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Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II - , PD-L1 lo ] neutrophils produced inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and "accelerated" deleterious inflammation, which was highly exacerbated in IFN-γR -/- mice. Regulatory [MHC-II + , PD-L1 hi ] neutrophils "brake" inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyperinflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1., (© 2024 Doz-Deblauwe et al.)

Protein ubiquitination regulates protein stability and modulates the composition of signaling complexes. A20 is a negative regulator of inflammatory signaling, but the molecular mechanisms involved are ill understood. Here, we generated Tnfaip3 gene-targeted A20 mutant mice bearing inactivating mutations in the zinc finger 7 (ZnF7) and ZnF4 ubiquitin-binding domains, revealing that binding to polyubiquitin is essential for A20 to suppress inflammatory disease. We demonstrate that a functional ZnF7 domain was required for recruiting A20 to the tumor necrosis factor receptor 1 (TNFR1) signaling complex and to suppress inflammatory signaling and cell death. The combined inactivation of ZnF4 and ZnF7 phenocopied the postnatal lethality and severe multiorgan inflammation of A20-deficient mice. Conditional tissue-specific expression of mutant A20 further revealed the key role of ubiquitin-binding in myeloid and intestinal epithelial cells. Collectively, these results demonstrate that the anti-inflammatory and cytoprotective functions of A20 are largely dependent on its ubiquitin-binding properties.

Caspases are an evolutionary conserved family of cysteine proteases that are centrally involved in cell death and inflammation responses. A wealth of foundational insight into the molecular mechanisms that control caspase activation has emerged in recent years. Important advancements include the identification of additional inflammasome platforms and pathways that regulate activation of inflammatory caspases; the discovery of gasdermin D as the effector of pyroptosis and interleukin (IL)-1 and IL-18 secretion; and the existence of substantial crosstalk between inflammatory and apoptotic initiator caspases. A better understanding of the mechanisms regulating caspase activation has supported initial efforts to modulate dysfunctional cell death and inflammation pathways in a suite of communicable, inflammatory, malignant, metabolic, and neurodegenerative diseases. Here, we review current understanding of caspase biology with a prime focus on the inflammatory caspases and outline important topics for future experimentation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Pyroptosis is an inflammasome-induced lytic cell death mode, the physiological role of which in chronic inflammatory diseases is unknown. Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease worldwide, affecting an estimated 150,000 patients. The disease is caused by missense mutations in Mefv that activate the Pyrin inflammasome, but the pathophysiologic mechanisms driving autoinflammation in FMF are incompletely understood. Here, we show that Clostridium difficile infection of FMF knock-in macrophages that express a chimeric FMF-associated Mefv V726A Pyrin elicited pyroptosis and gasdermin D (GSDMD)-mediated interleukin (IL)-1β secretion. Importantly, in vivo GSDMD deletion abolished spontaneous autoinflammatory disease. GSDMD-deficient FMF knock-in mice were fully protected from the runted growth, anemia, systemic inflammatory cytokine production, neutrophilia, and tissue damage that characterize this autoinflammatory disease model. Overall, this work identifies pyroptosis as a critical mechanism of IL-1β-dependent autoinflammation in FMF and highlights GSDMD inhibition as a potential antiinflammatory strategy in inflammasome-driven diseases., (© 2018 Kanneganti et al.)

