Great balls of fire: activation and signalling of inflammatory caspases

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

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Caspases in Cell Death, Inflammation, and Pyroptosis

Annual Review of Immunology ◽

10.1146/annurev-immunol-073119-095439 ◽

2020 ◽

Vol 38 (1) ◽

pp. 567-595 ◽

Cited By ~ 27

Author(s):

Sannula Kesavardhana ◽

R.K. Subbarao Malireddi ◽

Thirumala-Devi Kanneganti

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Responses ◽

Cross Talk ◽

Cysteine Proteases ◽

Proteolytic Processing ◽

Innate Immune ◽

Innate Immune Responses ◽

New Research ◽

Multicellular Organisms

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.

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Hepatitis C virus and autophagy

Biological Chemistry ◽

10.1515/hsz-2015-0172 ◽

2015 ◽

Vol 396 (11) ◽

pp. 1215-1222 ◽

Cited By ~ 32

Author(s):

Linya Wang ◽

Jing-hsiung James Ou

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Microbial Pathogens ◽

Innate Immune Responses ◽

Human Pathogen ◽

Severe Liver ◽

Catabolic Process

Abstract Autophagy is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. It can also be used by cells to remove intracellular microbial pathogens, including viruses, in a process known as xenophagy. However, many viruses have developed mechanisms to subvert this intracellular antiviral response and even use this pathway to support their own replications. Hepatitis C virus (HCV) is one such virus and is an important human pathogen that can cause severe liver diseases. Recent studies indicated that HCV could activate the autophagic pathway to support its replication. This review summarizes the current knowledge on the interplay between HCV and autophagy and how this interplay affects HCV replication and host innate immune responses.

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Innate immunology in COVID-19—a living review. Part II: dysregulated inflammation drives immunopathology

Oxford Open Immunology ◽

10.1093/oxfimm/iqaa005 ◽

2020 ◽

Vol 1 (1) ◽

Author(s):

Patrícia R S Rodrigues ◽

Aljawharah Alrubayyi ◽

Ellie Pring ◽

Valentina M T Bart ◽

Ruth Jones ◽

...

Keyword(s):

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Innate Immunology ◽

Viral Pathogen ◽

Health Crisis ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Abstract The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a global health crisis and will likely continue to impact public health for years. As the effectiveness of the innate immune response is crucial to patient outcome, huge efforts have been made to understand how dysregulated immune responses may contribute to disease progression. Here we have reviewed current knowledge of cellular innate immune responses to SARS-CoV-2 infection, highlighting areas for further investigation and suggesting potential strategies for intervention. We conclude that in severe COVID-19 initial innate responses, primarily type I interferon, are suppressed or sabotaged which results in an early interleukin (IL)-6, IL-10 and IL-1β-enhanced hyperinflammation. This inflammatory environment is driven by aberrant function of innate immune cells: monocytes, macrophages and natural killer cells dispersing viral pathogen-associated molecular patterns and damage-associated molecular patterns into tissues. This results in primarily neutrophil-driven pathology including fibrosis that causes acute respiratory distress syndrome. Activated leukocytes and neutrophil extracellular traps also promote immunothrombotic clots that embed into the lungs and kidneys of severe COVID-19 patients, are worsened by immobility in the intensive care unit and are perhaps responsible for the high mortality. Therefore, treatments that target inflammation and coagulation are promising strategies for reducing mortality in COVID-19.

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Vitamin D, infections and immunity

Reviews in Endocrine and Metabolic Disorders ◽

10.1007/s11154-021-09679-5 ◽

2021 ◽

Author(s):

Aiten Ismailova ◽

John H. White

Keyword(s):

Vitamin D ◽

Immune Responses ◽

Current Knowledge ◽

Intestinal Flora ◽

Antibacterial Properties ◽

Vitamin D Supplementation ◽

Innate Immune ◽

Innate Immune Responses ◽

Skeletal Health ◽

Vitamin D Signaling

AbstractVitamin D, best known for its role in skeletal health, has emerged as a key regulator of innate immune responses to microbial threat. In immune cells such as macrophages, expression of CYP27B1, the 25-hydroxyvitamin D 1α-hydroxylase, is induced by immune-specific inputs, leading to local production of hormonal 1,25-dihydroxyvitamin D (1,25D) at sites of infection, which in turn directly induces the expression of genes encoding antimicrobial peptides. Vitamin D signaling is active upstream and downstream of pattern recognition receptors, which promote front-line innate immune responses. Moreover, 1,25D stimulates autophagy, which has emerged as a mechanism critical for control of intracellular pathogens such as M. tuberculosis. Strong laboratory and epidemiological evidence links vitamin D deficiency to increased rates of conditions such as dental caries, as well as inflammatory bowel diseases arising from dysregulation of innate immune handling intestinal flora. 1,25D is also active in signaling cascades that promote antiviral innate immunity; 1,25D-induced expression of the antimicrobial peptide CAMP/LL37, originally characterized for its antibacterial properties, is a key component of antiviral responses. Poor vitamin D status is associated with greater susceptibility to viral infections, including those of the respiratory tract. Although the severity of the COVID-19 pandemic has been alleviated in some areas by the arrival of vaccines, it remains important to identify therapeutic interventions that reduce disease severity and mortality, and accelerate recovery. This review outlines of our current knowledge of the mechanisms of action of vitamin D signaling in the innate immune system. It also provides an assessment of the therapeutic potential of vitamin D supplementation in infectious diseases, including an up-to-date analysis of the putative benefits of vitamin D supplementation in the ongoing COVID-19 crisis.

