New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease

Nardo, Dominic De; Nardo, Christine M De; Latz, Eicke

doi:10.1016/j.ajpath.2013.09.007

Cited by 186 publications

(149 citation statements)

References 121 publications

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“…NLRP3 is regarded as the canonical sensor of sterile injury or stress, and so to consider how NLRC4 may sense DAMPs it is sensible to draw comparisons to NLRP3. Given the diverse structures of DAMPs that activate NLRP3 and the fact that no direct interactions have been observed, a direct interaction between a DAMP and NLRP3 is unlikely (32), and no accessory receptors have been described. Rather, the cellular stress imposed by DAMPs is suggested to give rise to a number of potential mechanisms that lead to posttranslational modification of NLRP3, leading to its activation (32).…”

Section: Discussionmentioning

confidence: 99%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

234

233

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Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated specklike protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.inflammation | inflammasome | cerebral ischemia | brain injury | cell death

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Section: Discussionmentioning

confidence: 99%

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Dénes

Coutts

Lénárt

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

234

233

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“…Amelioration of disease sequelae via inhibition or deficiency of NLRP3 inflammasome components or products has been demonstrated in a wide range of preclinical models, including models of autoinflammatory disease, pulmonary disease, renal disease, neurodegenerative disease, and metabolic disease (4,8,9,(12)(13)(14)(15). The contribution of the NLRP3 inflammasome to human disease is evidenced by the pathology observed in patients with cryopyrinassociated periodic syndrome (CAPS).…”

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confidence: 99%

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

Primiano

Lefker

Bowman

et al. 2016

The Journal of Immunology

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144

117

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A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains–containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro–IL-1β and pro–IL-18, as well as the subsequent release of biologically active IL-1β, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome–selective, IL-1β processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1β, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1β release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream–induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.

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“…The NLRP3 inflammasome has been most widely studied and is linked to several autoinflammatory and autoimmune diseases (17,38,39), and several bacterial toxins have been reported to trigger activation of this inflammasome (reviewed in references 17 and 18). Recently, NLRP3 inflammasome activation has also been connected to lung diseases, including asthma (40). Microbial growth in moisture-damaged buildings and the consequent exposure of occupants to microbes and microbe-associated biological agents (e.g., cell components and microbial toxins) are accepted as causes of various adverse health effects, including asthma, allergies, and other symptoms connected with the functioning of the immune system (41).…”

Section: Figmentioning

confidence: 99%

The Peptide Toxin Amylosin of Bacillus amyloliquefaciens from Moisture-Damaged Buildings Is Immunotoxic, Induces Potassium Efflux from Mammalian Cells, and Has Antimicrobial Activity

Rasimus-Sahari

Теплова

Andersson

et al. 2015

Appl Environ Microbiol

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f Amylosin, a heat-stable channel-forming non-ribosomally synthesized peptide toxin produced by strains of Bacillus amyloliquefaciens isolated from moisture-damaged buildings, is shown in this paper to have immunotoxic and cytotoxic effects on human cells as well as antagonistic effects on microbes. Human macrophages exposed to 50 ng of amylosin ml ؊1 secreted high levels of cytokines interleukin-1␤ (IL-1␤) and IL-18 within 2 h, indicating activation of the NLRP3 inflammasome, an integral part of the innate immune system. At the same exposure level, expression of IL-1␤ and IL-18 mRNA increased. Amylosin caused dose-dependent potassium ion efflux from all tested mammalian cells (human monocytes and keratinocytes and porcine sperm cells) at 1 to 2 M exposure. Amylosin also inhibited the motility of porcine sperm cells and depolarized the mitochondria of human keratinocytes. Amylosin may thus trigger the activation of the NLRP3 inflammasome and subsequently cytokine release by causing potassium efflux from exposed cells. The results of this study indicate that exposure to amylosin activates the innate immune system, which could offer an explanation for the inflammatory symptoms experienced by occupants of moisture-damaged buildings. In addition, the amylosin-producing B. amyloliquefaciens inhibited the growth of both prokaryotic and eukaryotic indoor microbes, and purified amylosin also had an antimicrobial effect. These antimicrobial effects could make amylosin producers dominant and therefore significant causal agents of health problems in some moisture-damaged sites.A mylosin is a heat-stable 1,197-Da peptide toxin originally found to be produced by strains of Bacillus amyloliquefaciens isolated from moisture-damaged buildings (1, 2). B. amyloliquefaciens belongs to the Bacillus subtilis group, members of which have been found in high numbers in moisture-damaged buildings where occupants have experienced building-related ill health symptoms (3, 4). Amylosin forms cation-permeant ion channels with high selectivity for K ϩ in lipid membranes (5) and thus depolarizes the plasma membrane and the mitochondria inside live mammalian cells, disrupting cellular ion homeostasis, mitochondrial functions, and energy metabolism (1, 2). It has been suggested that amylosin causes health risks for people living or working in moisture-damaged buildings contaminated with amylosin-producing bacteria (1). Amylosin has also been shown to be produced by B. subtilis and Bacillus mojavensis strains connected to foodborne illness (6).Moisture-damaged buildings harbor many kinds of fungi and bacteria, including producers of bioactive compounds (7, 8; reviewed in reference 9). The symptoms experienced by people living or working in moisture-damaged buildings vary (10), but they could at least partly result from activation of the innate immune system (11,12). Symptoms such as acute inflammatory responses and pseudoallergic reactions may be a result of the activation of inflammasomes (12,13). Inflammasomes are components of the innate immun...

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New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease

Cited by 186 publications

References 121 publications

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

Efficacy and Pharmacology of the NLRP3 Inflammasome Inhibitor CP-456,773 (CRID3) in Murine Models of Dermal and Pulmonary Inflammation

The Peptide Toxin Amylosin of Bacillus amyloliquefaciens from Moisture-Damaged Buildings Is Immunotoxic, Induces Potassium Efflux from Mammalian Cells, and Has Antimicrobial Activity

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