Injury and physical trauma may inflict accidental cell death, but we have come to realize during the past four decades that cells may also actively engage cell death when needed. These regulated cell death forms are intrinsically connected with human embryonic development, homeostatic maintenance and disease pathology. For instance, the human body is composed of approximately 10(14) cells, millions of which are removed daily by apoptosis and replaced with newly differentiated cells in order to secure organ functionality. Apoptotic cells are orderly packed in 'apoptotic bodies' for uptake by neighboring cells and professional phagocytes, thereby avoiding deleterious inflammatory responses by circulating leukocytes. Unlike apoptosis, however, more recently identified forms of regulated cell death - such as necroptosis and pyroptosis - are characterized by an early breach of the plasma membrane integrity, which results in extracellular spilling of the intracellular contents. Here, we will describe and discuss this and other features of pyroptosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Over recent years, inflammasomes have emerged as key regulators of immune and inflammatory responses. They induce programmed cell death and direct the release of danger signals and the inflammatory cytokines interleukin (IL)-1β and IL-18. The concerted actions of inflammasomes are of utmost importance for responding adequately to harmful environmental agents and infections. However, deregulated inflammasome signaling is increasingly linked to a diversity of human pathologies, including rheumatoid arthritis, inflammatory bowel disease, and rare, hereditary periodic fever syndromes. In this review, we discuss recent insight in the protective and detrimental roles of inflammasomes in selected infectious, autoinflammatory and autoimmune diseases, and cover clinically approved therapies that interfere with inflammasome signaling. These findings highlight the importance of fine-balancing the Ying and Yang activities of inflammasomes for sustained homeostasis and suggest that further understanding of inflammasome mechanisms may offer new cures for human diseases.

The innate immune system represents the first line of defence against infectious agents, and co-ordinates cellular and molecular mechanisms that result in effective inflammatory and anti-microbial responses against pathogens. Infection and cellular stress trigger assembly of canonical and noncanonical inflammasome complexes that activate the inflammatory caspases-1 and -11, respectively. These inflammatory caspases play key roles in innate immune responses by inducing pyroptosis to halt intracellular replication of pathogens, and by engaging the extracellular release of pro-inflammatory cytokines and danger signals. In addition, the inflammatory caspases-4, -5 and -11 were recently shown to directly bind microbial components. Although the immune roles of caspase-12 are debated, it was proposed to dampen inflammatory responses by interfering with caspase-1 activation and other innate immune pathways. Here, we recapitulate the reported roles of inflammatory caspases with an emphasis on recent insights into their biological functions.

Inflammasomes are a set of intracellular protein complexes that enable autocatalytic activation of inflammatory caspases, which drive host and immune responses by releasing cytokines and alarmins into circulation and by inducing pyroptosis, a proinflammatory cell death mode. The inflammasome type mediating these responses varies with the microbial pathogen or stress factor that poses a threat to the organism. Since the discovery that polymorphisms in inflammasome genes are linked to common autoimmune diseases and less frequent periodic fever syndromes, inflammasome signaling has been dissected at the molecular level. In this review, we present recently gained insight on the distinct inflammasome types, their activation and effector mechanisms, and their modulation by microbial virulence factors. In addition, we discuss recently gained knowledge on the role of deregulated inflammasome activity in human autoinflammatory, autoimmune, and infectious diseases.

Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis constitute a major health problem in developed countries. Moreover, IBD predisposes to the development of colorectal cancer. The intracellular NOD-like receptor Nlrp3 is rapidly emerging as a crucial regulator of intestinal homeostasis. This innate immune receptor mediates assembly of the inflammasome complex in the presence of microbial ligands, triggering caspase-1 activation and secretion of IL-1β and IL-18. Recent studies suggest that defective Nlrp3 inflammasome signaling in the gut contributes to IBD through increased permeability across the epithelial barrier and the induction of detrimental immune responses against invading commensals. Here, we review and discuss recent advances of the role of the Nlrp3 inflammasome in colitis and colon tumorigenesis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking, caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence of another caspase 1-dependent mediator of endotoxemia. Reduced serum high mobility group box 1 (HMGB1) levels in caspase 1-deficient mice correlated with their resistance to LPS. A critical role for HMGB1 in endotoxemia was confirmed when mice deficient for IL-1β and IL-18 were protected from a lethal dose of LPS by pretreatment with HMGB1-neutralizing Abs. We found that HMGB1 secretion from LPS-primed macrophages required the inflammasome components apoptotic speck protein containing a caspase activation and recruitment domain (ASC), caspase 1 and Nalp3, whereas HMGB1 secretion from macrophages infected in vitro with Salmonella typhimurium was dependent on caspase 1 and Ipaf. Thus, HMGB1 secretion, which is critical for endotoxemia, occurs downstream of inflammasome assembly and caspase 1 activation.

