scholarly journals A Type III Effector NleF from EHEC Inhibits Epithelial Inflammatory Cell Death by Targeting Caspase-4

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Ting Song ◽  
Kaiwu Li ◽  
Wei Zhou ◽  
Jing Zhou ◽  
Yuan Jin ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Gastrointestinal Disease ◽  
Highly Pathogenic ◽  
E Coli ◽  
Caspase 1 ◽  
T3ss Effector ◽  
Inflammatory Caspases ◽  
Epithelial Cell Death ◽  
Host Inflammatory Response

EnterohemorrhagicE. coli(EHEC) is a highly pathogenic bacterial strain capable of inducing severe gastrointestinal disease. Here, we show that EHEC uses the T3SS effector NleF to counteract the host inflammatory response by dampening caspase-4-mediated inflammatory epithelial cell death and by preventing the production of IL-1β. The other two inflammatory caspases, caspase-1 and caspase-5, are not involved in EHEC ΔnleF-induced inflammatory cell death. We found that NleF not only interrupted the heterodimerization of caspase-4-p19 and caspase-4-p10, but also inhibited the interaction of caspase-1 and caspase-4. The last four amino acids of the NleF carboxy terminus are essential in inhibiting caspase-4-dependent inflammatory cell death.

scholarly journals New insights in caspase-11 functions in noncanonical inflammasome signalling

Inflammasome ◽  
2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Mélanie Bodnar ◽  
Virginie Petrilli
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Protein Complexes ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Nucleotide Binding Domain ◽  
Gram Negative ◽  
Caspase 1 ◽  
Nlrp3 Inflammasome Activation ◽  
Dependent Pathway

AbstractInflammasomes are multi-protein complexes that play a crucial role in innate immunity. They are assembled by cytosolic sensors of the Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLR) and PYrin and HIN (PYHIN) domain-containing protein families upon sensing various pathogens and danger signals. Inflammasome formation culminates in caspase-1 activation, which causes the cleavage of pro-IL-1β and pro- IL-18 into active cytokines; this eventually results in the induction of an inflammatory cell death called pyroptosis. Recent data using Gram-negative bacteria suggests a role for caspase-11 not only in NLRP3 inflammasome activation but also in a caspase-1- and inflammasome-independent cell death. This novel caspase-11-dependent pathway is critical to control infection by Gram-negative bacteria and has been named the noncanonical inflammasome.

scholarly journals SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release

2021 ◽  
Author(s):  
Caroline Junqueira ◽  
Ângela Crespo ◽  
Shahin Ranjbar ◽  
Mercedes Lewandrowski ◽  
Jacob Ingber ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Infectious Virus ◽  
Multiorgan Failure ◽  
Inflammasome Activation ◽  
Invasive Infection ◽  
Blood Monocytes ◽  
Fluorescent Reporter ◽  
Caspase 1 ◽  
Monocytes And Macrophages

Abstract SARS-CoV-2 causes acute respiratory distress that can progress to multiorgan failure and death in a minority of patients. Although severe COVID-19 disease is linked to exuberant inflammation, how SARS-CoV-2 triggers inflammation is not understood. Monocytes and macrophages are sentinel immune cells in the blood and tissue, respectively, that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D (GSDMD) pores, leading to inflammatory death (pyroptosis) and processing and release of IL-1 family cytokines, potent inflammatory mediators. Here we show that expression quantitative trait loci (eQTLs) linked to higher GSDMD expression increase the risk of severe COVID-19 disease (odds ratio, 1.3, p<0.005). We find that about 10% of blood monocytes in COVID-19 patients are infected with SARS-CoV-2. Monocyte infection depends on viral antibody opsonization and uptake of opsonized virus by the Fc receptor CD16. After uptake, SARS-CoV-2 begins to replicate in monocytes, as evidenced by detection of double-stranded RNA and subgenomic RNA and expression of a fluorescent reporter gene. However, infection is aborted, and infectious virus is not detected in infected monocyte supernatants or patient plasma. Instead, infected cells undergo inflammatory cell death (pyroptosis) mediated by activation of the NLRP3 and AIM2 inflammasomes, caspase-1 and GSDMD. Moreover, tissue-resident macrophages, but not infected epithelial cells, from COVID-19 lung autopsy specimens showed evidence of inflammasome activation. These findings taken together suggest that antibody-mediated SARS-CoV-2 infection of monocytes/macrophages triggers inflammatory cell death that aborts production of infectious virus but causes systemic inflammation that contributes to severe COVID-19 disease pathogenesis.

