Blockade of RANKL/RANK and NF-ĸB signalling pathways as novel therapeutic strategies for allergic asthma: A comparative study in a mouse model of allergic airway inflammation

• Published in: European journal of pharmacology 2020-07, Vol.879, p.173129, Article 173129
• Main Authors: Gregorczyk, Izabela, Maślanka, Tomasz
• Format: Article
• Language: English
• Subjects: Animals; Anti-asthmatic drugs; Asthma - drug therapy; Asthma - immunology; Asthma - pathology; Bronchoalveolar Lavage Fluid - cytology; CD4+ T cells; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Disease Models, Animal; Inflammation - drug therapy; Inflammation - immunology; Inflammation - pathology; Lung - drug effects; Lung - immunology; Lung - pathology; Lymph Nodes - drug effects; Lymph Nodes - immunology; Mice, Inbred BALB C; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; NF-κB; Ovalbumin; RANK Ligand - antagonists & inhibitors; RANK Ligand - immunology; RANKL/RANK; Receptor Activator of Nuclear Factor-kappa B - antagonists & inhibitors; Receptor Activator of Nuclear Factor-kappa B - immunology; Signal Transduction - drug effects; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Treg cells
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173129

The main aims of this study were: (1) to investigate whether a blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK may have potential as a novel therapeutic strategy for allergic asthma; (2) to compare the efficacies of the blockade of RANKL/RANK interaction as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation to the nucleus, also in comparison with glucocorticosteroid treatment, in terms of the development of a mouse model of allergic airway inflammation (AAI) and accompanying immune response. The blockade of each of the targets fully prevented the development of AAI. All the tested therapeutic strategies seemed to have a certain advantage over glucocorticosteroids with regard to counteracting the development of AAI. Prevention of the activation and clonal expansion of CD4+ effector T (Teff) cells in the mediastinal lymph nodes (MLNs) constitutes a fundamental event underlying the anti-asthmatic effect induced by the blockade of IKK, NF-κB translocation or of RANKL/RANK interaction. The results indicate that attenuation of the CD11b+CD103-CD11chigh dendritic cell response in the MLNs is an initial but not the main mechanism responsible for this effect. In turn, the direct anti-proliferative action on CD4+ Teff cells seems to constitute the chief mechanism responsible for the anti-asthmatic effect of all the tested therapeutic strategies. A clinical implication is that local inhibition of RANKL/RANK interaction achieved via inhalatory administration of a RANKL antagonist can be considered as a novel therapeutic strategy in treatment of allergic asthma.