theories of inflammatory signalling, what questions these advances raise, and propose key areas for further investigation.

A ring-like model for ASC self-association via the CARD domain

Inflammasomes are molecular platforms controlling the innate immune response to pathogens and cellular stress. ASC is an adaptor protein common to most NLR (nucleotide-binding domain and leucine-rich repeat containing receptor) inflammasome complexes as its N-terminal PYD and C-terminal CARD interact with the homologous domains in NLR and procaspase-1. Although inflammasome activation depends on ASC oligomerization, the molecular basis of ASC self-association and the protein interactions mediating the inflammatory signaling pathway remain unknown. Both CARD and PYD domains are involved in the oligomerization process of ASC. Based on our previous structural and dynamics data on ASC we propose a model for its oligomerization consisting of a 7-member ring. In this model, CARD monomers associate via type I homotypic interactions leaving the remaining binding site of each monomer free for further oligomerization and thus ring formation. A second more open PYD ring is accommodated on top of the CARDs. Our model is discussed in light of previous work evidencing the formation of helical filaments and large globular structures by ASC. The double-ring model can help in the understanding of inflammasome assembly, nevertheless, ASC oligomerization has to be envisaged as a complex process that might include molecular organizations with structurally different features.

Inflammasomes take the acid test

Editorial highlight on Takenouchi et al., ‘Inflammasome activation by danger signals: extracellular ATP and pH.’

Inflammasome activation by danger signals: extracellular ATP and pH

Extracellular ATP has been recognized as a danger signal that alerts the innate immune system. High extracellular concentrations of ATP can trigger the maturation and secretion of pro-inflammatory cytokines (e.g., interleukin-1β and interleukin-18) through the inflammasome-dependent activation of caspase-1. The P2X7 receptor, an ATP-gated cation channel, plays a pivotal role in ATP-induced NLRP3 inflammasome assembly. Recently, intriguing evidence has emerged that acidic extracellular pH acts as a danger signal that activates inflammasomes. Extracellular acidification frequently occurs at sites of inflammation, infection, or injury. In addition, large amounts of ATP are readily released into the extracellular space from damaged cells at such sites. Thus, it is assumed that the ATP/P2X7 receptor pathway regulates the inflammatory response under acidic extracellular conditions. Here, we briefly discuss the mutual effects of extracellular ATP and pH on inflammasome activation and consider their roles in the regulation of inflammation.

Epilepsy and the inflammasome: Targeting inflammation as a novel therapeutic strategy for seizure disorders

Epilepsy is the most common serious brain disorder worldwide. Recent evidence from experimental models of epilepsy and clinical brain tissue from epilepsy surgery suggests inflammation may play a pathological role in this disorder. Activation of a multimolecular protein complex termed the ‘inflammasome’ occurs during inflammation to drive the innate immune response. Inflammasome activation, with release of inflammatory mediators including interleukin-1β and high-mobility group box-1, may play a crucial role in the development of epilepsy (epileptogenesis) after brain insult. Immunomodulatory drugs targeting the inflammasome pathway may represent a novel antiepileptogenic treatment strategy for epilepsy. This review summarises the current literature surrounding inflammasome activation and epilepsy.