Activation mechanisms of inflammasomes by bacterial toxins

Jing, Weidong; Pilato, Jordan Lo; Kay, Callum; Man, Si Ming

doi:10.1111/cmi.13309

Cited by 23 publications

(21 citation statements)

References 143 publications

(151 reference statements)

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“…In support of this, dispersion of the trans-Golgi network (TGN), an event that occurs with canonical NLRP3 inflammasome assembly ( 34 ), is triggered only upon internalization of the MAC. Previous work has established that other pore-forming toxins including α-haemolysin and streptolysin activate the NLRP3 inflammasome ( 53 ). These toxins are also known to be removed from the cell membrane through different mechanisms, including endocytosis ( 40 , 54 ).…”

Section: Discussionmentioning

confidence: 99%

Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

et al. 2021

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Interleukin 1β (IL-1β) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1β release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1β release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1β release in human macrophages.

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Section: Discussionmentioning

confidence: 99%

Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

et al. 2021

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“…There are currently seven known types of ‘canonical’ inflammasomes—the NLR family pyrin domain‐containing 1 (NLRP1), NLRP3 and NLRP6 inflammasomes, the NLR family CARD domain‐containing 4 (NLRC4) inflammasome, the absence in melanoma 2 (AIM2) inflammasome, the pyrin inflammasome, and the recently discovered CARD8 inflammasome (Evavold & Kagan, 2019; Johnson et al, 2018). The formation of these multiprotein complexes, which leads to caspase‐1 activation, can be triggered by a large variety of stimuli that have been extensively reviewed elsewhere (Evavold & Kagan, 2019; Jing, Pilato, Kay, & Man, 2021).…”

Section: Inflammasomes and Pyroptosismentioning

confidence: 99%

Inflammasome activation and IL ‐1β signalling in group A Streptococcus disease

Richter

Brouwer

Schroder

et al. 2021

Cellular Microbiology

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Group A Streptococcus (GAS) is a Gram‐positive bacterial pathogen that causes significant morbidity and mortality worldwide. Recent clinical evidence suggests that the inflammatory marker interleukin‐1β (IL‐1β) plays an important role in GAS disease progression, and presents a potential target for therapeutic intervention. Interaction with GAS activates the host inflammasome pathway to stimulate production and secretion of IL‐1β, but GAS can also stimulate IL‐1β production in an inflammasome‐independent manner. This review highlights progress that has been made in understanding the importance of host cell inflammasomes and IL‐1 signalling in GAS disease, and explores challenges and unsolved problems in this host‐pathogen interaction. Take Away Inflammasome signalling during GAS infection is an emerging field of research. GAS modulates the NLRP3 inflammasome pathway through multiple mechanisms. SpeB contributes to IL‐1β production independently of the inflammasome pathway. IL‐1β signalling can be host‐protective, but also drive severe GAS disease.

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“…[96][97][98] These studies highlight the engagement of inflammasome components with structural organization of cells. Moreover, bacterial toxins can activate pyrin inflammasome, 99 however, very few have studied the association between pyrin inflammasome and microbiome-mediated intestinal inflammation. 100-102…”

Section: Pyrin Inflammasomementioning

confidence: 99%

Therapeutic implications of inflammasome in inflammatory bowel disease

Khatri

Kalyanasundaram

2021

FASEB j.

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Inflammatory bowel disease (IBD) remains a persistent health problem with a global burden surging over 6.8 million cases currently. Clinical pathology of IBD is complicated; however, hyperactive inflammatory and immune responses in the gut is shown to be one of the persistent causes of the disease. Human gut inflammasome, the activator of innate immune system is believed to be a primary underlying cause for the pathology and is largely associated with the progression of IBD. To manage IBD, there is a need to fully understand the role of inflammasome activation in IBD.Since inflammasome potentially play a significant role in IBD, systemic modulation of inflammasome may provide an effective therapeutic and clinical approach to control IBD symptoms. In this review, we have focused on this association between IBD and gut inflammasome, and recent advances in the research and therapeutic strategies for IBD. We have discussed inflammasomes and their components, outcomes from the experimental animals and human studies, inflammasome inhibitors, and developments in the inflammasome-targeted therapies for IBD.

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Activation mechanisms of inflammasomes by bacterial toxins

Cited by 23 publications

References 143 publications

Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages

Inflammasome activation and IL ‐1β signalling in group A Streptococcus disease

Therapeutic implications of inflammasome in inflammatory bowel disease

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