Inflammasome signalling is an emerging pillar of innate immunity and has a central role in the regulation of gastrointestinal health and disease. Activation of the inflammasome complex mediates both ...the release of the pro-inflammatory cytokines IL-1β and IL-18 and the execution of a form of inflammatory cell death known as pyroptosis. In most cases, these mediators of inflammation provide protection against bacterial, viral and protozoal infections. However, unchecked inflammasome activities perpetuate chronic inflammation, which underpins the molecular and pathophysiological basis of gastritis, IBD, upper and lower gastrointestinal cancer, nonalcoholic fatty liver disease and obesity. Studies have also highlighted an inflammasome signature in the maintenance of gut microbiota and gut-brain homeostasis. Harnessing the immunomodulatory properties of the inflammasome could transform clinical practice in the treatment of acute and chronic gastrointestinal and extragastrointestinal diseases. This Review presents an overview of inflammasome biology in gastrointestinal health and disease and describes the value of experimental and pharmacological intervention in the treatment of inflammasome-associated clinical manifestations.
The inflammasome is a cytosolic immune signaling complex that induces inflammation and pyroptosis. Inflammasome complexes respond to a variety of pathogens, as well as danger or homeostasis-altering ...signals; they can play critical roles in the development of autoinflammatory conditions and cancer. Studies have now provided additional insights into the activation mechanisms and regulation of established inflammasome complexes, including NLRP1b, NLRP3, NOD-like receptor family apoptosis inhibitory protein (NAIP)–NLRC4, absent in melanoma (AIM)2, caspase-11, and pyrin. New activators and regulators of emerging NLRP6 and NLRP9b inflammasome complexes have also been described. We highlight the latest progress in our understanding of the molecular mechanisms governing inflammasome activation and pyroptosis, including the discovery of the pore-forming protein gasdermin D (GSDMD). We also discuss the importance of inflammasome activators and regulators in health and disease.
The inflammasome family is expanding and now includes the canonical AIM2, NAIP-NLRC4, NLRP1, NLRP3, NLRP6, NLRP9b, and pyrin inflammasomes and the noncanonical caspase-11 inflammasome.Inflammasome sensors detect a growing constellation of pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and homeostasis-altering molecular processes (HAMPs).Activation of human caspase-1, -4, and -5, or mouse caspase-1 and -11, induces cleavage of the pore-forming protein GSDMD, mediating pyroptosis.Assembly and signaling of the inflammasome often requires transcriptional and translational regulation, and spatial localization of inflammasome components at the site of organelles, such as the Golgi and mitochondria.Targeting inflammasome components has potential therapeutic value in the treatment of certain infections, cancers, and inflammatory conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cytosolic innate immune sensing is a cornerstone of innate immunity in mammalian cells and provides a surveillance system for invading pathogens and endogenous danger signals. The NAIP‐NLRC4 ...inflammasome responds to cytosolic flagellin, and the inner rod and needle proteins of the type 3 secretion system of bacteria. This complex induces caspase‐1‐dependent proteolytic cleavage of the proinflammatory cytokines IL‐1β and IL‐18, and the pore‐forming protein gasdermin D, leading to inflammation and pyroptosis, respectively. Localized responses triggered by the NAIP‐NLRC4 inflammasome are largely protective against bacterial pathogens, owing to several mechanisms, including the release of inflammatory mediators, liberation of concealed intracellular pathogens for killing by other immune mechanisms, activation of apoptotic caspases, caspase‐7, and caspase‐8, and expulsion of an entire infected cell from the mammalian host. In contrast, aberrant activation of the NAIP‐NLRC4 inflammasome caused by de novo gain‐of‐function mutations in the gene encoding NLRC4 can lead to macrophage activation syndrome, neonatal enterocolitis, fetal thrombotic vasculopathy, familial cold autoinflammatory syndrome, and even death. Some of these clinical manifestations could be treated by therapeutics targeting inflammasome‐associated cytokines. In addition, the NAIP‐NLRC4 inflammasome has been implicated in the pathogenesis of colorectal cancer, melanoma, glioma, and breast cancer. However, no consensus has been reached on its function in the development of any cancer types. In this review, we highlight the latest advances in the activation mechanisms and structural assembly of the NAIP‐NLRC4 inflammasome, and the functions of this inflammasome in different cell types. We also describe progress toward understanding the role of the NAIP‐NLRC4 inflammasome in infectious diseases, autoinflammatory diseases, and cancer.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Invasive pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Aspergillus fumigatus infection produces ligands that could activate ...inflammasomes, but the contribution of these host defenses remains unclear. We show that two inflammasome receptors, AIM2 and NLRP3, recognize intracellular A. fumigatus and collectively induce protective immune responses. Mice lacking both AIM2 and NLRP3 fail to confine Aspergillus hyphae to inflammatory foci, leading to widespread hyphal dissemination to lung blood vessels. These mice succumb to infection more rapidly than WT mice or mice lacking a single inflammasome receptor. AIM2 and NLRP3 activation initiates assembly of a single cytoplasmic inflammasome platform, composed of the adaptor protein ASC along with caspase-1 and caspase-8. Combined actions of caspase-1 and caspase-8 lead to processing of pro-inflammatory cytokines IL-1β and IL-18 that critically control the infection. Thus, AIM2 and NLRP3 form a dual cytoplasmic surveillance system that orchestrates responses against A. fumigatus infection.
