Monitoring of the cytosolic compartment by the innate immune system for pathogen-encoded products or pathogen activities often enables the activation of a subset of caspases. In most cases, the ...cytosolic surveillance pathways are coupled to activation of caspase-1 via canonical inflammasome complexes. A related set of caspases, caspase-11 in rodents and caspase-4 and caspase-5 in humans, monitors the cytosol for bacterial lipopolysaccharide (LPS). Direct activation of caspase-11, caspase-4 and caspase-5 by intracellular LPS elicits the lytic cell death called 'pyroptosis', which occurs in multiple cell types. The pyroptosis is executed by the pore-forming protein GSDMD, which is activated by cleavage mediated by caspase-11, caspase-4 or caspase-5. In monocytes, formation of GSDMD pores can induce activation of the NLRP3 inflammasome for maturation of the cytokines IL-1β and IL-18. Caspase-11-mediated pyroptosis in response to cytosolic LPS is critical for antibacterial defense and septic shock. Here we review the emerging literature on the sensing of cytosolic LPS and its regulation and pathophysiological functions.
Sensing of lipopolysaccharide (LPS) in the cytosol triggers caspase-11 activation and is central to host defense against Gram-negative bacterial infections and to the pathogenesis of sepsis. Most ...Gram-negative bacteria that activate caspase-11, however, are not cytosolic, and the mechanism by which LPS from these bacteria gains access to caspase-11 in the cytosol remains elusive. Here, we identify outer membrane vesicles (OMVs) produced by Gram-negative bacteria as a vehicle that delivers LPS into the cytosol triggering caspase-11-dependent effector responses in vitro and in vivo. OMVs are internalized via endocytosis, and LPS is released into the cytosol from early endosomes. The use of hypovesiculating bacterial mutants, compromised in their ability to generate OMVs, reveals the importance of OMVs in mediating the cytosolic localization of LPS. Collectively, these findings demonstrate a critical role for OMVs in enabling the cytosolic entry of LPS and, consequently, caspase-11 activation during Gram-negative bacterial infections.
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•OMVs secreted by bacteria enable intracellular LPS localization•OMVs activate caspase-11-mediated cytosolic LPS sensing•OMVs enter the cells by endocytosis, and LPS accesses cytosol from early endosomes•OMVs are essential for the activation of caspase-11 during bacterial infections.
Gram-negative bacteria secrete outer membrane vesicles that deliver lipopolysaccharide (LPS) to the host cell cytosol, where it can trigger caspase-11 activation—a critical mechanism against bacterial infections and to sepsis pathogenesis.
Canonical activation of the inflammasome is critical to promote caspase-1-dependent maturation of the proinflammatory cytokines IL-1β and IL-18, as well as to induce pyroptotic cell death in response ...to pathogens and endogenous danger signals. Recent discoveries, however, are beginning to unveil new components of the inflammasome machinery as well as the full spectrum of inflammasome functions, extending their influence beyond canonical functions to regulation of eicosanoid storm, autophagy, and metabolism. In addition, the receptor components of the inflammasome can also regulate diverse biological processes, such as cellular proliferation, gene transcription, and tumorigenesis, all of which are independent of their inflammasome complex-forming capabilities. Here, we review these recent advances that are shaping our understanding of the complex biology of the inflammasome and its constituents.
Recent discoveries are helping to unveil the complexity of the inflammasome’s biology, extending its function beyond the traditional roles in cytokine maturation and cell death to a variety of non-canonical functions, such as regulation of autophagy, metabolism, gene expression, cellular proliferation, and tumorigenesis.
Citrobacter rodentium is a mucosal pathogen of mice that shares several pathogenic mechanisms with enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC), which are two ...clinically important human gastrointestinal pathogens. Thus, C. rodentium has long been used as a model to understand the molecular basis of EPEC and EHEC infection in vivo. In this Review, we discuss recent studies in which C. rodentium has been used to study mucosal immunology, including the deregulation of intestinal inflammatory responses during bacteria-induced colitis and the role of the intestinal microbiota in mediating resistance to colonization by enteric pathogens. These insights should help to elucidate the roles of mucosal inflammatory responses and the microbiota in the virulence of enteric pathogens.
Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline‐encoded innate immune receptors detect microbial DNA in various compartments ...of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor‐dependent type I IFN synthesis followed by JAK/STAT‐dependent interferon‐stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase‐1. Caspase‐1 cleaves and activates the pro‐inflammatory cytokines such as IL‐1β and IL‐18 and a pore‐forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome‐dependent and inflammasome‐independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.
