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

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.

Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation

“…Since previous studies suggested a mediating role of BLT2 in neutrophilic airway inflammation [ 29 , 30 , 31 ], we investigated whether BLT2 had any role in the production of G-CSF. Lung inflammation and mucus secretion were markedly suppressed by treatment with the BLT2 antagonist, LY255283 ( Figure 3 A,B).…”

“…NLRP3 inflammasome-dependent IL-1β production also acts as a major chemoattractant of neutrophils and contributes to the development of neutrophilic airway inflammation [ 43 , 47 ]. We previously reported the mediating roles of BLT2 in regulating the production of IL-17 and NLRP3-dependent IL-1β in neutrophilic airway inflammation [ 29 , 30 , 31 ]. Thus, we were curious about the signaling network linking BLT2-mediated G-CSF production to IL-17 or IL-1β production.…”

“…Recently, we observed that BLT2 and its ligand 12( S )-HETE played critical roles in asthmatic airway inflammation [ 23 , 24 , 25 , 26 , 27 , 28 ]. Especially, BLT2 was shown to play mediatory roles in the production of IL-17 and IL-1β, eventually contributing to the neutrophilic asthma development in the murine models [ 29 , 30 , 31 ]. However, the mediatory role of BLT2 in G-CSF production in neutrophilic asthma has not been elucidated yet.…”

Inhibition of type III secretion system induced leukotriene B4production byYersinia pestis: A mechanism for early immune evasion

“…First, in the absence of LTB 4 , sentinel leukocytes will not undergo autocrine signaling via LTB 4 -BLT1. Because LTB 4 -BLT1 engagement activates antimicrobial programs in leukocytes (29,30,45,(57)(58)(59), the absence of autocrine signaling diminishes the ability of sentinel leukocytes directly interacting with Y. pestis to mount an effective antimicrobial response to kill the bacteria. LTB 4 synthesis is also regulated by BLT1 signaling, and autocrine signaling is required to amplify the production of LTB 4 needed to rapidly recruit additional tissue-resident immune cells to the site of infection (29,30,58,60,61).…”

The role of the NLRP3 inflammasome in chronic inflammation in asthma and chronic obstructive pulmonary disease

“…Its receptors BLT1 and BLT2 have been thought to contribute to the production of airway inflammation in neutrophil‐dominated asthma. Kwak et al 43 established a neutrophil airway inflammation model by attacking mice with house dust mite. It was found that blocking BLT1 or BLT2 could significantly inhibit the activation of NLRP3 inflammasome and the synthesis of IL‐1 β.…”