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Caspase-1 activated in inflammasomes triggers a programmed necrosis called pyroptosis, which is mediated by gasdermin D (GSDMD). However, GSDMD-deficient cells are still susceptible to caspase-1-mediated cell death. Therefore, here, we investigate the mechanism of caspase-1-initiated cell death in GSDMD-deficient cells. Inflammasome stimuli induce apoptosis accompanied by caspase-3 activation in GSDMD-deficient macrophages, which largely relies on caspase-1. Chemical dimerization of caspase-1 induces pyroptosis in GSDMD-sufficient cells, but apoptosis in GSDMD-deficient cells. Caspase-1-induced apoptosis involves the Bid-caspase-9-caspase-3 axis, which can be followed by GSDME-dependent secondary necrosis/pyroptosis. However, Bid ablation does not completely abolish the cell death, suggesting the existence of an additional mechanism. Furthermore, cortical neurons and mast cells exhibit little or low GSDMD expression and undergo apoptosis after oxygen glucose deprivation and nigericin stimulation, respectively, in a caspase-1- and Bid-dependent manner. This study clarifies the molecular mechanism and biological roles of caspase-1-induced apoptosis in GSDMD-low/null cell types. In inflammasomes, caspase-1 activation leads to pyroptosis mediated by gasdermin D, but cells lacking gasdermin-D still initiate caspase-dependent cell death. Here, Tsuchiya et al. show that these cells undergo Bid- and caspase-3-dependent apoptosis.

Obesity is generally considered an inflammatory state. Vishwa Dixit and his colleagues have now shown that excess dietary lipids leads to the activation of the Nlrp3 inflammasome, a sensor of the innate immune system, and that its genetic deficiency results in decreased inflammation and improved insulin sensitivity. These results suggest a possible new therapeutic avenue to treat the effects of obesity. The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.

Infection with Burkholderia pseudomallei or B. thailandensis triggers activation of the NLRP3 and NLRC4 inflammasomes leading to release of IL-1β and IL-18 and death of infected macrophages by pyroptosis, respectively. The non-canonical inflammasome composed of caspase-11 is also activated by these bacteria and provides protection through induction of pyroptosis. The recent generation of bona fide caspase-1-deficient mice allowed us to reexamine in a mouse model of pneumonic melioidosis the role of caspase-1 independently of caspase-11 (that was also absent in previously generated Casp1-/- mice). Mice lacking either caspase-1 or caspase-11 were significantly more susceptible than wild type mice to intranasal infection with B. thailandensis. Absence of caspase-1 completely abolished production of IL-1β and IL-18 as well as pyroptosis of infected macrophages. In contrast, in mice lacking caspase-11 IL-1β and IL-18 were produced at normal level and macrophages pyroptosis was only marginally affected. Adoptive transfer of bone marrow indicated that caspase-11 exerted its protective action both in myeloid cells and in radio-resistant cell types. B. thailandensis was shown to readily infect mouse lung epithelial cells triggering pyroptosis in a caspase-11-dependent way in vitro and in vivo. Importantly, we show that lung epithelial cells do not express inflammasomes components or caspase-1 suggesting that this cell type relies exclusively on caspase-11 for undergoing cell death in response to bacterial infection. Finally, we show that IL-18's protective action in melioidosis was completely dependent on its ability to induce IFNγ production. In turn, protection conferred by IFNγ against melioidosis was dependent on generation of ROS through the NADPH oxidase but independent of induction of caspase-11. Altogether, our results identify two non-redundant protective roles for caspase-1 and caspase-11 in melioidosis: Caspase-1 primarily controls pyroptosis of infected macrophages and production of IL-18. In contrast, caspase-11 mediates pyroptosis of infected lung epithelial cells.

The inflammasome is a complex of proteins that has a critical role in mounting an inflammatory response in reply to a harmful stimulus that compromises the homeostatic state of the tissue. The NLRP3 inflammasome, which is found in a wound-like environment, is comprised of three components: the NLRP3, the adaptor protein ASC and caspase-1. Interestingly, although ASC levels do not fluctuate, caspase-1 levels are elevated in both physiological and pathological conditions. Despite the observation that merely raising caspase-1 levels is sufficient to induce inflammation, the crucial question regarding the mechanism governing its expression is unexplored. We found that, in an inflammatory microenvironment, caspase-1 is regulated by NF-κB. Consistent with this association, the inhibition of caspase-1 activity parallels the effects on wound healing caused by the abrogation of NF-κB activation. Surprisingly, not only does inhibition of the NF-κB/caspase-1 axis disrupt the inflammatory phase of the wound-healing program, but it also impairs the stimulation of cutaneous epithelial stem cells of the proliferative phase. These data provide a mechanistic basis for the complex interplay between different phases of the wound-healing response in which the downstream signaling activity of immune cells can kindle the amplification of local stem cells to advance tissue repair.