Caspase-mediated cleavage of the DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP1) is a hallmark of apoptosis. However, it remains unclear whether PARP1 is processed during pyroptosis, a specialized cell-death program that occurs upon activation of caspase-1 in inflammasome complexes. In this article, we show that activation of the Nlrp3 and Nlrc4 inflammasomes induces processing of full-length PARP1 into a fragment of 89 kDa in a stimulus-dependent manner. Macrophages deficient for caspase-1 and those lacking the inflammasome adaptors Nlrp3, Nlrc4, and ASC were highly resistant to cleavage, whereas macrophages lacking the downstream inflammasome effector caspase-7 were partially protected. A modest, but statistically significant, reduction in Nlrp3 inflammasome-induced pyroptosis was observed in PARP1 knockout macrophages. Thus, protease-mediated inactivation of PARP1 is a shared feature of apoptotic, necrotic, and pyroptotic cells.

Recent years have witnessed a marked progress in our knowledge of NOD-like receptors (NLR), intracellular sensors with central roles in innate and adaptive immunity. A majority of the research has focused on caspase-1 inflammasomes. However, several members of the mammalian NLR family exert important roles in immunity beyond inflammasome signaling. Here we highlight the emerging roles of several of these NLR.

Caspase-7 was considered to be redundant with caspase-3 because these related cysteine proteases share an optimal peptide recognition sequence and have several endogenous protein substrates in common. In addition, both caspases are proteolytically activated by the initiator caspase-8 and -9 during death receptor- and DNA-damage-induced apoptosis, respectively. However, a growing body of biochemical and physiological data indicate that caspase-7 also differs in significant ways from caspase-3. For instance, several substrates are specifically cleaved by caspase-7, but not caspase-3. Moreover, caspase-7 activation requires caspase-1 inflammasomes under inflammatory conditions, while caspase-3 processing proceeds independently of caspase-1. Finally, caspase-7 deficient mice are resistant to endotoxemia, whereas caspase-3 knockout mice are susceptible. These findings suggest that specifically interfering with caspase-7 activation may hold therapeutic value for the treatment of cancer and inflammatory ailments.

Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1beta (IL-1beta) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking K(ATP) subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1beta secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome-associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1beta secretion.

Some fungal species are opportunistic pathogens that can cause infection in people with compromised immune systems. Activation of caspase-1 and the subsequent secretion of mature interleukin (IL)-1beta is a major signaling pathway of the innate immune system, but how yeasts induce caspase-1 activation is unknown. We show here that stimulation of macrophages and dendritic cells with heat-killed Saccharomyces cerevisiae or the purified cell wall components zymosan and mannan induced caspase-1 activation and IL-1beta secretion when combined with ATP. Macrophages deficient for the inflammasome adaptor ASC were defective in caspase-1 activation and IL-1beta secretion, suggesting involvement of an ASC-dependent inflammasome. Indeed, caspase-1 activation was abrogated in macrophages lacking the NOD-like (NLR) protein Cryopyrin/Nalp3 and in wild type macrophages pretreated with the pannexin-1 inhibitor probenecid. IL-1beta secretion further required the Toll-like receptor (TLR) adaptors MyD88 and TRIF, and partially relied on TLR2. We previously showed that bacterial molecules such as lipopolysaccharide (LPS) and peptidoglycan induce activation of caspase-7 through the Cryopyrin inflammasome. Similarly, Cryopyrin and ASC were required for activation of caspase-7 in macrophages stimulated with zymosan or mannan and ATP. These results demonstrate that the conserved fungal components zymosan and mannan require ASC and Cryopyrin for caspase-1 activation and IL-1beta secretion and suggest an important role for the Cryopyrin inflammasome during fungal infections.