Recognition of DNA by the innate immune system is central to antiviral and antibacterial defenses, as well as an important contributor to autoimmune diseases involving self DNA. AIM2 (absent in ...melanoma 2) and IFI16 (interferon-inducible protein 16) have been identified as DNA receptors that induce inflammasome formation and interferon production, respectively. Here we present the crystal structures of their HIN domains in complex with double-stranded (ds) DNA. Non-sequence-specific DNA recognition is accomplished through electrostatic attraction between the positively charged HIN domain residues and the dsDNA sugar-phosphate backbone. An intramolecular complex of the AIM2 Pyrin and HIN domains in an autoinhibited state is liberated by DNA binding, which may facilitate the assembly of inflammasomes along the DNA staircase. These findings provide mechanistic insights into dsDNA as the activation trigger and oligomerization platform for the assembly of large innate signaling complexes such as the inflammasomes.
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► Electrostatic attraction underlies innate dsDNA recognition by the HIN domains ► Both OB folds and the linker between them engage the dsDNA backbone ► An autoinhibited state of AIM2 is activated by DNA that liberates the PYD domain ► DNA serves as an oligomerization platform for the inflammasome assembly
Highlights • New inflammasomes and new microbial triggers of inflammasomes have been identified. • Cytosolic LPS is detected by caspase-11 resulting in its activation. • A novel pyrin inflammasome ...responds to pathogen-induced modifications of host proteins. • Identification of a new NLRP6 pathway controlling mucus production.
Abstract
The language and speech of individuals with psychosis reflect their impairments in cognition and motor processes. These language disturbances can be used to identify individuals with and at ...high risk for psychosis, as well as help track and predict symptom progression, allowing for early intervention and improved outcomes. However, current methods of language assessment—manual annotations and/or clinical rating scales—are time intensive, expensive, subject to bias, and difficult to administer on a wide scale, limiting this area from reaching its full potential. Computational methods that can automatically perform linguistic analysis have started to be applied to this problem and could drastically improve our ability to use linguistic information clinically. In this article, we first review how these automated, computational methods work and how they have been applied to the field of psychosis. We show that across domains, these methods have captured differences between individuals with psychosis and healthy controls and can classify individuals with high accuracies, demonstrating the promise of these methods. We then consider the obstacles that need to be overcome before these methods can play a significant role in the clinical process and provide suggestions for how the field should address them. In particular, while much of the work thus far has focused on demonstrating the successes of these methods, we argue that a better understanding of when and why these models fail will be crucial toward ensuring these methods reach their potential in the field of psychosis.
Most reward-related electroencephalogram (EEG) studies focus exclusively on the feedback-related negativity (FRN, also known as feedback negativity or FN, medial-frontal negativity or MFN, feedback ...error-related negativity or fERN, and reward positivity or RewP). This component is usually measured approximately 200–300 ms post-feedback at a single electrode in the frontal-central area (e.g., Fz or FCz). The present review argues that this singular focus on the FRN fails to leverage EEG's greatest strength, its temporal resolution, by underutilizing the rich variety of event-related potential (ERP) and EEG time-frequency components encompassing the wider temporal heterogeneity of reward processing. The primary objective of this review is to provide a comprehensive understanding of often overlooked ERP and EEG correlates beyond the FRN in the context of reward processing with the secondary goal of guiding future research toward multistage experimental designs and multicomponent analyses that leverage the temporal power of EEG. We comprehensively review reward-related ERPs (including the FRN, readiness potential or RP, stimulus-preceding negativity or SPN, contingent-negative variation or CNV, cue-related N2 and P3, Feedback-P3, and late-positive potential or LPP/slow-wave), and reward-related EEG time-frequency components (changes in power at alpha, beta, theta, and delta bands). These electrophysiological signatures display distinct time-courses, scalp topographies, and reflect independent psychological processes during anticipatory and/or outcome stages of reward processing. Special consideration is given to the time-course of each component and factors that significantly contribute to component variation. Concluding remarks identify current limitations along with recommendations for potential important future directions.
•Reward processing is heterogenous with multiple temporally distinct stages.•EEG/ERP methods are well-suited to decompose the time-course of reward processing.•Reward outcome and anticipatory ERP and time-frequency components are reviewed.•Multistage and multicomponent analyses beyond the FRN are emphasized.
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