The leukotriene B4 receptors contributes to neutrophil-dominant asthmatic airway inflammation via IL-1β and IL-17 production

Abstract

Abstract The leukotriene B4 is one of the chemo-attractant molecule for neutrophils, its receptors, BLT1/2 may contribute to neutrophil-dominant airway inflammation. Therefore, we investigated whether BLT1/2 signaling was associated with neutrophil-dominant severe asthma. The role of BLT1/2 as well as 5-/12-lipoxygenase in neutrophil-dominant airway inflammation was investigated using pharmacological inhibitors in murine model. Blockade of BLT1/2 significantly suppressed airway inflammation including thickness of airway wall, recruitment of immune cells and IL-17 production in neutrophil-dominant airway inflammation. 5-/12-LOX, upstream of LTB4 receptors was also critical for neutrophil-dominant airway inflammation and synthesis of IL-17. Furthermore, inhibition of 5-/12-LOX, BLT1/2, suppressed NF-κB activation, thus attenuating airway inflammation and production of IL-17, suggesting that NF-κB lies downstream of BLT1/2 in neutrophilic airway inflammation. Our results suggest that ‘5-/12-LOX-BLT1/2-NF-κB’ cascade significantly contributes to neutrophil-dominant airway inflammation through IL-17 synthesis. What is interesting is IL-1β also acts important role in the neutrophil-dominant asthmatic condition with IL-17 production. The high-expression level of IL-1β which is mainly produced by NLRP3 inflammasome activation already reported clinically in the sputum of neutrophilic asthma patients. Consequentially, our studies suggest that the cooperative mechanism of IL-1β and IL-17 considerably acts to neutrophil-dominant airway inflammation and the leukotriene B4 receptors have possibilities to control the severity via regulation effect of IL-1β and IL-17.