المؤلفون: Thygesen, Sara J, Burgener, Sabrina S, Mudai, Prerna, Monteleone, Mercedes, Boucher, Dave, Sagulenko, Vitaliya, Schroder, Kate, Stacey, Katryn J

المصدر: European Journal of Immunology; May2024, Vol. 54 Issue 5, p1-5, 5p

مصطلحات موضوعية: CASPASES, CYSTEINE proteinases, MACROPHAGES

مستخلص: The article discusses the limited cell-membrane permeability of fluorochrome-labeled inhibitors of caspase-1 (FLICA reagents) and its implications for studying caspase-1 activation and its role in inflammation and cell death. The study found that FLICA reagents require gasdermin D (GSDMD) membrane pores to efficiently enter cells and bind active caspase-1. The article emphasizes the importance of considering the permeability of FLICA reagents and the appropriateness of controls when planning experiments and interpreting data. The research was supported by various funding sources and the authors declare potential conflicts of interest. [Extracted from the article]

: Copyright of European Journal of Immunology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Coll, Rebecca C, Schroder, Kate, Pelegrín, Pablo

المصدر: Coll , R C , Schroder , K & Pelegrín , P 2022 , ' NLRP3 and pyroptosis blockers for treating inflammatory diseases ' , Trends in Pharmacological Sciences , vol. 43 , no. 8 , pp. 653-668 . https://doi.org/10.1016/j.tips.2022.04.003Test

مصطلحات موضوعية: NASH, NLRP3, diabetes, drug-like candidates, gasdermin D, inflammasome, intestinal inflammation, neurodegenerative diseases, small-molecule inhibitors, stroke

الوصف: The nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key mediator of pathological inflammation in many diseases and is an exciting drug target. Here, we review the molecular basis of NLRP3 inhibition by drug-like small molecules under development as novel therapeutics. We also summarize recent strategies to block pyroptosis as a novel approach to suppress chronic inflammation. Major recent developments in this area include the elucidation of mechanisms of action (MoAs) by which small molecules block NLRP3 inflammasome assembly and gasdermin D (GSDMD)-induced pyroptosis. We also discuss the status of clinical trials using agents that block specific components of the NLRP3 pathway, including their potential clinical applications for the treatment of many diseases.

وصف الملف: application/pdf

العلاقة: https://pure.qub.ac.uk/en/publications/3de14ea4-9827-4625-8630-3bc3636ae5d3Test

الإتاحة: https://doi.org/10.1016/j.tips.2022.04.003Test
https://pure.qub.ac.uk/en/publications/3de14ea4-9827-4625-8630-3bc3636ae5d3Test
https://pureadmin.qub.ac.uk/ws/files/349355868/PIIS0165614722000839.pdfTest

المؤلفون: Chong, Wai Chin, Shastri, Madhur D., Peterson, Gregory M., Patel, Rahul P., Pathinayake, Prabuddha S., Dua, Kamal, Hansbro, Nicole G., Hsu, Alan C., Wark, Peter A., Shukla, Shakti Dhar, Johansen, Matt D., Schroder, Kate, Hansbro, Philip M.

المساهمون: The University of Newcastle. College of Health, Medicine & Wellbeing, School of Medicine and Public Health

مصطلحات موضوعية: endoplasmic reticulum stress, inflammasome, inflammatory disorder, NLRP3, SDG 3, Sustainable Development Goals

الوصف: Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders.

العلاقة: NHMRC.1079187 http://purl.org/au-research/grants/nhmrc/1079187Test; Clinical and Translational Immunology Vol. 10, Issue 2, no. e1247; http://hdl.handle.net/1959.13/1455435Test; uon:45088

الإتاحة: http://hdl.handle.net/1959.13/1455435Test

المؤلفون: Monteleone, Mercedes, Stanley, Amanda, C, Chen, Kaiwen, W, Brown, Darren, L, Bezbradica, Jelena, S, von Pein, Jessica, B, Holley, Caroline, L, Boucher, Dave, Shakespear, Melanie, R, Kapetanovic, Ronan, Rolfes, Verena, Sweet, Matthew, J, Stow, Jennifer, L, Schroder, Kate

المساهمون: Institute for Molecular Bioscience, The University of Queensland (UQ All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations )

المصدر: ISSN: 2211-1247.