Alcoholic liver disease (ALD) is characterized by steatosis and upregulation of proinflammatory cytokines, including IL-1β. IL-1β, type I IL-1 receptor (IL-1R1), and IL-1 receptor antagonist (IL-1Ra) are all important regulators of the IL-1 signaling complex, which plays a role in inflammation. Furthermore, IL-1β maturation is dependent on caspase-1 (Casp-1). Using IL-1Ra-treated mice as well as 3 mouse models deficient in regulators of IL-1β activation (Casp-1 and ASC) or signaling (IL-1R1), we found that IL-1β signaling is required for the development of alcohol-induced liver steatosis, inflammation, and injury. Increased IL-1β was due to upregulation of Casp-1 activity and inflammasome activation. The pathogenic role of IL-1 signaling in ALD was attributable to the activation of the inflammasome in BM-derived Kupffer cells. Importantly, in vivo intervention with a recombinant IL-1Ra blocked IL-1 signaling and markedly attenuated alcohol-induced liver inflammation, steatosis, and damage. Furthermore, physiological doses of IL-1β induced steatosis, increased the inflammatory and prosteatotic chemokine MCP-1 in hepatocytes, and augmented TLR4-dependent upregulation of inflammatory signaling in macrophages. In conclusion, we demonstrated that Casp-1-dependent upregulation of IL-1β and signaling mediated by IL-1R1 are crucial in ALD pathogenesis. Our findings suggest a potential role of IL-1R1 inhibition in the treatment of ALD.

Caspase-1 also triggers an uncontrolled form of cell death known as pyroptosis, which results in the release of pro-inflammatory mediators and other cellular contents into the extracellular environment, further inducing inflammatory responses. [...]activation of the inflammasome is crucial for the induction of caspase-1-dependent processing, maturation and secretion of IL-1[beta]. Inflammasome-mediated IL-1[beta] responses are induced in the lung during smoke exposure and infection. [...]it is likely that excessive inflammasome activation and IL-1[beta] responses contribute to the complex inflammatory processes that underpin the development of COPD and neutrophilic asthma as well as infection-associated exacerbations that promote progression into more severe disease ( figure 1 ).

BackgroundThe proinflammatory cytokines interleukin 1β (IL-1β) and IL-18 are central players in the pathogenesis of inflammatory bowel disease (IBD). In response to a variety of microbial components and crystalline substances, both cytokines are processed via the caspase-1-activating multiprotein complex, the NLRP3 inflammasome. Here, the role of the NLRP3 inflammasome in experimental colitis induced by dextran sodium sulfate (DSS) was examined.MethodsIL-1β production in response to DSS was studied in macrophages of wild-type, caspase-1−/−, NLRP3−/−, ASC−/−, cathepsin B−/− or cathepsin L−/− mice. Colitis was induced in C57BL/6 and NLRP3−/− mice by oral DSS administration. A clinical disease activity score was evaluated daily. Histological colitis severity and expression of cytokines were determined in colonic tissue.ResultsMacrophages incubated with DSS in vitro secreted high levels of IL-1β in a caspase-1-dependent manner. IL-1β secretion was abrogated in macrophages lacking NLRP3, ASC or caspase-1, indicating that DSS activates caspase-1 via the NLRP3 inflammasome. Moreover, IL-1β secretion was dependent on phagocytosis, lysosomal maturation, cathepsin B and L, and reactive oxygen species (ROS). After oral administration of DSS, NLRP3−/− mice developed a less severe colitis than wild-type mice and produced lower levels of proinflammatory cytokines in colonic tissue. Pharmacological inhibition of caspase-1 with pralnacasan achieved a level of mucosal protection comparable with NLRP3 deficiency.ConclusionsThe NLRP3 inflammasome was identified as a critical mechanism of intestinal inflammation in the DSS colitis model. The NLRP3 inflammasome may serve as a potential target for the development of novel therapeutics for patients with IBD.

