NLRP3 inflammasome inhibition attenuates sepsis-induced platelet activation and prevents multi-organ injury in cecal-ligation puncture

Cornelius, Denise C.; Travis, Olivia K.; Tramel, Robert; Borges-Rodriguez, Marivee; Baik, Cedar; Greer, Mallory; Giachelli, Chelsea; Tardo, Geilda A.; Williams, Jan Michael

doi:10.1371/journal.pone.0234039

Cited by 51 publications

(41 citation statements)

References 36 publications

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“…Moreover, treatment of diabetic rats after stroke with MCC950 ameliorated cognitive function, vascular permeability, and neurovascular remodeling 114 . More recently, it has been found that sepsis-related endothelial dysfunction was also improved with MCC950 intervention in in vivo and in vitro models 115,116 . Additionally, CY-09, OLT1177, 3,4-methylenedioxy-β-nitrostyrene (MNS), N-[3′,4′-dimethoxycinnamoyl]-anthranilic acid (Tranilast), and oridonin are also specific inhibitors of NLRP3 inflammasome 33,117 .…”

Section: Other Anti-inflammatory or Antioxidant Drugsmentioning

confidence: 99%

NLRP3 inflammasome in endothelial dysfunction

et al. 2020

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Inflammasomes are a class of cytosolic protein complexes. They act as cytosolic innate immune signal receptors to sense pathogens and initiate inflammatory responses under physiological and pathological conditions. The NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex. Its activation triggers the cleavage of pro-interleukin (IL)-1β and pro-IL-18, which are mediated by caspase-1, and secretes mature forms of these mediators from cells to promote the further inflammatory process and oxidative stress. Simultaneously, cells undergo pro-inflammatory programmed cell death, termed pyroptosis. The danger signals for activating NLRP3 inflammasome are very extensive, especially reactive oxygen species (ROS), which act as an intermediate trigger to activate NLRP3 inflammasome, exacerbating subsequent inflammatory cascades and cell damage. Vascular endothelium at the site of inflammation is actively involved in the regulation of inflammation progression with important implications for cardiovascular homeostasis as a dynamically adaptable interface. Endothelial dysfunction is a hallmark and predictor for cardiovascular ailments or adverse cardiovascular events, such as coronary artery disease, diabetes mellitus, hypertension, and hypercholesterolemia. The loss of proper endothelial function may lead to tissue swelling, chronic inflammation, and the formation of thrombi. As such, elimination of endothelial cell inflammation or activation is of clinical relevance. In this review, we provided a comprehensive perspective on the pivotal role of NLRP3 inflammasome activation in aggravating oxidative stress and endothelial dysfunction and the possible underlying mechanisms. Furthermore, we highlighted the contribution of noncoding RNAs to NLRP3 inflammasome activation-associated endothelial dysfunction, and outlined potential clinical drugs targeting NLRP3 inflammasome involved in endothelial dysfunction. Collectively, this summary provides recent developments and perspectives on how NLRP3 inflammasome interferes with endothelial dysfunction and the potential research value of NLRP3 inflammasome as a potential mediator of endothelial dysfunction.

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Section: Other Anti-inflammatory or Antioxidant Drugsmentioning

confidence: 99%

NLRP3 inflammasome in endothelial dysfunction

et al. 2020

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“…Many studies have found that inhibiting the activation of NLRP3 inflammasome has a protective effect on septic animals ( 24 ). In particular, the NLRP3 inhibitor MCC950 attenuates multi-organ injuries in septic rats ( 25 ), highlighting the potential of using NLRP3 inhibitors in the treatment of sepsis.…”

Section: Types and Activation Of Inflammasomes In Sepsismentioning

confidence: 99%

“…In vivo , lack of Casp1 (instead of CASP11) protects mice from EprJ-induced lethality associated with the reduction of DIC biomarkers in blood ( 30 ). In polymicrobial sepsis induced by cecal ligation and puncture (CLP), inhibiting the activity of CASP1 with the NLRP3 inhibitor MCC950 also reduces platelet activation in rats ( 25 , 55 ). These animal studies suggest that CASP1 has a potential role in regulating septic coagulation in mice and rats.…”

Section: Modulation and Function Of Inflammasome In Coagulationmentioning

confidence: 99%

Inflammasome-Dependent Coagulation Activation in Sepsis

Wang

Comish

et al. 2021

Front. Immunol.

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Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.

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“…Similar results were observed using interleukin 1 receptor antagonist (IL-1ra) [ 13 ], corroborating the importance of this pathway. Multiple early life events in the lung have been associated with NLRP3 activation, including viral and bacterial infections, Bronchopulmonary dysplasia and even septic events, which have been associated with increased susceptibility to later disease [ 13 , 45 , 46 , 47 ]. Perhaps targeting NLRP3 during these early life events may provide a common therapeutic pathway for controlling long term sequelae that are often observed later in these children, including childhood asthma.…”

Section: Discussionmentioning

confidence: 99%

NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

Malinczak

Schuler

Duran

et al. 2021

Viruses

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Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

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NLRP3 inflammasome inhibition attenuates sepsis-induced platelet activation and prevents multi-organ injury in cecal-ligation puncture

Cited by 51 publications

References 36 publications

NLRP3 inflammasome in endothelial dysfunction

NLRP3 inflammasome in endothelial dysfunction

Inflammasome-Dependent Coagulation Activation in Sepsis

NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development

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