Airway epithelium key to eosinophil extracellular trap-mediated inflammation in asthma
medwireNews: Eosinophil extracellular traps (EETs) activate type 2 innate lymphoid cells (ILC2s) and associated immune responses in patients with severe asthma by stimulating airway epithelium, say researchers.
They suggest that the potent toxicity of EETs – a “mesh of DNA fibers and granule proteins” released by activated eosinophils – could be a possible causative factor involved in steroid resistance, and highlight the beneficial role epithelium-targeting biologics may play in preventing type 2 immune responses and the ensuing airway hyperresponsiveness (AHR) in patients with severe asthma.
Hae-Sim Park (Ajou University School of Medicine, Suwon, South Korea) and colleagues studied EET-forming eosinophils in 13 patients with severe asthma, 17 with non-severe asthma, and eight without asthma. They found that levels were significantly elevated in those with severe asthma compared with the other two groups, at around 350 cells/µL versus 225 and 50 cells/µL, respectively (p<0.05 for each based on a one-way ANOVA with Bonferroni’s post-hoc test).
This was also true for ILC2s (approximately 550 cells/mL vs 220 and 100 cells/mL, respectively; p<0.05 for each) and there was a strong positive correlation between EET-forming eosinophils and ILC2 levels (correlation coefficient=0.539; p=0.001).
Moreover, further study in mice showed that injection of EETs resulted in significantly elevated numbers of eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF; p<0.001 in each case based on a one-way ANOVA with Bonferroni’s post-hoc test), as well as increased immune cell infiltration and epithelium thickness.
Epithelium-derived cytokines, including interleukin (IL)-1α, IL-1β, CXCL-1, CCL24, IL-33, and thymic stromal lymphopoietin (TSLP), in BALF also increased following EET injection and levels of IL33 and TSLP messenger RNA were significantly elevated in isolated airway epithelial cells (BALF; p<0.001 in each case based on a one-way ANOVA with Bonferroni’s post hoc test).
“These findings indicate that EETs could elevate the activation status of airway epithelium and innate immune responses,” the researchers write in Allergy.
Noting that IL-33 and TSLP “are known as strong ILC2 stimulators,” the team isolated lung ILC2s and using flow cytometry found that they released a higher proportion of IL-5 and IL-13 after mice were injected with EETs. These two cytokines stimulated AHR with eosinophilia in BALF and IL-13 in particular enhanced the production of epithelial IL-33 and TSLP.
“As IL-5 is essential for eosinophil survival/activation, it could form a vicious cycle to release EETs from eosinophils,” while “IL-13 is known to disrupt airway epithelial barrier integrity by targeting tight junctions,” the team comments.
The researchers highlight, however, that new biologics targeting IL-33 or TSLP were able to suppress EET-mediated airway inflammation following injection of ILC2s in mice lacking mature T and B lymphocytes.
“[T]hese findings imply that 2 epithelium-targeting biologics under clinical trial may have potential benefit to suppress type 2 or eosinophilic inflammation associated with the EET-ILC2 axis in patients with [severe asthma],” say Park et al.
By Lucy Piper
medwireNews (www.medwirenews.com) is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group