scholarly journals Bacterial infection drives trained immunity through epigenetic remodeling of epithelial stem cells

2021 ◽  
Author(s):  
Scott Hultgren ◽  
Seongmi Russell ◽  
Hyung Joo Lee ◽  
Benjamin Olson ◽  
Jonathan Livny ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Death ◽  
Bacterial Infection ◽  
Bacterial Infections ◽  
Inflammatory Cell ◽  
Host Susceptibility ◽  
Epithelial Stem Cells ◽  
Caspase 1

Abstract Recurrent bacterial infections are a major health burden worldwide, yet the mechanisms dictating host susceptibility to recurrence are poorly understood. Here we demonstrate that an initial bacterial infection of the urinary bladder with uropathogenic E. coli (UPEC) can induce sustained epigenetic changes in the bladder epithelial (urothelial) stem cells that reprogram the differentiated urothelium. We established urothelial stem cell (USC) lines from isogenic mice with different urinary tract infection histories (naïve, chronic or self-resolving). Differentiation of the USC lines in Transwell culture resulted in polarized urothelial cultures that recapitulated distinct remodeling morphologies seen in vivo. In addition, we discovered differences in chromatin accessibility that segregated by disease history, resulting in differences in gene expression upon differentiation of the USC lines in vitro, based on ATAC-seq analysis of the USC lines. Differential basal expression of Caspase-1 led to divergent susceptibilities to inflammatory cell death upon UPEC infection. In mice with a history of chronic infection, enhanced caspase 1-mediated inflammatory cell death was found to be a protective response that enhanced bacterial clearance upon challenge infection. Thus, UPEC infection reshapes the epigenome leading to epithelial-intrinsic remodeling that trains the mucosal immune response to subsequent infection. These findings may have broad implications for the prevention of chronic/recurrent bacterial infections.

CASP1 variants influence subcellular caspase-1 localization, pyroptosome formation, pro-inflammatory cell death and macrophage deformability

2019 ◽  
Vol 208 ◽  
pp. 108232
Author(s):  
Franz Kapplusch ◽  
Felix Schulze ◽  
Sabrina Rabe-Matschewsky ◽  
Susanne Russ ◽  
Maik Herbig ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Caspase 1

scholarly journals Extended subsite profiling of the pyroptosis effector protein gasdermin D reveals a region recognized by inflammatory caspase-11

2020 ◽  
Vol 295 (32) ◽  
pp. 11292-11302 ◽  
Author(s):  
Betsaida Bibo-Verdugo ◽  
Scott J. Snipas ◽  
Sonia Kolt ◽  
Marcin Poreba ◽  
Guy S. Salvesen
Keyword(s):  
Inflammatory Cell ◽  
Effector Protein ◽  
Protein Substrates ◽  
Caspase 1 ◽  
Human Orthologs ◽  
Noncanonical Pathway ◽  
D Region ◽  
Inflammatory Caspases ◽  
Human Caspase

Pyroptosis is the caspase-dependent inflammatory cell death mechanism that underpins the innate immune response against pathogens and is dysregulated in inflammatory disorders. Pyroptosis occurs via two pathways: the canonical pathway, signaled by caspase-1, and the noncanonical pathway, regulated by mouse caspase-11 and human caspase-4/5. All inflammatory caspases activate the pyroptosis effector protein gasdermin D, but caspase-1 mostly activates the inflammatory cytokine precursors prointerleukin-18 and prointerleukin-1β (pro-IL18/pro-IL1β). Here, in vitro cleavage assays with recombinant proteins confirmed that caspase-11 prefers cleaving gasdermin D over the pro-ILs. However, we found that caspase-11 recognizes protein substrates through a mechanism that is different from that of most caspases. Results of kinetics analysis with synthetic fluorogenic peptides indicated that P1′–P4′, the C-terminal gasdermin D region adjacent to the cleavage site, influences gasdermin D recognition by caspase-11. Furthermore, introducing the gasdermin D P1′–P4′ region into pro-IL18 enhanced catalysis by caspase-11 to levels comparable with that of gasdermin D cleavage. Pro-IL1β cleavage was only moderately enhanced by similar substitutions. We conclude that caspase-11 specificity is mediated by the P1′–P4′ region in its substrate gasdermin D, and similar experiments confirmed that the substrate specificities of the human orthologs of caspase-11, i.e. caspase-4 and caspase-5, are ruled by the same mechanism. We propose that P1′–P4′-based inhibitors could be exploited to specifically target inflammatory caspases.

