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

Dong-Wook Kwak,Jae-Hong Kim,Donghwan Park

doi:10.3390/biomedicines9050535

Dong-Wook Kwak, Jae-Hong Kim + Show 1 more

Open Access

https://doi.org/10.3390/biomedicines9050535

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Journal: Biomedicines	Publication Date: May 11, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Korea University

Abstract

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.

Highlights

These results suggested that the stimulation of the NLRP3 inflammasome is necessary for house dust mite (HDM)/LPS-induced neutrophilic airway inflammation
We demonstrated that the Leukotriene B4 (LTB4) receptors BLT1 and BLT2 play an important role in the stimulation of the NLRP3 inflammasome and IL-1β synthesis in HDM/LPS-driven neutrophilic airway inflammation
We found that the levels of BLT1 and BLT2, as well as the synthesis of their ligands LTB4 and 12(S)-HETE, were markedly upregulated in our neutrophildominant model and that blockade of BLT1/2 or 5-/12-LOX significantly reduced NLRP3 stimulation and IL-1β production, attenuating neutrophilic airway inflammation (Figures 3 and 4)

Summary

Introduction

Asthma is an airway inflammatory disease consisting of various phenotypes that are driven by different pathways. Severe asthma is more strongly associated with Th1/Th17 responses and neutrophilic airway inflammation [1,2,3,4,5,6]. 5–20% of asthma patients respond poorly to corticosteroids even at high doses, and no effective treatments are currently available for severe, steroid-resistant asthma [3,7,8]. Recent studies have reported that NLRP3-dependent IL-1β is associated with severe neutrophilic asthmatic progression and pathological exacerbation, and the levels of IL-1β in sputum were elevated with the severity of the disease [9,10]. The detailed signaling pathway for the synthesis of the NLRP3 inflammasome and IL-1β in neutrophil-dominant asthmatic airway inflammation remains to be determined

Results

Discussion

Conclusion