A Selective α7 Nicotinic Acetylcholine Receptor Agonist, PNU-282987, Attenuates ILC2s Activation and Alternaria-Induced Airway Inflammation

Background The anti-inflammatory effect of an alpha 7nAChR agonist, PNU-282987, has previously been explored in the context of inflammatory disease. However, the effects of PNU-282987 on type 2 innate lymphoid cells (ILC2s)-mediated allergic airway inflammation has not yet been established. Aims To determine the effects of PNU-282987 on the function of ILC2s in the context of IL-33- or Alternaria Alternata (AA)- induced airway inflammation. Methods PNU-282987 was administered to mice that received recombinant IL-33 or AA intranasal challenges. Lung histological analysis and flow cytometry were performed to determine airway inflammation and the infiltration and activation of ILC2s. The previously published alpha 7nAChR agonist GTS-21 was employed as a comparable reagent. ILC2s were isolated from murine lung tissue and cultured in vitro in the presence of IL-33, IL-2, and IL-7 with/without either PNU-282987 or GTS-21. The expression of the transcription factors GATA3, IKK, and NF-kappa B were also determined. Results PNU-282987 and GTS-21 significantly reduced goblet cell hyperplasia in the airway, eosinophil infiltration, and ILC2s numbers in BALF, following IL-33 or AA challenge. In vitro IL-33 stimulation of isolated lung ILC2s showed a reduction of GATA3 and Ki67 in response to PNU-282987 or GTS-21 treatments. There was a significant reduction in IKK and NF-kappa B phosphorylation in the PNU-282987-treated group when compared to the GTS-21-treated ILC2s. Conclusion PNU-282987 inhibits ILC2-associated airway inflammation, where its effects were comparable to that of GTS-21.

Automated summary

The study found that PNU-282987 significantly reduced goblet cell hyperplasia, eosinophil infiltration, and ILC2 numbers in the airways following IL-33 or AA challenges. In vitro experiments showed a decrease in GATA3 and Ki67 expression in isolated lung ILC2s after treatment with PNU-282987 or GTS-21. Additionally, PNU-282987 treatment resulted in decreased IKK and NF-kappa B phosphorylation compared to GTS-21 in ILC2s.