Les inflammasomes

Jamilloux, Yvan; Henry, Thomas

doi:10.1051/medsci/20132911013

Cited by 26 publications

(6 citation statements)

References 54 publications

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“…We examined the effect of Atg7 knock-out on inflammasome activation by PAO1 infection using primary mouse BMDMs. Since IL-1β precursor is induced by activation of the NF-κB pathway in response to the stimuli of pathogen-associated molecular patterns (PAMPs) (42), we pre-stimulated BMDMs with LPS for 5 hours with different doses, and infected the cells with PAO1 for another 4 hours. In Atg7 knock-out conditions, we found that inflammasome activation was markedly increased as shown by hypersecretion of the active forms of both IL-1β and caspase-1 by western blotting (Figure 4A).…”

Section: Resultsmentioning

confidence: 99%

Atg7 Deficiency Intensifies Inflammasome Activation and Pyroptosis in Pseudomonas Sepsis

Gan

et al. 2017

The Journal of Immunology

130

110

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Sepsis is a severe and complicated syndrome symbolized by dysregulation of host inflammatory responses and organ failure with high morbidity and mortality. The literature implies that autophagy is a crucial regulator of inflammation in sepsis. Here, we report that autophagy-related protein 7 (Atg7) is involved in inflammasome activation in Pseudomonas aeruginosa abdominal infection. Following intraperitoneal challenge with P. aeruginosa, atg7fl/fl mice showed impaired pathogen clearance, decreased survival, and widespread dissemination of bacteria into the blood and lung tissue compared to wild type mice. The septic atg7fl/fl mice also exhibited elevated neutrophil infiltration and severe lung injury. Loss of Atg7 resulted in increased production of IL-1β and pyroptosis, consistent with enhanced inflammasome activation. Furthermore, we demonstrated that P. aeruginosa flagellin is a chief trigger of inflammasome activation in the sepsis model. Collectively, our results provide insight into innate immunity and inflammasome activation in sepsis.

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Section: Resultsmentioning

confidence: 99%

Atg7 Deficiency Intensifies Inflammasome Activation and Pyroptosis in Pseudomonas Sepsis

Gan

et al. 2017

The Journal of Immunology

130

110

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“…Inflammasomes are large complexes formed by multiple copies of three distinct proteins: a receptor, that recognizes intracellular danger signals (PAMPs or DAMPs); a procaspase, that gets auto-activated upon oligomerization once recruited within the active inflammasome; and an adaptor protein, that connects the activated receptor to the procaspase [245]. The primary aim of these cytosolic platforms is to activate the cysteine protease caspase-1 [246].…”

Section: Inflammasomesmentioning

confidence: 99%

“…In the canonical inflammasome pathway, the adaptor protein is always ASC (apoptosisassociated speck-like protein containing a caspase activation or CARD domain). On the other hand, the receptor belongs to one of the following families [245]: the NLR (nucleotideoligomerization domain or NOD-like), the RLR (retinoic acid-inducible gene or RIG-like), or the ALR (AIM2-like) receptor family. NLRs contain leucine-rich repeat domains and can recognize a large range of danger signals, including LPS, bacterial lipopetides and toxins, or endogenous damage molecules.…”

Section: Inflammasomesmentioning

confidence: 99%

Molecular Actors of Inflammation and Their Signaling Pathways: Mechanistic Insights from Zebrafish

Leiba

Özbilgiç

Hernández

et al. 2023

Biology

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Inflammation is a hallmark of the physiological response to aggressions. It is orchestrated by a plethora of molecules that detect the danger, signal intracellularly, and activate immune mechanisms to fight the threat. Understanding these processes at a level that allows to modulate their fate in a pathological context strongly relies on in vivo studies, as these can capture the complexity of the whole process and integrate the intricate interplay between the cellular and molecular actors of inflammation. Over the years, zebrafish has proven to be a well-recognized model to study immune responses linked to human physiopathology. We here provide a systematic review of the molecular effectors of inflammation known in this vertebrate and recapitulate their modes of action, as inferred from sterile or infection-based inflammatory models. We present a comprehensive analysis of their sequence, expression, and tissue distribution and summarize the tools that have been developed to study their function. We further highlight how these tools helped gain insights into the mechanisms of immune cell activation, induction, or resolution of inflammation, by uncovering downstream receptors and signaling pathways. These progresses pave the way for more refined models of inflammation, mimicking human diseases and enabling drug development using zebrafish models.

