Leukotriene B4 Receptors are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation

The stimulation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and IL-1β synthesis are associated with chronic respiratory diseases such as neutrophil-dominant severe asthma. Leukotriene B4 (LTB4) is a principal chemoattractant molecule for neutrophil recruitment, and its receptors BLT1 and BLT2 have been suggested to contribute to neutrophil-dominant asthmatic airway inflammation. However, the relationship between BLT1/2 and NLRP3 in neutrophil-dominant asthmatic airway inflammation has not been previously studied. In the present study, we investigated whether BLT1/2 play any roles in stimulating the NLRP3 inflammasome and IL-1βsynthesis. The blockade of BLT1 or BLT2 clearly suppressed the stimulation of the NLRP3 inflammasome and IL-1β synthesis in house dust mite (HDM)/lipopolysaccharide (LPS)-induced neutrophilic airway inflammation. The enzymes 5-lipoxygenase and 12-lipoxygenase, which catalyze the synthesis of BLT1/2 ligands [LTB4, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), and 12-hydroxyheptadecatreinoic acid (12-HHT)], were also critically associated with the stimulation of NLRP3 and IL-1β synthesis. Together, our results suggest that the 5-/12-LOX-BLT1/2-linked cascade are necessary for the simulation of the NLRP3 inflammasome and IL-1β synthesis, thus contributing to HDM/LPS-induced neutrophil-dominant airway inflammation.

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Leukotriene B4 receptors contribute to house dust mite-induced eosinophilic airway inflammation via TH2 cytokine production

BMB Reports ◽

10.5483/bmbrep.2021.54.3.247 ◽

2021 ◽

Vol 54 (3) ◽

pp. 182-187

Author(s):

Donghwan Park ◽

Dong-Wook Kwak ◽

Jae-Hong Kim

Keyword(s):

Airway Inflammation ◽

House Dust ◽

House Dust Mite ◽

Cytokine Production ◽

Leukotriene B4 ◽

Th2 Cytokine ◽

Dust Mite

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New insights into the relationship between airway inflammation and asthma

Clinical Science ◽

10.1042/cs1030201 ◽

2002 ◽

Vol 103 (2) ◽

pp. 201-211 ◽

Cited By ~ 50

Author(s):

A.J. WARDLAW ◽

C.E. BRIGHTLING ◽

R. GREEN ◽

G. WOLTMANN ◽

P. BRADDING ◽

...

Keyword(s):

Allergic Rhinitis ◽

Smooth Muscle ◽

Airway Inflammation ◽

Physiological Responses ◽

Airflow Obstruction ◽

Mucus Hypersecretion ◽

Neutrophilic Inflammation ◽

Eosinophilic Bronchitis ◽

Dust Mite ◽

The Relationship

Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved–for reasons that remain to be established–that asthma occurs.

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HMGB1-induced NLRP3 Inflammasome Participating in Platelet Activation and Thrombocytopenia in Heatstroke

10.21203/rs.3.rs-659150/v1 ◽

2021 ◽

Author(s):

Huimei Yin ◽

Ming Wu ◽

Yong Lu ◽

Xinghui Wu ◽

Baojun Yu ◽

...

Keyword(s):

Platelet Count ◽

Platelet Activation ◽

Nlrp3 Inflammasome ◽

Heat Stroke ◽

High Mobility ◽

Molecular Probes ◽

Toll Like Receptor 4 ◽

Pyrin Domain ◽

The Relationship ◽

Related Mortality

Abstract Background: Previous studies have suggested that NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays an important role in heat stroke (HS). As a common complication in HS, thrombocytopenia has been widely considered as a good predictor of HS-related mortality. However, little is known about the relationship between inflammasome and thrombocytopenia as well as platelet activation in HS. Methods: We established a rat HS model to investigate the roles of NLRP3 inflammasome in both platelet activation and thrombocytopenia, platelet activation was reflected with Flow cytometry while thrombocytopenia was measured by platelet count. The colocalization of NLRP3 inflammasome was detected by confocal fluorescence microscopy. Mitochondrial-derived reactive oxygen species (ROS) were detected using the molecular probes. Plasma HMGB1 levels were measured by ELISA.Results: Activation of the inflammasome was detected in platelet of rats in HS. Elevated ROS activated NLRP3 inflammasome in HS group could significantly induce platelet activation and thrombocytopenia. The upregulated P-selectin (CD62P ) and decreased platelet count triggered by NLRP3 inflammasome were attributed to the high mobility group box protein 1 (HMGB1) in plasma. Moreover, inhibition of HMGB1, caspase-1, NLRP3, or ROS in rats with HS suppressed platelet activation and the decline of platelet count. Similar results were obtained when the receptor toll-like receptor 4 (TLR4) / advanced glycation end product (RAGE) was blocked. Conclusions: This study indicated that platelets were activated by NLRP3 inflammasome through TLR4/RAGE/HMGB1 signaling pathway. The NLRP3 inflammasome might be the potential target for HS treatment.

