Inflammasome activation by danger signals: extracellular ATP and pH

Takenouchi, Takato; Tsukimoto, Mitsutoshi; Hashimoto, Makoto; Kitani, Hiroshi

doi:10.2478/infl-2014-0008

Cited by 7 publications

(5 citation statements)

References 26 publications

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“…In contrast, it is also possible that extracellular acidosis inhibits IL-1β-dependent innate immune activation following stimulation of purinergic receptors with ATP. This probably takes place as an attempt to dampen an exacerbated innate immune response [ 74 ], which is consistent with our findings showing decreased inflammasome activation at pH levels of 6.5. In this study, the protein expression levels correspond to the active form of IL-1β and IL-18.…”

Section: Discussionsupporting

confidence: 92%

Acidification changes affect the inflammasome in human nucleus pulposus cells

et al. 2016

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BackgroundInterleukin (IL)-1β is involved in the pathology of intervertebral disc degeneration. Under normal conditions, IL-1β is present in cells in an inactive form (pro-IL-1β). However, under pathological conditions, pro-IL-1β is turned into its active form (IL-1β) by the inflammasome, a multi-protein complex of the innate immune response that activates caspase-1. Under conditions of degeneration, the disc experiences an environment of increased acidification. However, the implications of acidification on the innate immune response remain poorly explored.MethodsHere we have studied how pH changes in human nucleus pulposus cells affect inflammasome activation by immunoblot analysis of protein lysates obtained from nucleus pulposus cells that were exposed to different pH levels in culture.ResultsIn this study, we have found that in nucleus pulposus cells, with increased acidification, there was a decrease in inflammasome activation consistent with lower levels of active IL-1β. However, this effect at a pH of 6.5, the lowest pH level tested, was abrogated when cells were treated with IL-1β.ConclusionsTaken together, these findings suggest that the inflammatory response through IL-1β experienced by the human disc is not initiated in nucleus pulposus cells when the stimulus is acidification.Electronic supplementary materialThe online version of this article (doi:10.1186/s12950-016-0137-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Acidification changes affect the inflammasome in human nucleus pulposus cells

et al. 2016

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“…Indeed, we did not find bacteria colonizing the cornea despite their presence on the lens. The requirement of IL-1R for these parainflammatory responses could also indicate microbial triggers [43,70,71], but would not exclude other potential (non-microbial) factors associated with the lens or post-lens environment that could activate endogenous danger-associated molecular patterns, with IL-1α and/or IL-1β release, and similar cellular responses [61,72–74].…”

Section: Discussionmentioning

confidence: 99%

A novel murine model for contact lens wear reveals clandestine IL-1R dependent corneal parainflammation and susceptibility to microbial keratitis upon inoculation with Pseudomonas aeruginosa

et al. 2019

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Purpose Contact lens wear carries a risk of complications, including corneal infection. Solving these complications has been hindered by limitations of existing animal models. Here, we report development of a new murine model of contact lens wear. Methods C57BL/6 mice were fitted with custom-made silicone-hydrogel contact lenses with or without prior inoculation with Pseudomonas aeruginosa (PAO1-GFP). Contralateral eyes served as controls. Corneas were monitored for pathology, and examined ex vivo using high-magnification, time-lapse imaging. Fluorescent reporter mice allowed visualization of host cell membranes and immune cells. Lens-colonizing bacteria were detected by viable counts and FISH. Direct-colony PCR was used for bacterial identification. Results Without deliberate inoculation, lens-wearing corneas remained free of visible pathology, and retained a clarity similar to non-lens wearing controls. CD11c-YFP reporter mice revealed altered numbers, and distribution, of CD11c-positive cells in lens-wearing corneas after 24 h. Worn lenses showed bacterial colonization, primarily by known conjunctival or skin commensals. Corneal epithelial cells showed vacuolization during lens wear, and after 5 days, cells with phagocyte morphology appeared in the stroma that actively migrated over resident keratocytes that showed altered morphology. Immunofluorescence confirmed stromal Ly6G-positive cells after 5 days of lens wear, but not in MyD88 or IL-1R gene-knockout mice. P. aeruginosa-contaminated lenses caused infectious pathology in most mice from 1 to 13 days. Conclusions This murine model of contact lens wear appears to faithfully mimic events occurring during human lens wear, and could be valuable for experiments, not possible in humans, that help solve the pathogenesis of lens-related complications.

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“…P2X7, P2Y 1 , and P2Y 2 R on immune and inflammatory cells are important in immunomodulation and inflammation, and the purinergic contribution to neuroinflammation underlying neuropathology has been discussed in several recent reviews ( Jacob et al, 2013 ; Takenouchi et al, 2014 ; Di Virgilio and Vuerich, 2015 ; Beamer et al, 2016 ). The role of P2X7R in particular in diseases related to neuroinflammation and the use of P2X7R centrally penetrant antagonists has been highlighted ( Baudelet et al, 2015 ; Di Virgilio, 2015 ; Gentile et al, 2015 ; Burnstock, 2016b ; Danquah et al, 2016 ; Karmakar et al, 2016 ; Rech et al, 2016 ; Corrêa et al, 2017 ; Giuliani A.L.…”

Section: Immune System and Inflammationmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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Inflammasome activation by danger signals: extracellular ATP and pH

Cited by 7 publications

References 26 publications

Acidification changes affect the inflammasome in human nucleus pulposus cells

Acidification changes affect the inflammasome in human nucleus pulposus cells

A novel murine model for contact lens wear reveals clandestine IL-1R dependent corneal parainflammation and susceptibility to microbial keratitis upon inoculation with Pseudomonas aeruginosa

Purinergic Signalling: Therapeutic Developments

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