Role of IL‐18‐transformed CD274‐expressing eosinophils in promoting airway obstruction in experimental asthma

Abstract

Background IL‐5‐dependent residential and IL‐18‐transformed pathogenic eosinophils have been reported; however, the role of IL‐18‐transformed CD274‐expressing pathogenic eosinophils compared to IL‐5‐generated eosinophils in promoting airway obstruction in asthma has not yet been examined. Methods Eosinophils are detected by tissue anti‐MBP and anti‐EPX immunostaining, CD274 expression by flow cytometry, and airway resistance using the Buxco FinePointe RC system. Results We show that A. fumigatus‐challenged wild‐type mice, and different gene‐deficient mice including naïve CC10‐IL‐18‐transgenic mice, accumulate mostly peribronchial and perivascular CD274‐expressing eosinophils except naïve CD2‐IL‐5‐transgenic mice. Additionally, we show that CD2‐IL‐5 transgenic mice following rIL‐18 treatment accumulate high number of CD274‐expressing perivascular and peribronchial eosinophils with induced collagen, goblet cell hyperplasia and airway resistance compared to saline‐challenged CD2‐IL5 transgenic mice. Furthermore, we also show that even A. fumigatus‐challenged IL‐5 −/− mice and rIL‐18 given ΔdblGATA mice accumulate CD274‐expressing eosinophil‐associated asthma pathogenesis including airway obstruction. Most importantly, we provide evidence that neutralization of CD274 and IL‐18 in A. fumigatus‐challenged mice ameliorate experimental asthma. Taken together, the data presented are clinically significant in establishing that anti‐IL‐18 neutralization is a novel immunotherapy to restrict asthma pathogenesis. Conclusions We demonstrate that IL‐18 is critical for inducing asthma pathogenesis, and neutralization of CD274 is a potential immunotherapeutic strategy for asthma.

Allergen-induced NLRP3/caspase1/IL-18 signaling initiate eosinophilic esophagitis and respective inhibitors protect disease pathogenesis

“…We injected five doses of 10 µg rIL-18 plus 100 µl saline or only 100 µl saline intravenously into wild-type and GATA1 -deficient (Δ dblGATA ) mice on alternate days for 10 days. We chose the intravenous route because ΔdblGATA mice are deficient in tissue eosinophils but have bone marrow eosinophil precursors 18 . The rIL-18-treated mice developed esophageal eosinophilia compared to no or few eosinophils in saline-treated mice (Fig.…”

“…IL-18 is an IFN-γ-inducing factor and a member of the IL-1 family of cytokines, which has a wide range of inflammatory and allergy disease-related functions 15 . In previous work, we established that IL-18 can generate an IL-5-independent subset of CD274 - expressed pathogenic eosinophils and transform IL-5-generated naïve eosinophils into CD274 + pathogenic eosinophils 17 , 18 . IL-18 is produced by antigen-presenting cells and epithelial cells via activation of the inflammasome NLRP3 (NOD-like receptor protein-3)/caspse-1 pathway 19 .…”

“…NLRP3 activation is also implicated in inflammatory responses in allergic diseases including asthma and several gastrointestinal disorders 20 . We recently found evidence for the role of IL-18 in promoting eosinophilic asthma pathogenesis 18 and observed induced IL-18 in blood and IL-18R mRNA in biopsies of EoE patients 15 . Several inhibitors of the NLRP3 inflammasome have been reported to prevent tissue destruction in NLRP3-related allergic diseases in experimental models 21 , and our current data provide evidence that NLRP3 and caspase-1 are potential therapeutic targets for EoE.…”

The role of hypoxia in the pathophysiology of chronic rhinosinusitis

“…Eosinophilia has long been associated with inflammation in allergic diseases, including allergic rhinitis and asthma, acting primarily through Th2 inflammation, and in particular via IL-5 release. [134][135][136][137] Eosinophil infiltration, with subsequent release of inflammatory mediators such as IL-4, IL-5, and IL-13, is also a major inflammatory pathogenic mechanism in CRSwNP, especially in Europeans. 9 Hypoxia has been reported to inhibit eosinophil activity by upregulating CD300a expression.…”

Extracellular HSP90α promotes cellular senescence by modulating TGF ‐β signaling in pulmonary fibrosis

“…Pulmonary function was characterized at the endpoint using a Buxco FinePointe RC system as previously described. 28,29 Mice were euthanized by an intraperitoneal injection of 2, 2, 2-tribromoethanol and connected to the Buxco system after tracheotomy. Dynamic lung compliance and resistance values were obtained from the respiratory system.…”