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

Abstract

Background:

The 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.

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 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.

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-κB 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.

• Authors: Fang Yuan, Lili Jiang, Qianyang Li, Leon Sokulsky, Yuanyuan Wanyan, Lingli Wang, Xiaojie Liu, Lujia Zhou, Hock L Tay, Guojun Zhang, Ming Yang, Fuguang Li
• Journal: Frontiers in immunology (Front Immunol) Vol. 11 Pg. 598165 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 33597946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Yuan, Jiang, Li, Sokulsky, Wanyan, Wang, Liu, Zhou, Tay, Zhang, Yang and Li.

Chemical References

• Benzamides
• Benzylidene Compounds
• Biomarkers
• Bridged Bicyclo Compounds
• Cytokines
• Interleukin-33
• Nicotinic Agonists
• PNU-282987
• Pyridines
• alpha7 Nicotinic Acetylcholine Receptor
• 3-(2,4-dimethoxybenzylidene)anabaseine

Topics

• Animals
• Asthma (drug therapy, etiology, metabolism, pathology)
• Benzamides (pharmacology)
• Benzylidene Compounds (pharmacology)
• Biomarkers
• Bridged Bicyclo Compounds (pharmacology)
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Immunity, Innate (drug effects)
• Immunohistochemistry
• Immunophenotyping
• Interleukin-33 (metabolism)
• Lymphocytes (drug effects, physiology)
• Mice
• Nicotinic Agonists (pharmacology)
• Pyridines (pharmacology)
• alpha7 Nicotinic Acetylcholine Receptor (agonists)