Molecular Mechanism of NLRP3 Inflammasome Activation

Jin, Chengcheng; Flavell, Richard A.

doi:10.1007/s10875-010-9440-3

Cited by 381 publications

(295 citation statements)

References 36 publications

Supporting

Mentioning

280

Contrasting

Unclassified

Order By: Relevance

“…It was previously reported that intranasal administration of chitin beads induced infiltration of IL-4-expressing cells in lung, but administration of chitin beads that were pretreated with recombinant AMCase failed to induce infiltration of IL-4-expressing cells in lung (11). It was also reported that mice that expressed AMCase constitutively in lung demonstrated a significant reduction of eosinophil infiltration after administration of chitin beads or fungal challenge (11,35). These reports support our observations that enzymatically inactive AMCase-ED mice showed enhanced infiltration of eosinophils in lung and type 2 immune responses after administration of HDM or chitin.…”

Section: Discussionmentioning

confidence: 99%

“…The results support the following model. The enzymatically cleaved chitin is taken up by cells through phagocytosis, which then triggers activation of caspase-1 through this wellcharacterized pathway (35,36), whereas uncleaved chitin promotes the release of IL-33 probably due to mechanical damage to lung tissue. The activation of caspase-1 leads in turn to the activation of caspase-7, which inactivates IL-33, thereby resolving type 2 immune responses (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

Kim¹,

Morita²,

Kobayashi³

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33. These data suggest that AMCase is a crucial regulator of type 2 immune responses to inhaled chitin-containing aeroallergens.AMCase | chitin | house dust mite | IL-33

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

Kim¹,

Morita²,

Kobayashi³

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Furthermore, DTA0118 significantly inhibited the synthesis of cytokines. IL-1β was generated presumably by activation of the inflammasome, 19 which has been linked to the pathogenesis of ARDS. 20 This inhibition of proinflammatory cytokines has also been …”

Section: Discussionmentioning

confidence: 99%

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Cabrera-Benítez

Pérez-Roth

Ramos-Nuez

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS.

show abstract

“…Iwata et al (2015) have found that exposure to acute immobilization stress (60 min) resulted in the intrahippocampal release of ATP concomitant with IL-1β protein as well as NLRP3 inflammasome activation. These effects of stress were prevented in a Nlrp3 KO mouse and were blocked by peripheral administration of an antagonist to the P2X7 receptor, which mediates ATP activation of the NLRP3 inflammasome (Jin and Flavell, 2010), suggesting that stress-induced release of ATP mediates NLRP3 inflammasome activation and subsequent release of IL-1β. Further, they found that chronic administration of a P2X7 receptor antagonist during exposure to CUS ameliorated several effects of stress on depressive-like behaviors including the sucrose preference test, the novelty suppressed feeding test, and elevated plus maze.…”

Section: Atpmentioning

confidence: 98%

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Fleshner

Frank

Maier

2016

Neuropsychopharmacol

176

125

View full text Add to dashboard Cite

Major depressive disorder (MDD) and other mood disorders remain difficult to effectively treat, and innovative interventions and therapeutic targets are needed. Psychological stressors and inappropriate inflammation increase the risk and severity of mood disorders; however, only recently have the importance of sterile inflammatory processes in this effect been revealed. This review will introduce the reader to pathogen vs sterile inflammation, inflammatory receptor-ligand interactions, microbialassociated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and the more recent discovery of the role of the inflammasome in peripheral and central nervous system cytokine/chemokine inflammatory responses. The review will focus on current preclinical and clinical evidence that sterile inflammation and inflammasome-dependent signaling may contribute to mood disorders. By understanding these inflammatory signaling processes, new approaches for quieting chronic or inappropriate inflammatory states may be revealed and this could serve as novel pharmacological targets for the treatment of mood disorders.

show abstract

Molecular Mechanism of NLRP3 Inflammasome Activation

Cited by 381 publications

References 36 publications

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Contact Info

Product

Resources

About