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•Mice lacking both AIM2 and NLRP3 are highly susceptible to aspergillosis•AIM2 and NLRP3 are required to confine Aspergillus to inflammatory foci in the lung•Activation of AIM2 and NLRP3 induces a single cytoplasmic inflammasome platform•AIM2- and NLRP3-mediated release of IL-1β and IL-18 is crucial for survival
Aspergillosis is a major health concern for immunocompromised individuals. Karki et al. show that two cytosolic inflammasome receptors, AIM2 and NLRP3, protect against A. fumigatus infection. AIM2 and NLRP3 activation induces a single cytoplasmic inflammasome platform containing ASC, caspase-1, and caspase-8 that mediates pro-inflammatory cytokine release and A. fumigatus clearance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Caspase-1, also known as interleukin-1β (IL-1β)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within ...an inflammasome complex, caspase-1 induces pyroptosis and converts pro-IL-1β and pro-IL-18 into their biologically active forms. "ICE
" or "Casp1
" mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on the caspase-11 locus, essentially making them deficient in both caspase-1 and caspase-11. The overlapping and unique functions of caspase-1 and caspase-11 are difficult to unravel without additional genetic tools. Here, we generated caspase-1-deficient mouse (Casp1
) on the C57BL/6 J background that expressed caspase-11. Casp1
cells did not release IL-1β and IL-18 in response to NLRC4 activators Salmonella Typhimurium and flagellin, canonical or non-canonical NLRP3 activators LPS and ATP, Escherichia coli, Citrobacter rodentium and transfection of LPS, AIM2 activators Francisella novicida, mouse cytomegalovirus and DNA, and the infectious agents Listeria monocytogenes and Aspergillus fumigatus. We further demonstrated that caspase-1 and caspase-11 differentially contributed to the host defense against A. fumigatus infection and to endotoxemia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Guanylate‐binding proteins (GBPs) are essential components of cell‐autonomous immunity. In response to IFN signaling, GBPs are expressed in the cytoplasm of immune and nonimmune cells, where they ...unleash their antimicrobial activity toward intracellular bacteria, viruses, and parasites. Recent studies have revealed that GBPs are essential for mediating activation of the caspase‐1 inflammasome in response to the gram‐negative bacteria Salmonella enterica serovar Typhimurium, Francisella novicida, Chlamydia muridarum, Chlamydia trachomatis, Legionella pneumophila, Vibrio cholerae, Enterobacter cloacae, and Citrobacter koseri. During infection with vacuolar‐restricted gram‐negative bacteria, GBPs disrupt the vacuolar membrane to ensure liberation of LPS for cytoplasmic detection by caspase‐11 and the noncanonical NLRP3 inflammasome. In response to certain cytosolic bacteria, GBPs liberate microbial DNA for activation of the DNA‐sensing AIM2 inflammasome. GBPs also promote the recruitment of antimicrobial proteins, including NADPH oxidase subunits and autophagy‐associated proteins to the Mycobacterium‐containing vacuole to mediate intracellular bacterial killing. Here, we provide an overview on the emerging relationship between GBPs and activation of the inflammasome in innate immunity to microbial pathogens.