مصطلحات موضوعية: caspase-1, gasdermin, inflammasome, interleukin-1, macrophage, neutrophil, phosphoinositides, pyroptosis, trafficking, unconventional protein secretion, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology

الوصف: International audience ; IL-1β requires processing by caspase-1 to generate the active, pro-inflammatory cytokine. Acute IL-1β secretion from inflammasome-activated macrophages requires caspase-1-dependent GSDMD cleavage, which also induces pyroptosis. Mechanisms of IL-1β secretion by pyroptotic and non-pyroptotic cells, and the precise functions of caspase-1 and GSDMD therein, are unresolved. Here, we show that, while efficient early secretion of endogenous IL-1β from primary non-pyroptotic myeloid cells in vitro requires GSDMD, later IL-1β release in vitro and in vivo proceeds independently of GSDMD. IL-1β maturation is sufficient for slow, caspase-1/GSDMD-independent secretion of ectopic IL-1β from resting, non-pyroptotic macrophages, but the speed of IL-1β release is boosted by inflammasome activation, via caspase-1 and GSDMD. IL-1β cleavage induces IL-1β enrichment at PIP2-enriched plasma membrane ruffles, and this is a prerequisite for IL-1β secretion and is mediated by a polybasic motif within the cytokine. We thus reveal a mechanism in which maturation-induced IL-1β trafficking facilitates its unconventional secretion.

العلاقة: hal-04346604; https://hal.inrae.fr/hal-04346604Test; https://hal.inrae.fr/hal-04346604/documentTest; https://hal.inrae.fr/hal-04346604/file/1-s2.0-S2211124718311173-main.pdfTest

الإتاحة: https://doi.org/10.1016/j.celrep.2018.07.027Test
https://hal.inrae.fr/hal-04346604Test
https://hal.inrae.fr/hal-04346604/documentTest
https://hal.inrae.fr/hal-04346604/file/1-s2.0-S2211124718311173-main.pdfTest

المؤلفون: Tseng, Hsu-Wen, Samuel, Selwin Gabriel, Schroder, Kate, Lévesque, Jean-Pierre, Alexander, Kylie A

المصدر: Current Osteoporosis Reports; Jun2022, Vol. 20 Issue 3, p170-185, 16p

مستخلص: Purpose of Review: Inflammasomes are multimeric protein structures with crucial roles in host responses against infections and injuries. The importance of inflammasome activation goes beyond host defense as a dysregulated inflammasome and subsequent secretion of IL-1 family members is believed to be involved in the pathogenesis of various diseases, some of which also produce skeletal manifestations. The purpose of this review is to summarize recent developments in the understanding of inflammasome regulation and IL-1 family members in bone physiology and pathology and current therapeutics will be discussed. Recent Findings: Small animal models have been vital to help understand how the inflammasome regulates bone dynamics. Animal models with gain or loss of function in various inflammasome components or IL-1 family signaling have illustrated how these systems can impact numerous bone pathologies and have been utilized to test new inflammasome therapeutics. Summary: It is increasingly clear that a tightly regulated inflammasome is required not only for host defense but for skeletal homeostasis, as a dysregulated inflammasome is linked to diseases of pathological bone accrual and loss. Given the complexities of inflammasome activation and redundancies in IL-1 activation and secretion, targeting these pathways is at times challenging. Ongoing research into inflammasome-mediated mechanisms will allow the development of new therapeutics for inflammasome/IL-1 diseases. [ABSTRACT FROM AUTHOR]