scholarly journals Impact of vaginal douching products on vaginal Lactobacillus, Escherichia coli and epithelial immune responses

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Helai Hesham ◽  
Alissa J. Mitchell ◽  
Agnes Bergerat ◽  
Kristin Hung ◽  
Caroline M. Mitchell
Keyword(s):  
Escherichia Coli ◽  
Cell Death ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immune Responses ◽  
E Coli ◽  
Vaginal Douching ◽  
Vaginal Epithelial Cells ◽  
Epithelial Disruption ◽  
Epithelial Cell Death

AbstractWe compared the effect of commercial vaginal douching products on Lactobacillus crispatus, L. jensenii, L. gasseri, L. iners, E. coli, and immortalized vaginal epithelial cells (VK2). All studied douching products (vinegar, iodine and baking soda based) induced epithelial cell death, and all inhibited growth of E. coli. Co-culture of vaginal epithelial cells with any of the lactobacilli immediately following exposure to douching products resulted in a trend to less human cell death. However, co-culture of epithelial cells with L. iners was associated with higher production of IL6 and IL8, and lower IL1RA regardless of presence or type of douching solution. Co-culture with L. crispatus or L. jensenii decreased IL6 production in the absence of douches, but increased IL6 production after exposure to vinegar. Douching products may be associated with epithelial disruption and inflammation, and may reduce the anti-inflammatory effects of beneficial lactobacilli.

scholarly journals Human caspase-4 mediates noncanonical inflammasome activation against gram-negative bacterial pathogens

2015 ◽  
Vol 112 (21) ◽  
pp. 6688-6693 ◽  
Author(s):  
Cierra N. Casson ◽  
Janet Yu ◽  
Valeria M. Reyes ◽  
Frances O. Taschuk ◽  
Anjana Yadav ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Pathogens ◽  
Inflammasome Activation ◽  
Gram Negative Bacteria ◽  
Secretion Systems ◽  
Gram Negative ◽  
Human Macrophages ◽  
Caspase 1 ◽  
Inflammatory Caspases ◽  
Human Caspase

Inflammasomes are critical for host defense against bacterial pathogens. In murine macrophages infected by gram-negative bacteria, the canonical inflammasome activates caspase-1 to mediate pyroptotic cell death and release of IL-1 family cytokines. Additionally, a noncanonical inflammasome controlled by caspase-11 induces cell death and IL-1 release. However, humans do not encode caspase-11. Instead, humans encode two putative orthologs: caspase-4 and caspase-5. Whether either ortholog functions similar to caspase-11 is poorly defined. Therefore, we sought to define the inflammatory caspases in primary human macrophages that regulate inflammasome responses to gram-negative bacteria. We find that human macrophages activate inflammasomes specifically in response to diverse gram-negative bacterial pathogens that introduce bacterial products into the host cytosol using specialized secretion systems. In primary human macrophages, IL-1β secretion requires the caspase-1 inflammasome, whereas IL-1α release and cell death are caspase-1–independent. Instead, caspase-4 mediates IL-1α release and cell death. Our findings implicate human caspase-4 as a critical regulator of noncanonical inflammasome activation that initiates defense against bacterial pathogens in primary human macrophages.

scholarly journals N-terminal degradation activates the Nlrp1b inflammasome

2018 ◽  
Author(s):  
Ashley J. Chui ◽  
Marian C. Okondo ◽  
Sahana D. Rao ◽  
Kuo Gai ◽  
Andrew R. Griswold ◽  
...  
Keyword(s):  
Cell Death ◽  
Lethal Factor ◽  
Proteasomal Degradation ◽  
Degradation Pathway ◽  
Common Mechanism ◽  
Caspase 1 ◽  
C Terminus ◽  
Anthrax Lethal Factor ◽  
N Terminus ◽  
Inflammatory Caspases