The aspartate-specific cysteine protease caspase-1 is activated by the inflammasomes and is responsible for the proteolytic maturation of the cytokines IL-1 beta and IL-18 during infection and inflammation. To discover new caspase-1 substrates, we made use of a proteome-wide gel-free differential peptide sorting methodology that allows unambiguous localization of the processing site in addition to identification of the substrate. Of the 1022 proteins that were identified, 20 were found to be specifically cleaved after Asp in the setup incubated with recombinant caspase-1. Interestingly, caspase-7 emerged as one of the identified caspase-1 substrates. Moreover half of the other identified cleavage events occurred at sites closely resembling the consensus caspase-7 recognition sequence DEVD, suggesting caspase-1-mediated activation of endogenous caspase-7 in this setup. Consistently recombinant caspase-1 cleaved caspase-7 at the canonical activation sites Asp(23) and Asp(198), and recombinant caspase-7 processed a subset of the identified substrates. In vivo, caspase-7 activation was observed in conditions known to induce activation of caspase-1, including Salmonella infection and microbial stimuli combined with ATP. Interestingly Salmonella- and lipopolysaccharide + ATP-induced activation of caspase-7 was abolished in macrophages deficient in caspase-1, the pattern recognition receptors Ipaf and Cryopyrin, and the inflammasome adaptor ASC, demonstrating an upstream role for the caspase-1 inflammasomes in caspase-7 activation in vivo. In contrast, caspase-1 and the inflammasomes were not required for caspase-3 activation. In conclusion, we identified 20 new substrates activated downstream of caspase-1 and validated caspase-1-mediated caspase-7 activation in vitro and in knock-out macrophages. These results demonstrate for the first time the existence of a nucleotide binding and oligomerization domain-like receptor/caspase-1/caspase-7 cascade and the existence of distinct activation mechanisms for caspase-3 and -7 in response to microbial stimuli and bacterial infection.

Nucleotide-binding and oligomerization domain-like receptors (NLRs) constitute a family of germline-encoded pattern-recognition receptors, which allow the host to respond rapidly to a wide variety of pathogenic microorganisms. Here, we discuss recent advances in the study of a subset of NLRs, which control the activation of caspase-1 through the assembly of large protein complexes, inflammasomes. The NALP1b inflammasome recognizes anthrax lethal toxin, and flagellin from Salmonella and Legionella induces assembly of the Ipaf inflammasome. Cryopyrin/NALP3 mediates caspase-1 activation in response to a wide variety of bacterial ligands, imidazoquinolines, dsRNA, and the endogenous danger signal uric acid. The importance of these cytosolic receptors in immune regulation is underscored by the identification of mutations in cryopyrin/NALP3, which are genetically linked to human autoinflammatory disorders.

This review provides an overview of the biochemistry and activation of inflammatory caspases, and focuses on their therapeutic potential as disease targets in pathologies such as sepsis, Crohn's disease, rheumatoid arthritis, traumatic brain injury and amyotrophic lateral sclerosis (ALS). We summarize the proof-of-principal evidence obtained by studies in several corresponding experimental disease models confirming the validity of strategies targeting inflammatory caspases. We discuss the use of inflammatory caspase inhibitors, such as VX-740 (Pralnacasan) and VX-765, in clinical studies for rheumatoid arthritis and osteoarthritis. Finally, we point out recent approaches identifying novel peptidomimetic or non-peptide caspase inhibitors with suitable clinical profiles.

