Tight junction, mucin, and inflammasome‐related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice

Abstract

Background: Asthma is a chronic respiratory disease with marked clinical and pathophysiological heterogeneity. Specific pathways are thought to be involved in the pathomechanisms of different inflammatory phenotypes of asthma; however, direct in vivo comparison has not been performed. Methods:We developed mouse models representing three different phenotypes of allergic airway inflammation-eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT-PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air-liquid interface were used to study the mechanisms revealed in the in vivo models.Results: By whole-genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome-related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo-1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation.Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1, and IL-1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine-IL-1βmay transiently impair epithelial barrier function, while IL-1β and IL-17 increase mucin expressions in primary human bronchial epithelial cells.Conclusion: Our findings suggest that differential expression of TJ, mucin, and inflammasome-related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic. K E Y W O R D Sendotype, epithelial barrier, house dust mite, phenotype, precision medicine Tan and Hagner equal first-author contribution.

The Role of Lung and Gut Microbiota in the Pathology of Asthma

“…However, often endotypes can co-exist and/or include other mixed processes, which cannot be easily categorized (Kuo et al, 2017;Agache and Akdis, 2016;Cosío et al, 2017). Less well-defined forms of asthma, situated between clinical phenotypes and molecular endotypes, include inflammatory phenotypes of eosinophilic, neutrophilic, mixed, and paucigranulocytic asthma (Wang et al, 2011;Tan et al, 2019). Type 2 asthma is usually observed in the clinic as earlyonset allergic asthma, late-onset eosinophilic asthma, or exercise-induced asthma (Fahy, 2015).…”

“…Non-type 2 asthma, observed more often in obesity-related asthma, neutrophilic asthma, and paucigranulocytic asthma (Kuo et al, 2017;Cosío et al, 2017;Ray and Kolls, 2017), is usually connected with poor responsiveness to steroids and more severe phenotypes, even in childhood (Ramratnam et al, 2017). Nontype 2 inflammation is characterized by infiltration of Th1 and Th17 cells and neutrophils, the presence of type I interferons, NLRP3 inflammasome activation, and an IL-1b and IL-17 signature (Rossios et al, 2018;Kim et al, 2017;Tan et al, 2019). The effect of microbiota dysbiosis on asthma heterogeneity seems intuitive, but, until recently (Taylor et al, 2018;Boutin et al, 2017), lung and gut microbiome composition have not been addressed in (Turnbaugh et al, 2007), lungs were not sampled, partially due to the existing dogma at the time that lungs are sterile.…”

Recent developments and highlights in food allergy

“…Consequently, epithelial dysregulation and mutations or polymorphisms of genes important for skin barrier, such as filaggrin, SPINK5, 1 and SERPINB7, have been linked to eczema development and also food allergy. [2][3][4][5][6] Recently, electrical impedance spectroscopy has shown promising results in rodents to measure skin barrier function. This is of relevance since it can be easily adapted for usage on humans.…”

Leukotriene B4 receptors mediate the production of IL‐17, thus contributing to neutrophil‐dominant asthmatic airway inflammation

“…Together, these results suggested that BLT1 and BLT2 contribute to IL-17 production and airway inflammation in neutrophil-dominant pulmonary inflammation. LTB 4 We observed that 5-/12-LO expression in the lungs and LTB 4 and 12(S)-HETE serum levels were elevated in LPS/OVA-induced pulmonary inflammation group (Figure 2A,B). Histology analysis showed that MK886 or baicalein reduced airway inflammation compared to F I G U R E 2 Upregulation of BLT2 ligands, LTB 4 and 12(S)-HETE, is associated with neutrophil-dominant airway inflammation and IL-17 production.…”

“…Recently, IL-17 was shown to be associated with severe neutrophilic asthma development and exacerbation, and IL-17 levels in serum and sputum were shown to increase with disease severity. 3,4 Meanwhile, a previous study demonstrated that leukotriene B4 (LTB 4 ) is present at higher concentrations in sputum of patients with severe asthma, who have relatively pronounced neutrophil influx, than in those with mild asthma. 5 Furthermore, LTB 4 receptors, BLT1 and BLT2, were suggested to contribute to the development of asthmatic airway inflammation.…”