AbstractIntracellular pathogens and danger signals trigger the formation of inflammasomes, which activate inflammatory caspases and induce pyroptotic cell death. The anthrax lethal factor metalloprotease and small molecule DPP8/9 inhibitors both activate the Nlrp1b inflammasome, but the molecular mechanism of Nlrp1b activation is not known. Here, we used genome-wide CRISPR/Cas9 knockout screens to identify genes required for Nlrp1b-mediated pyroptosis, and discovered that lethal factor induces cell deathviathe N-end rule proteasomal degradation pathway. Lethal factor directly cleaves Nlrp1b, which induces the N-end rule-mediated degradation of the Nlrp1b N-terminus and thereby frees the Nlrp1b C-terminus to activate caspase-1. DPP8/9 inhibitors also induce proteasomal degradation of the Nlrp1b N-terminus, but, in contrast, not through the N-end rule pathway. Overall, these data reveal that N-terminal degradation is the common mechanism for activation of this innate immune sensor protein.One Sentence SummaryProteasome-mediated degradation of the Nlrp1b N-terminus releases the Nlrp1b C-terminus to activate caspase-1 and induce pyroptotic cell death.

scholarly journals Pyroptosis: A Common Feature of Immune Cells of Haemodialysis Patients

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 839
Author(s):  
Christof Ulrich ◽  
Leonie Kneser ◽  
Roman Fiedler ◽  
Julia Beckert ◽  
Susann Wildgrube ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Cell ◽  
Risk Groups ◽  
Model System ◽  
Inflammasome Activation ◽  
Uremic Toxin ◽  
Caspase 1 ◽  
Regulated Cell Death ◽  
Patient Groups ◽  
Intact Kidney

NLRP-3 inflammasome activation can result in interleukin-1β (IL-1β) release and inflammatory cell death (pyroptosis). Caspase-1 is able to trigger both processes. However, other caspases, caspase-4, -5 and -8, are believed to initiate pyroptosis without affecting IL-1 secretion. In this study, we evaluated two cardiovascular risk groups, haemodialysis patients (HD) and patients with intact kidney function but high blood pressure (BP), to analyse the mechanisms driving pyroptosis. Twenty HD were age-, gender- and diabetes-matched to BP. We found a common pyroptotic pattern in both patient groups, at which pyroptosis rates but not IL-1 β levels were significantly higher in monocytes (HD vs. BP: p < 0.05), granulocytes (p < 0.01) and lymphocytes (p < 0.01) of HD patients. As uremic toxins are drivers of inflammation and regulated cell death, we applied a monocyte- and macrophage-like THP-1 model system to demonstrate that the protein-bound uremic toxin indoxyl sulfate (IS) is an inducer of pyroptotic cell death, particularly engaging caspase-4/caspase-5 and to a lesser extent caspase-8 and caspase-1. These data suggest that the uremic toxin IS can mediate pyroptosis in HD patients and the inflammatory caspase-4 and/or caspase-5 contribute to pyroptosis rates to a higher extent in comparison to caspase-1.

scholarly journals Clustering of Tir during enteropathogenic E. coli infection triggers calcium influx–dependent pyroptosis in intestinal epithelial cells

PLoS Biology ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. e3000986
Author(s):  
Qiyun Zhong ◽  
Theodoros I. Roumeliotis ◽  
Zuza Kozik ◽  
Massiel Cepeda-Molero ◽  
Luis Ángel Fernández ◽  
...  
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Type Iii Secretion ◽  
Calcium Influx ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Independent Manner ◽  
E Coli ◽  
T3ss Effector

Clustering of the enteropathogenic Escherichia coli (EPEC) type III secretion system (T3SS) effector translocated intimin receptor (Tir) by intimin leads to actin polymerisation and pyroptotic cell death in macrophages. The effect of Tir clustering on the viability of EPEC-infected intestinal epithelial cells (IECs) is unknown. We show that EPEC induces pyroptosis in IECs in a Tir-dependent but actin polymerisation-independent manner, which was enhanced by priming with interferon gamma (IFNγ). Mechanistically, Tir clustering triggers rapid Ca2+ influx, which induces lipopolysaccharide (LPS) internalisation, followed by activation of caspase-4 and pyroptosis. Knockdown of caspase-4 or gasdermin D (GSDMD), translocation of NleF, which blocks caspase-4 or chelation of extracellular Ca2+, inhibited EPEC-induced cell death. IEC lines with low endogenous abundance of GSDMD were resistant to Tir-induced cell death. Conversely, ATP-induced extracellular Ca2+ influx enhanced cell death, which confirmed the key regulatory role of Ca2+ in EPEC-induced pyroptosis. We reveal a novel mechanism through which infection with an extracellular pathogen leads to pyroptosis in IECs.

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