: Copyright of Current Osteoporosis Reports is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Sreejit, Gopalkrishna, Abdel-Latif, Ahmed, Athmanathan, Baskaran, Annabathula, Rahul, Dhyani, Ashish, Noothi, Sunil K, Quaife-Ryan, Gregory A., Al-Sharea, Annas, Pernes, Gerard, Dragoljevic, Dragana, Lal, Hind, Schroder, Kate, Hanaoka, Beatriz Y., Raman, Chander, Grant, Maria B., Hudson, James E., Smyth, Susan, Porrello, Enzo R., Murphy, Andrew J., Nagareddy, Prabhakara R.

مصطلحات موضوعية: Inflammasome, Myelopoiesis, Neutrophils, S100A8/A9, interleukin 1 beta, 2705 Cardiology and Cardiovascular Medicine, 2737 Physiology (medical)

الوصف: Myocardial infarction (MI) triggers myelopoiesis resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. Using a mouse model of the permanent ligation of the left anterior descending (LAD) artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of acute inflammatory response and the underlying signaling pathways. Utilizing a combination of genetic and pharmacological strategies, we identified the sequalae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indices of neutrophilia with major adverse cardiovascular events (MACE) was studied in a cohort of acute MI patients. Induction of MI resulted in a rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll Like Receptor (TLR) 4 and prime the Nod Like Receptor (NLR) family Pyrin Domain-Containing 3 (Nlrp3) inflammasome in naïve neutrophils and promote interleukin 1 (IL-1β) secretion. The released IL-1β interact with its receptor (Interleukin 1 Receptor Type 1, IL1R1) on hematopoietic stem and progenitor cells in the bone marrow (BM), and stimulate granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and its downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome (ACS), higher neutrophil count on admission and post-revascularization correlates positively with major adverse cardiovascular disease (CVD) outcomes. Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response following ...

العلاقة: orcid:0000-0002-0012-9934; orcid:0000-0001-9261-3805; orcid:0000-0003-0832-9356; AR068450; HL122505; HL137799; HL124266; HL138488; APP1106154; APP1142938

الإتاحة: https://doi.org/10.1161/CIRCULATIONAHA.119.043833Test
https://espace.library.uq.edu.au/view/UQ:cbc800dTest

المؤلفون: Holley, Caroline L., Schroder, Kate

مصطلحات موضوعية: NLRP3, ROS, infection, inflammasome, mitochondria, 2900 Nursing, 2403 Immunology, 2723 Immunology and Allergy

الوصف: The nod-like receptor protein 3 (NLRP3) inflammasome drives inflammation in response to mitochondrial dysfunction. As metabolic powerhouses with prokaryotic ancestry, mitochondria are a cache for danger-associated molecular patterns and pathogen-associated molecular pattern-like molecules that elicit potent innate immune responses. Persistent mitochondrial damage caused by infection, or genetic or environmental factors, can lead to inappropriate or sustained inflammasome signalling. Here, we review the features of mitochondria that drive inflammatory signalling, with a particular focus on mitochondrial activation of the NLRP3 inflammasome. Given that mitochondrial network dynamics, metabolic activity and redox state are all intricately linked to each other and to NLRP3 inflammasome activity, we highlight the importance of a holistic approach to investigations of NLRP3 activation by dysfunctional mitochondria.

العلاقة: orcid:0000-0002-2231-0136; orcid:0000-0001-9261-3805; 1141131; DP160102702; Not set

الإتاحة: https://doi.org/10.1002/cti2.1109Test
https://espace.library.uq.edu.au/view/UQ:feca929Test

المؤلفون: Burgener, Sabrina Sofia, Schroder, Kate

مصطلحات موضوعية: Protein-Kinase-C, Nadph Oxidase, Gasdermin-D, Mitochondrial-Dna, Cell-Death, Myeloperoxidase, Inflammasome, Elastase, Release, Netosis

الوصف: Neutrophils are produced in the bone marrow and then patrol blood vessels from which they can be rapidly recruited to a site of infection. Neutrophils bind, engulf, and efficiently kill invading microbes via a suite of defense mechanisms. Diverse extracellular and intracellular microbes induce neutrophils to extrude neutrophil extracellular traps (NETs) through the process of NETosis. Here, we review the signaling mechanisms and cell biology underpinning the key NETosis pathways during infection and the antimicrobial functions of NETs in host defense.

