Abstract
BackgroundThe anti-inflammatory effect of an α7nAChR 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.AimsTo determine the effects of PNU-282987 on the function of ILC2s in the context of IL-33– or Alternaria Alternata (AA)– induced airway inflammation.MethodsPNU-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 α7nAChR 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-κB were also determined.ResultsPNU-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-κB phosphorylation in the PNU-282987–treated group when compared to the GTS-21–treated ILC2s.ConclusionPNU-282987 inhibits ILC2-associated airway inflammation, where its effects were comparable to that of GTS-21.
Highlights
Asthma is an immune disorder of the lungs associated with airway inflammation, mucus secretion, and airway hyperresponsiveness (AHR), and is associated with the type 2 cytokines, interleukin (IL)-4, IL-5, and IL-13 [1, 2]
There was a significant reduction in I-kB kinase (IKK) and NF-kB phosphorylation in the PNU-282987–treated group when compared to the GTS-21–treated ILC2s
By using recombinant IL-33 to induce lung inflammation in vivo, we explored the effects of PNU282987 and GTS-21 on IL-33–mediated airway inflammation
Summary
Asthma is an immune disorder of the lungs associated with airway inflammation, mucus secretion, and airway hyperresponsiveness (AHR), and is associated with the type 2 cytokines, interleukin (IL)-4, IL-5, and IL-13 [1, 2]. While CD4+ T helper 2 (Th2) cells play an important role in the development of allergic cascades, innate immune cells including macrophages, eosinophils, and type 2 innate lymphoid cells (ILC2s) critically contribute to the pathogenesis of the disease [3]. The discovery of the ILC2s highlighted a new class of cells that can induce inflammatory cascades independent of T and B cells in response to epithelial alarmin factors, such as IL-25 and IL-33 [4, 5] Upon exposure to these factors, ILC2s secrete Th2 cytokines including IL-4, IL-5, and IL-13 through GATA3 transcription [6,7,8,9]. In Rag2−/−Il2rg−/− mice (lacking T cells, B cells, and ILCs), the levels of eosinophilic inflammation and the secretion of mucus decreased significantly, highlighting the importance of the IL33/ILC2s axis in the development of asthma [12]. The effects of PNU-282987 on type 2 innate lymphoid cells (ILC2s)-mediated allergic airway inflammation has not yet been established
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