Phylogenetic analysis clusters caspase-12 with the inflammatory caspases 1 and 11. We analyzed the expression of caspase-12 in mouse embryos, adult organs, and different cell types and tested the effect of interferons (IFNs) and other proinflammatory stimuli. Constitutive expression of the caspase-12 protein was restricted to certain cell types, such as epithelial cells, primary fibroblasts, and L929 fibrosarcoma cells. In fibroblasts and B16/B16 melanoma cells, caspase-12 expression is stimulated by IFN-gamma but not by IFN-alpha or -beta. The effect is increased further when IFN-gamma is combined with TNF, lipopolysaccharide (LPS), or dsRNA. These stimuli also induce caspase-1 and -11 but inhibit the expression of caspase-3 and -9. In contrast to caspase-1 and -11, no caspase-12 protein was detected in macrophages in any of these treatments. Transient overexpression of full-length caspase-12 leads to proteolytic processing of the enzyme and apoptosis. Similar processing occurs in TNF-, LPS-, Fas ligand-, and thapsigargin (Tg)-induced apoptosis. However, B16/B16 melanoma cells die when treated with the ER stress-inducing agent Tg whether they express caspase-12 or not.

Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H+ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated. We have previously shown upregulation of NLRP2 in human cystinotic proximal tubular epithelial cells and its role in promoting inflammatory and profibrotic responses. Herein, we have investigated the role of NLRP2 in vivo using a mouse model of cystinosis in which we have confirmed upregulation of Nlrp2 in the renal parenchyma. Our studies show that double knock out Ctns-/- Nlrp2-/- animals exhibit delayed development of Fanconi syndrome and kidney tissue damage. Specifically, we observed at 4-6 months of age that animals had less glucosuria and calciuria and markedly preserved renal tissue, as assessed by significantly lower levels of inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis. Also, the mRNA expression of some inflammatory mediators (Cxcl1 and Saa1) and the rate of apoptosis were significantly decreased in 4-6-month old kidneys harvested from Ctns-/- Nlrp2-/- mice compared to those obtained from Ctns-/-mice. At 12-14 months of age, renal histological was markedly altered in both genetic models, although double KO animals had lower degree of polyuria and low molecular weight proteinuria and decreased mRNA expression levels of Il6 and Mcp1. Altogether, these data indicate that Nlrp2 is a potential pharmacological target for delaying progression of kidney disease in cystinosis. [ABSTRACT FROM AUTHOR]

Inflammasomes are macromolecular complexes formed in response to pathogen‐associated molecular patterns (PAMPs) and danger‐associated molecular patterns (DAMPs) that drive maturation of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18, and cleave gasdermin D (GSDMD) for induction of pyroptosis. Inflammasomes are highly important in protecting the host from various microbial pathogens and sterile insults. Inflammasome pathways are strictly regulated at both transcriptional and post‐translational checkpoints. When these checkpoints are not properly imposed, undue inflammasome activation may promote inflammatory, metabolic and oncogenic processes that give rise to autoinflammatory, autoimmune, metabolic and malignant diseases. In addition to clinically approved IL‐1‐targeted biologics, upstream targeting of inflammasome pathways recently gained interest as a novel pharmacological strategy for selectively modulating inflammasome activation in pathological conditions. [ABSTRACT FROM AUTHOR]

Two decades of inflammasome research has led to a vast body of knowledge on the complex regulatory mechanisms and pathological roles of canonical and non-canonical inflammasome activation in a plethora of research models of primarily rodent origin. More recently, the field has made notable progress in characterizing human-specific inflammasomes and their regulation mechanisms, including an expansion of inflammasome biology to adaptive immune cells. These exciting developments in basic research have been accompanied by potentially transformative results from large clinical trials and translational efforts to develop inflammasome-targeted small molecule inhibitors for therapeutic use. Here, we will discuss recent findings in the field with a specific emphasis on activation mechanisms of human inflammasomes and their potential role in auto-inflammatory, metabolic and neoplastic diseases. [ABSTRACT FROM AUTHOR]