Review of how GBPs attack pathogens and activate inflammasomes, cell death, and innate immunity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Inflammasomes are cytosolic innate immune complexes, which assemble in mammalian cells in response to microbial components and endogenous danger signals. A major family of inflammasome activators is ...bacterial toxins. Inflammasome sensor proteins, such as the nucleotide‐binding oligomerisation domain‐like receptor (NLR) family members NLRP1b and NLRP3, and the tripartite motif family member Pyrin+ efflux triggered by pore‐forming toxins or by other toxin‐induced homeostasis‐altering events such as lysosomal rupture. Pyrin senses perturbation of host cell functions induced by certain enzymatic toxins resulting in impairment of RhoA GTPase activity. Assembly of the inflammasome complex activates the cysteine protease caspase‐1, leading to the proteolytic cleavage of the proinflammatory cytokines IL‐1β and IL‐18, and the pore‐forming protein gasdermin D causing pyroptosis. In this review, we discuss the latest progress in our understanding on the activation mechanisms of inflammasome complexes by bacterial toxins and effector proteins and explore avenues for future research into the relationships between inflammasomes and bacterial toxins.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer is a leading cause of cancer-related deaths. Mutations in the innate immune sensor AIM2 are frequently identified in patients with colorectal cancer, but how AIM2 modulates colonic ...tumorigenesis is unknown. Here, we found that Aim2-deficient mice were hypersusceptible to colonic tumor development. Production of inflammasome-associated cytokines and other inflammatory mediators was largely intact in Aim2-deficient mice; however, intestinal stem cells were prone to uncontrolled proliferation. Aberrant Wnt signaling expanded a population of tumor-initiating stem cells in the absence of AIM2. Susceptibility of Aim2-deficient mice to colorectal tumorigenesis was enhanced by a dysbiotic gut microbiota, which was reduced by reciprocal exchange of gut microbiota with healthy wild-type mice. These findings uncover a synergy between a specific host genetic factor and gut microbiota in determining the susceptibility to colorectal cancer. Therapeutic modulation of AIM2 expression and microbiota has the potential to prevent colorectal cancer.
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•AIM2 is required to mediate protection against colorectal cancer•AIM2 suppresses overt proliferation in enterocytes•AIM2 inhibits expansion of the intestinal stem cell population•Transfer of healthy microbiota dampens tumor development in Aim2-deficient mice
The cytosolic DNA sensor AIM2 regulates stem cell proliferation in the intestinal mucosa in an inflammasome-independent fashion, contributing to a decrease in the likelihood of colorectal cancer development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A growing number of Campylobacter species other than C. jejuni and C. coli have been recognized as emerging human and animal pathogens. Although C. jejuni continues to be the leading cause of ...bacterial gastroenteritis in humans worldwide, advances in molecular biology and development of innovative culture methodologies have led to the detection and isolation of a range of under-recognized and nutritionally fastidious Campylobacter spp., including C. concisus, C. upsaliensis and C. ureolyticus. These emerging Campylobacter spp. have been associated with a range of gastrointestinal diseases, particularly gastroenteritis, IBD and periodontitis. In some instances, infection of the gastrointestinal tract by these bacteria can progress to life-threatening extragastrointestinal diseases. Studies have shown that several emerging Campylobacter spp. have the ability to attach to and invade human intestinal epithelial cells and macrophages, damage intestinal barrier integrity, secrete toxins and strategically evade host immune responses. Members of the Campylobacter genus naturally colonize a wide range of hosts (including pets, farm animals and wild animals) and are frequently found in contaminated food products, which indicates that these bacteria are at risk of zoonotic transmission to humans. This Review presents the latest information on the role and clinical importance of emerging Campylobacter spp. in gastrointestinal health and disease.
Acinetobacter baumannii is an emerging nosocomial, opportunistic pathogen with growing clinical significance globally. A. baumannii has an exceptional ability to rapidly develop drug resistance. It ...is frequently responsible for ventilator-associated pneumonia in clinical settings and inflammation resulting in severe sepsis. The inflammatory response is mediated by host pattern-recognition receptors and the inflammasomes. Inflammasome activation triggers inflammatory responses, including the secretion of the pro-inflammatory cytokines IL-1beta and IL-18, the recruitment of innate immune effectors against A. baumannii infection, and the induction programmed cell death by pyroptosis. An important knowledge gap is how variation among clinical isolates affects the host's innate response and activation of the inflammasome during A. baumannii infection. In this study, we compared nine A. baumannii strains, including clinical locally-acquired isolates, in their ability to induce activation of the inflammasome and programmed cell death in primary macrophages, epithelial lung cell line and mice. We found a variation in survival outcomes of mice and bacterial dissemination in organs among three commercially available A. baumannii strains, likely due to the differences in virulence between strains. Interestingly, we found variability among A. baumannii strains in activation of the NLRP3 inflammasome, non-canonical Caspase-11 pathway, plasmatic secretion of the pro-inflammatory cytokine IL-1beta and programmed cell death. Our study highlights the importance of utilising multiple bacterial strains and clinical isolates with different virulence to investigate the innate immune response to A. baumannii infection.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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