Extracellular ATP is a signal of tissue damage and induces macrophage responses that amplify inflammation and coagulation. Here we demonstrate that ATP signaling through macrophage P2X7 receptors uncouples the thioredoxin (TRX)/TRX reductase (TRXR) system and activates the inflammasome through endosome-generated ROS. TRXR and inflammasome activity promoted filopodia formation, cellular release of reduced TRX, and generation of extracellular thiol pathway-dependent, procoagulant microparticles (MPs). Additionally, inflammasome-induced activation of an intracellular caspase-1/calpain cysteine protease cascade degraded filamin, thereby severing bonds between the cytoskeleton and tissue factor (TF), the cell surface receptor responsible for coagulation activation. This cascade enabled TF trafficking from rafts to filopodia and ultimately onto phosphatidylserine-positive, highly procoagulant MPs. Furthermore, caspase-1 specifically facilitated cell surface actin exposure, which was required for the final release of highly procoagulant MPs from filopodia. Together, the results of this study delineate a thromboinflammatory pathway and suggest that components of this pathway have potential as pharmacological targets to simultaneously attenuate inflammation and innate immune cell-induced thrombosis.

Key Points In addition to mediating the maturation and secretion of the cytokines interleukin-1β (IL-1β) and IL-18, caspase 1 activation by inflammasome complexes controls a set of non-canonical effectors that might contribute to the immune response during infection and autoimmunity. These mechanisms include unconventional protein secretion, pyroptosis, regulation of metabolic pathways and restriction of bacterial replication. Caspase 1 activation in macrophages, epithelial cells and keratinocytes drives unconventional protein secretion of leaderless cytokines such as IL-1α, IL-1β and IL-18, growth factors such as fibroblast growth factor 2 and possibly damage-associated molecular patterns such as high mobility group box 1. After their release into the extracellular environment, these factors can enhance inflammatory and healing responses. Infected myeloid cells can remove intracellular replication niches for pathogens by inducing pyroptosis, a specialized caspase 1-dependent cell death programme. Pyroptosis is accompanied by osmotic lysis and the release of the intracellular content into the extracellular milieu, and this is thought (together with other inflammasome functions) to render it an inherently pro-inflammatory cell death mode. Pyroptosis is thought to confer resistance to infection with intracellular pathogens in vivo , illustrating the importance of this cell death mode for host defence. Caspase 1 can cleave poly(ADP-ribose) polymerase 1 (PARP1) and glycolysis enzymes (such as glyceraldehyde-3-phosphate dehydrogenase) to preserve ATP energy stores and to decrease the metabolic rate of infected cells. As such, caspase 1-mediated targeting of bioenergetic pathways might help to preserve cellular energy stores during infection. Caspase 1 activates lipid metabolic pathways in fibroblasts intoxicated with pore-forming toxins or infected with bacteria that produce these toxins. This leads to the repair of toxin-induced damage to the plasma membrane and promotes cell survival. In a process that proceeds independently of IL-1β and IL-18, caspase 1-mediated activation of caspase 7, an executioner caspase, contributes to the restriction of Legionella pneumophila replication in infected macrophages. In vivo studies have shown the importance of this inflammasome pathway for host defence against L. pneumophila infection in the lungs. Recent studies have shown that caspase 1 activation by inflammasomes controls a set of non-canonical effector mechanisms that might contribute to the immune response during infection and autoimmunity. These mechanisms include unconventional protein secretion, pyroptosis, regulation of metabolic pathways and restriction of bacterial replication. Caspase 1 activation by inflammasome complexes in response to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) induces the maturation and secretion of the pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Recent reports have begun to identify additional inflammasome effector mechanisms that proceed independently of IL-1β and IL-18. These include the induction of pyroptotic cell death, the restriction of bacterial replication, the activation of lipid metabolic pathways for cell repair and the secretion of DAMPs and leaderless cytokines. These non-canonical functions of caspase 1 illustrate the diverse mechanisms by which inflammasomes might contribute to innate immunity, repair responses and host defence.

This Timeline article provides an overview of the discovery and proposed mechanisms of action of aluminium salts, the most widely used vaccine adjuvants. The recent progresses and outstanding controversies on how aluminium salts function as adjuvants are also discussed. The efficacy of vaccines depends on the presence of an adjuvant in conjunction with the antigen. Of these adjuvants, the ones that contain aluminium, which were first discovered empirically in 1926, are currently the most widely used. However, a detailed understanding of their mechanism of action has only started to be revealed. In this Timeline article, we briefly describe the initial discovery of aluminium adjuvants and discuss historically important advances. We also summarize recent progress in the field and discuss their implications and the remaining questions on how these adjuvants work.