Inflammasomes are multi-protein platforms that are organized in the cytosol to cope with pathogens and cellular stress. The pattern recognition receptors NLRP1, NLRP3, NLRC4, AIM2 and Pyrin all assemble canonical platforms for caspase-1 activation, while caspase-11-dependent inflammasomes respond to intracellular Gram-negative pathogens. Inflammasomes are chiefly known for their roles in maturation and secretion of the inflammatory cytokines interleukin-(IL)1β and IL18, but they can also induce regulated cell death. Activation of caspases 1 and 11 in myeloid cells can trigger pyroptosis, a lytic and inflammatory cell death mode. Pyroptosis has been implicated in secretion of IL1β, IL18 and intracellular alarmins. Akin to these factors, it may have beneficial roles in controlling pathogen replication, but become detrimental in the context of chronic autoinflammatory diseases. Inflammasomes are increasingly implicated in induction of additional regulated cell death modes such as pyronecrosis and apoptosis. In this review, we overview recent advances in inflammasome-associated cell death research, illustrating the polyvalent roles of these macromolecular platforms in regulated cell death signaling. [ABSTRACT FROM AUTHOR]

Membrane-bound and intracellular immune receptors respond to microbial pathogens by initiating signaling cascades that result in production of inflammatory cytokines and antimicrobial factors. These host responses need to be tightly regulated to prevent tissue damage and other harmful consequences of excessive inflammation. CARD-only proteins ( COPs) and Pyrin-only proteins ( POPs) are human- and primate-specific dominant negative inhibitors that modulate inflammatory and innate immune responses. In addition, several poxviruses encode POPs that interfere with inflammatory and host defense responses. COPs and POPs modulate inflammatory signaling at several checkpoints by sequestering key components of the inflammasome and NF-κB signaling cascades, thus hampering downstream signal transduction. Here, we review and discuss current understanding of the evolutionary history and molecular mechanisms by which roles of host- and virus-encoded COPs and POPs may regulate inflammatory and immune responses. In addition, we address their (patho)physiological roles and highlight topics for further research. [ABSTRACT FROM AUTHOR]

The innate immune system represents the first line of defence against infectious agents, and co-ordinates cellular and molecular mechanisms that result in effective inflammatory and anti-microbial responses against pathogens. Infection and cellular stress trigger assembly of canonical and noncanonical inflammasome complexes that activate the inflammatory caspases-1 and -11, respectively. These inflammatory caspases play key roles in innate immune responses by inducing pyroptosis to halt intracellular replication of pathogens, and by engaging the extracellular release of pro-inflammatory cytokines and danger signals. In addition, the inflammatory caspases-4, -5 and -11 were recently shown to directly bind microbial components. Although the immune roles of caspase-12 are debated, it was proposed to dampen inflammatory responses by interfering with caspase-1 activation and other innate immune pathways. Here, we recapitulate the reported roles of inflammatory caspases with an emphasis on recent insights into their biological functions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of interleukin-1β in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20myel-KO mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients. Rheumatoid arthritis in A20myel-KO mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2). Here we show, however, that it crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, because deletion of Nlrp3, caspase-1 and the interleukin-1 receptor markedly protects against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20myel-KO mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20myel-KO mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The respiratory tract of human subjects is constantly exposed to harmful microbes and air pollutants. The immune system responds to these offenders to protect the host, but an unbalanced inflammatory response itself may promote tissue damage and ultimately lead to acute and chronic respiratory diseases. Deregulated inflammasome activation is emerging as a key modulator of respiratory infections and pathologic airway inflammation in patients with asthma, COPD, and pulmonary fibrosis. Assembly of these intracellular danger sensors in cells of the respiratory mucosa and alveolar compartment triggers a proinflammatory cell death mode termed pyroptosis and leads to secretion of bioactive IL-1β and IL-18. Here, we summarize and review the inflammasome and its downstream effectors as therapeutic targets for the treatment of respiratory diseases. [ABSTRACT FROM AUTHOR]