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Granulocyte apoptosis in the pathogenesis and resolution of lung disease

Clinical Science ◽

10.1042/cs20050178 ◽

2006 ◽

Vol 110 (3) ◽

pp. 293-304 ◽

Cited By ~ 43

Author(s):

Stephen M. Bianchi ◽

David H. Dockrell ◽

Stephen A. Renshaw ◽

Ian Sabroe ◽

Moira K. B. Whyte

Keyword(s):

Immune Responses ◽

Lung Disease ◽

Inflammatory Cell ◽

Control Point ◽

Innate Immune ◽

Innate Immune Responses ◽

Potential Control ◽

Cellular Processes ◽

Cell Type Specific ◽

Eosinophil Granulocytes

Apoptosis, programmed cell death, of neutrophil and eosinophil granulocytes is a potential control point in the physiological resolution of innate immune responses. There is also increasing evidence that cellular processes of apoptosis can be dysregulated by pathogens as a mechanism of immune evasion and that delayed apoptosis, resulting in prolonged inflammatory cell survival, is important in persistence of tissue inflammation. The identification of cell-type specific pathways to apoptosis may allow the design of novel anti-inflammatory therapies or agents to augment the innate immune responses to infection. This review will explore the physiological roles of granulocyte apoptosis and their importance in infectious and non-infectious lung disease.

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Viral Evasion of RIG-I-Like Receptor-Mediated Immunity through Dysregulation of Ubiquitination and ISGylation

Viruses ◽

10.3390/v13020182 ◽

2021 ◽

Vol 13 (2) ◽

pp. 182

Author(s):

Cindy Chiang ◽

Guanqun Liu ◽

Michaela U. Gack

Keyword(s):

Immune Responses ◽

Current Knowledge ◽

Innate Immune ◽

Type I ◽

Innate Immune Responses ◽

Deubiquitinating Enzymes ◽

Viral Pathogens ◽

Dna Viruses ◽

E3 Ligases ◽

Antiviral Responses

Viral dysregulation or suppression of innate immune responses is a key determinant of virus-induced pathogenesis. Important sensors for the detection of virus infection are the RIG-I-like receptors (RLRs), which, in turn, are antagonized by many RNA viruses and DNA viruses. Among the different escape strategies are viral mechanisms to dysregulate the post-translational modifications (PTMs) that play pivotal roles in RLR regulation. In this review, we present the current knowledge of immune evasion by viral pathogens that manipulate ubiquitin- or ISG15-dependent mechanisms of RLR activation. Key viral strategies to evade RLR signaling include direct targeting of ubiquitin E3 ligases, active deubiquitination using viral deubiquitinating enzymes (DUBs), and the upregulation of cellular DUBs that regulate RLR signaling. Additionally, we summarize emerging new evidence that shows that enzymes of certain coronaviruses such as SARS-CoV-2, the causative agent of the current COVID-19 pandemic, actively deISGylate key molecules in the RLR pathway to escape type I interferon (IFN)-mediated antiviral responses. Finally, we discuss the possibility of targeting virally-encoded proteins that manipulate ubiquitin- or ISG15-mediated innate immune responses for the development of new antivirals and vaccines.

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Oral Immune Activation by Disgust and Disease-Related Pictures

Journal of Psychophysiology ◽

10.1027/0269-8803/a000143 ◽

2015 ◽

Vol 29 (3) ◽

pp. 119-129 ◽

Cited By ~ 4

Author(s):

Richard J. Stevenson ◽

Deborah Hodgson ◽

Megan J. Oaten ◽

Luba Sominsky ◽

Mehmet Mahmut ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Innate Immune Response ◽

Negative Control ◽

Innate Immune ◽

Innate Immune Responses ◽

Immune Markers ◽

Before And After ◽

Secondary Analyses ◽

Image Set

Abstract. Both disgust and disease-related images appear able to induce an innate immune response but it is unclear whether these effects are independent or rely upon a common shared factor (e.g., disgust or disease-related cognitions). In this study we directly compared these two inductions using specifically generated sets of images. One set was disease-related but evoked little disgust, while the other set was disgust evoking but with less disease-relatedness. These two image sets were then compared to a third set, a negative control condition. Using a wholly within-subject design, participants viewed one image set per week, and provided saliva samples, before and after each viewing occasion, which were later analyzed for innate immune markers. We found that both the disease related and disgust images, relative to the negative control images, were not able to generate an innate immune response. However, secondary analyses revealed innate immune responses in participants with greater propensity to feel disgust following exposure to disease-related and disgusting images. These findings suggest that disgust images relatively free of disease-related themes, and disease-related images relatively free of disgust may be suboptimal cues for generating an innate immune response. Not only may this explain why disgust propensity mediates these effects, it may also imply a common pathway.

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