العلاقة: orcid:0000-0002-9332-7998; orcid:0000-0001-9261-3805; 1163924

الإتاحة: https://doi.org/10.1101/cshperspect.a037028Test
https://espace.library.uq.edu.au/view/UQ:09dabb3Test

المؤلفون: Ross, Connie, Chan, Amy H., von Pein, Jessica B., Maddugoda, Madhavi P., Boucher, Dave, Schroder, Kate

المصدر: Annual Review of Immunology; Apr2022, Vol. 40, p249-269, 16p

مستخلص: Inflammasomes are inflammatory signaling complexes that provide molecular platforms to activate the protease function of inflammatory caspases. Caspases-1, -4, -5, and -11 are inflammatory caspases activated by inflammasomes to drive lytic cell death and inflammatory mediator production, thereby activating host-protective and pathological immune responses. Here, we comprehensively review the mechanisms that govern the activity of inflammatory caspases. We discuss inflammatory caspase activation and deactivation mechanisms, alongside the physiological importance of caspase activity kinetics. We also examine mechanisms of caspase substrate selection and how inflammasome and cell identities influence caspase activity and resultant inflammatory and pyroptotic cellular programs. Understanding how inflammatory caspases are regulated may offer new strategies for treating infection and inflammasome-driven disease. [ABSTRACT FROM AUTHOR]

: Copyright of Annual Review of Immunology is the property of Annual Reviews Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Richter, Johanna, Monteleone, Mercedes M, Cork, Amanda J, Barnett, Timothy C, Nizet, Victor, Brouwer, Stephan, Schroder, Kate, Walker, Mark J

المصدر: Immunology & Cell Biology; Nov2021, Vol. 99 Issue 10, p1040-1052, 13p

مصطلحات موضوعية: INFLAMMASOMES, STREPTOCOCCUS pyogenes, CELL membrane formation, NLRP3 protein, MACROPHAGES

مستخلص: Group A Streptococcus (GAS) is a Gram‐positive bacterial pathogen that causes an array of infectious diseases in humans. Accumulating clinical evidence suggests that proinflammatory interleukin (IL)‐1β signaling plays an important role in GAS disease progression. The host regulates the production and secretion of IL‐1β via the cytosolic inflammasome pathway. Activation of the NLR family pyrin domain‐containing 3 (NLRP3) inflammasome complex requires two signals: a priming signal that stimulates increased transcription of genes encoding the components of the inflammasome pathway, and an activating signal that induces assembly of the inflammasome complex. Here we show that GAS‐derived lipoteichoic acid can provide a priming signal for NLRP3 inflammasome activation. As only few GAS‐derived proteins have been associated with inflammasome‐dependent IL‐1β signaling, we investigated novel candidates that might play a role in activating the inflammasome pathway by infecting mouse bone marrow‐derived macrophages and human THP‐1 macrophage‐like cells with a panel of isogenic GAS mutant strains. We found that the cytolysins streptolysin O (SLO) and streptolysin S are the main drivers of IL‐1β release in proliferating logarithmic phase GAS. Using a mutant form of recombinant SLO, we confirmed that bacterial pore formation on host cell membranes is a key mechanism required for inflammasome activation. Our results suggest that streptolysins are major determinants of GAS‐induced inflammation and present an attractive target for therapeutic intervention. [ABSTRACT FROM AUTHOR]

: Copyright of Immunology & Cell Biology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)