The protein-tyrosine phosphatase SHP-1 has critical roles in immune signalling, but how mutations in SHP-1 cause inflammatory disease in humans remains poorly defined. Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation. Here we report that receptor-interacting protein 1 (RIP1)-regulated interleukin (IL)-1α production by haematopoietic cells critically mediates chronic inflammatory disease in Ptpn6spin mice, whereas inflammasome signalling and IL-1β-mediated events are dispensable. IL-1α was also crucial for exacerbated inflammatory responses and unremitting tissue damage upon footpad microabrasion of Ptpn6spin mice. Notably, pharmacological and genetic blockade of the kinase RIP1 protected against wound-induced inflammation and tissue damage in Ptpn6spin mice, whereas RIP3 deletion failed to do so. Moreover, RIP1-mediated inflammatory cytokine production was attenuated by NF-κB and ERK inhibition. Together, our results indicate that wound-induced tissue damage and chronic inflammation in Ptpn6spin mice are critically dependent on RIP1-mediated IL-1α production, whereas inflammasome signalling and RIP3-mediated necroptosis are dispensable. Thus, we have unravelled a novel inflammatory circuit in which RIP1-mediated IL-1α secretion in response to deregulated SHP-1 activity triggers an inflammatory destructive disease that proceeds independently of inflammasomes and programmed necrosis. [ABSTRACT FROM AUTHOR]

Inflammasomes are emerging as key regulators of the host response against microbial pathogens. These cytosolic multiprotein complexes recruit and activate the cysteine protease caspase-1 when microbes invade sterile tissues or elicit cellular damage. Inflammasome-activated caspase-1 induces inflammation by cleaving the proinflammatory cytokines IL-1β and IL-18 into their biologically active forms and by releasing the alarmin HMGB1 into the extracellular milieu. Additionally, inflammasomes counter bacterial replication and clear infected immune cells through an inflammatory cell death program termed pyroptosis. As a countermeasure, bacterial and viral pathogens evolved virulence factors to antagonize inflammasome pathways. In this review, we discuss recent progress on how inflammasomes contribute to host defense against bacterial and viral pathogens, and we review how viruses and bacteria modulate inflammasome function to their benefit. [ABSTRACT FROM AUTHOR]

Caspases are a family of cysteine proteases that are essential in the initiation and execution of apoptosis and the proteolytic maturation of inflammatory cytokines such as IL-1β and IL-18. Caspases can be subdivided into those that have a large prodomain and those that have not. In general, apoptotic and inflammatory signalling pathways are initiated when large-prodomain caspases are recruited to large protein complexes via homotypic interactions involving death domain folds. The formation of these specialised multimeric platforms involves three major functions: (1) the sensing of cellular stress, damage, infection or inflammation; (2) multimerisation of the platform; and (3) recruitment and conformational activation of caspases. In this overview we discuss the complexes implicated in the regulation of cell death and inflammatory processes such as the death-inducing signalling complex (DISC), the apoptosome, the inflammasomes and the PIDDosome. We describe their sensing functions, compositions and functional outcomes. Inhibitory protein families such as FLIPs and CARD-only proteins prevent the recruitment of caspases in these sensing complexes, avoiding inappropriate initiation of cell death or inflammation. [ABSTRACT FROM AUTHOR]

The proteolytic activity of the cysteinyl aspartate--specific proteases, named caspases, mainly connotes their central role in apoptosis and inflammation. In this review we report on recent data on the role of caspases in the activation of nuclear factor κB (NF-κB), a transcription factor that fulfils a central role in innate and adaptive immunity, in cellular stress responses and in the induction of anti-apoptotic factors. Two different mechanisms by which caspases activate the NF-κB pathway are discussed. [ABSTRACT FROM AUTHOR]