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“…There are also other NLRs that do not directly engage the inflammatory caspase but instead activate NF‐κB, mitogen‐activated protein kinases (MAPKs) and IRFs (Zhong, Kinio, & Saleh, 2013). Moreover, in addition to NLRs, some CLRs, RLRs and ALRs are also known to activate caspase‐1 (Allen, 2014; Jamilloux & Henry, 2013; Zheng et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial damage and clearance in retinal pigment epithelial cells

Gurubaran

2024

Acta Ophthalmologica

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Age‐related macular degeneration (AMD) is a devastating eye disease that causes permanent vision loss in the central part of the retina, known as the macula. Patients with such severe visual loss face a reduced quality of life and are at a 1.5 times greater risk of death compared to the general population. Currently, there is no cure for or effective treatment for dry AMD. There are several mechanisms thought to underlie the disease, for example, ageing‐associated chronic oxidative stress, mitochondrial damage, harmful protein aggregation and inflammation. As a way of gaining a better understanding of the molecular mechanisms behind AMD and thus developing new therapies, we have created a peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha and nuclear factor erythroid 2‐related factor 2 (PGC1α/NFE2L2) double‐knockout (dKO) mouse model that mimics many of the clinical features of dry AMD, including elevated levels of oxidative stress markers, damaged mitochondria, accumulating lysosomal lipofuscin and extracellular drusen‐like structures in retinal pigment epithelial cells (RPE). In addition, a human RPE cell‐based model was established to examine the impact of non‐functional intracellular clearance systems on inflammasome activation. In this study, we found that there was a disturbance in the autolysosomal machinery responsible for clearing mitochondria in the RPE cells of one‐year‐old PGC1α/NFE2L2‐deficient mice. The confocal immunohistochemical analysis revealed an increase in autophagosome marker microtubule‐associated proteins 1A/1B light chain 3B (LC3B) as well as multiple mitophagy markers such as PTE‐induced putative kinase 1 (PINK1) and E3 ubiquitin ligase (PARKIN), along with signs of damaged mitochondria. However, no increase in autolysosome formation was detected, nor was there a colocalization of the lysosomal marker LAMP2 or the mitochondrial marker, ATP synthase β. There was an upregulation of late autolysosomal fusion Ras‐related protein (Rab7) in the perinuclear space of RPE cells, together with autofluorescent aggregates. Additionally, we observed an increase in the numbers of Toll‐like receptors 3 and 9, while those of NOD‐like receptor 3 were decreased in PGC1α/NFE2L2 dKO retinal specimens compared to wild‐type animals. There was a trend towards increased complement component C5a and increased involvement of the serine protease enzyme, thrombin, in enhancing the terminal pathway producing C5a, independent of C3. The levels of primary acute phase C‐reactive protein and receptor for advanced glycation end products were also increased in the PGC1α/NFE2L2 dKO retina. Furthermore, selective proteasome inhibition with epoxomicin promoted both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondrial‐mediated oxidative stress, leading to the release of mitochondrial DNA to the cytosol, resulting in potassium efflux‐dependent activation of the absent in melanoma 2 (AIM2) inflammasome and the subsequent secretion of interleukin‐1β in ARPE‐19 cells. In conclusion, the data suggest that there is at least a relative decrease in mitophagy, increases in the amounts of C5 and thrombin and decreased C3 levels in this dry AMD‐like model. Moreover, selective proteasome inhibition evoked mitochondrial damage and AIM2 inflammasome activation in ARPE‐19 cells.

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Les inflammasomes

Cited by 26 publications

References 54 publications

Atg7 Deficiency Intensifies Inflammasome Activation and Pyroptosis in Pseudomonas Sepsis

Atg7 Deficiency Intensifies Inflammasome Activation and Pyroptosis in Pseudomonas Sepsis

Molecular Actors of Inflammation and Their Signaling Pathways: Mechanistic Insights from Zebrafish

Mitochondrial damage and clearance in retinal pigment epithelial cells

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