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Estrogen ameliorates allergic airway inflammation by regulating activation of NLRP3 in mice

Bioscience Reports ◽

10.1042/bsr20181117 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 11

Author(s):

Cheng Cheng ◽

Huimei Wu ◽

Muzi Wang ◽

Lixia Wang ◽

Hongyun Zou ◽

...

Keyword(s):

Airway Inflammation ◽

Nlrp3 Inflammasome ◽

Inflammatory Cytokine ◽

Allergic Airway Inflammation ◽

Protective Role ◽

Inflammatory Factors ◽

Inflammasome Activation ◽

Mucus Production ◽

Caspase 1 ◽

Pyrin Domain

Abstract Background: Estrogen has been suggested to play a protective role against airway inflammations, such as asthma. In these processes, the inflammasome nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) partly accounts for the activation of pro-inflammatory factors. The aim of the present study was to investigate whether NLRP3 was involved in the protective effect of estrogen against allergic airway inflammation. Methods: An ovariectomy was performed on female C57BL/6 mice; some were sham-operated (sham). We then sensitized and challenged them with ovalbumin (OVA) to establish an airway inflammation model. Meanwhile, some mice were treated with 17β-estradiol (E2) for 28 days. Results: The expression of NLRP3 inflammasome and its downstream products, caspase-1 and the pro-inflammatory cytokine interleukin (IL)-1β (IL-1β), increased concomitantly with OVA-challenged airway inflammation and decreased with the expression of estrogen receptor β (ERβ). In addition, treating ovariectomized (OVX) mice with E2 dramatically ameliorated airway inflammation via such mechanisms as leukocyte recruitment, mucus production, and secretion of pro-inflammatory cytokines other than IL-18 in bronchoalveolar lavage (BAL) fluid (BALF). Furthermore, E2 suppressed both the mRNA expression and protein expression of NLRP3, caspase-1, and IL-1β. In summary, our study showed that NLRP3 inflammasome activation and pro-inflammatory cytokine production markedly increased in OVA-induced airway inflammation, and E2 effectively abrogated such inflammation by regulating the activation of NLRP3.

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Involvement of NLRP3 inflammasome in schizophrenia-like behaviour in young animals after maternal immune activation

Acta Neuropsychiatrica ◽

10.1017/neu.2020.27 ◽

2020 ◽

Vol 32 (6) ◽

pp. 321-327

Author(s):

Letícia Ventura ◽

Viviane Freiberger ◽

Vinicius B. Thiesen ◽

Paula Dias ◽

Matheus L. Dutra ◽

...

Keyword(s):

Locomotor Activity ◽

Immune Activation ◽

Nlrp3 Inflammasome ◽

Biochemical Analysis ◽

Future Studies ◽

Maternal Immune Activation ◽

Pyrin Domain ◽

Behavioural Tests ◽

The Relationship ◽

The Brain

AbstractObjective:To evaluate the involvement of nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in schizophrenia-like behaviour in young animals exposed to maternal immune activation (MIA).Methods:To this aim, on the 15th gestational day, the females received an injection of lipopolysaccharides. When the animals completed 7, 14 and 45 postnatal days, they were killed and the whole brain was dissected for biochemical analysis. Animals with 45 postnatal days were submitted to behavioural tests of locomotor activity, social interaction and stereotyped movements.Results:It was observed that the animals presented schizophrenia-like behaviour at 45 postnatal days associated with the increase of NLRP3 inflammasome expression and IL-1β levels on 7, 14 and 45 postnatal days.Conclusion:This study shows that MIA may be associated with a schizophrenia-like behaviour. This behaviour can be induced to a neuroinflammatory profile in the brain. These evidences may base future studies on the relationship between neuroinflammation and psychiatric disorders.

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