The enzymatic activity of caspases is implicated in the execution of apoptosis and inflammation. Here we demonstrate a novel nonenzymatic function for caspase-2 other than its reported proteolytic role in apoptosis. Caspase-2, unlike caspase-3, -6, -7, -9, -11, -12, and -14, is a potent inducer of NF-κB and p38 MAPK activation in a TRAF2-mediated way. Caspase-2 interacts with TRAF1, TBAF2, and RIP1. Furthermore, we demonstrate that endogenous caspase-2 is recruited into a large and inducible protein complex, together with TRAF2 and RIP1. Structure-function analysis shows that NF-κB activation occurs independent of enzymatic activity of the protease and that the caspase recruitment domain of caspase-2 is sufficient for the activation of NF-κB and p38 MAPK. These results demonstrate the inducible assembly of a novel protein complex consisting of caspase-2, TRAF2, and RIP1 that activates NF-κB and p38 MAPK through the caspase recruitment domain of caspase-2 independently of its proteolytic activity. [ABSTRACT FROM AUTHOR]

The proteolytic activity of caspases is involved in apoptosis and inflammation. In this regard, caspase-1 is required for pro-interleukin (IL)-1β and pro-IL-18 maturation. We report here on a novel function of caspase-1 as an activator of nuclear factor of the κ-enhancer in B-cells (NF-κB) and p38 mitogen-activated protein kinase (MAPK). This function is not shared by the murine caspase-1 homologues caspase-11 and -12. In contrast to pro-IL-1β maturation, caspase-1-induced NF-κB activation is not inhibited by the virus-derived caspase-1 inhibitor cytokine response modifier A and is equally induced by the enzymatically inactive caspase-1 C285A mutant. Although the general NF-κB-inhibiting protein A20 inhibits caspase-1-derived activation of NF-κB, dominant-negative forms of TRAF2 and RIP1 have no effect. We demonstrate that caspase-1 interacts with RIP2 and that dominant-negative forms of RIP2 and IκB kinase complex-β inhibit caspase-1-mediated NF-κB activation. Structure-function analysis shows that the caspase recruitment domain of caspase-1 mediates the activation of NF-κB and p38 MAPK. These data demonstrate that caspase-1 contributes to inflammation by two distinct pathways: proteolysis of pro-IL-1β, and RIP2-dependent activation of NF-κB and p38 MAPK mediated by the caspase recruitment domain. [ABSTRACT FROM AUTHOR]

Colorectal cancer is a major health problem in developed countries. Chronic intestinal inflammation predisposes individuals to the development of colorectal cancer. The intracellular NOD-like receptors (NLRs) have emerged as crucial regulators of intestinal inflammation and colorectal tumorigenesis. Activation of several NLRs leads to the formation of a protein complex called the inflammasome, which then triggers the activation of the cysteine protease caspase-1 and the downstream maturation and secretion of the inflammatory cytokines interleukin (IL)-1β and -18. Defective inflammasome signaling in the gut contributes to colitis and colorectal tumorigenesis by increasing the permeability of the epithelial barrier, dysregulating the proliferation of epithelial cells, and inducing oncogenic mediators. In this review, we discuss our current knowledge on how the inflammasome protects against colorectal tumorigenesis. [ABSTRACT FROM AUTHOR]

Neutrophils are among the most abundant immune cells, representing about 50%− 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation. [ABSTRACT FROM AUTHOR]

Summary: Decreased expression of the Nlrp3 protein is associated with susceptibility to Crohn''s disease. However, the role of Nlrp3 in colitis has not been characterized. Nlrp3 interacts with the adaptor protein ASC to activate caspase-1 in inflammasomes, which are protein complexes responsible for the maturation and secretion of interleukin-1β (IL-1β) and IL-18. Here, we showed that mice deficient for Nlrp3 or ASC and caspase-1 were highly susceptible to dextran sodium sulfate (DSS)-induced colitis. Defective inflammasome activation led to loss of epithelial integrity, resulting in systemic dispersion of commensal bacteria, massive leukocyte infiltration, and increased chemokine production in the colon. This process was a consequence of a decrease in IL-18 in mice lacking components of the Nlrp3 inflammasome, resulting in higher mortality rates. Thus, the Nlrp3 inflammasome is critically involved in the maintenance of intestinal homeostasis and protection against colitis. [Copyright &y& Elsevier]