Targeting PP2A and proteasome activity ameliorates features of allergic airway disease in mice

• Published in: Allergy (Copenhagen) Vol. 72; no. 12; pp. 1891 - 1903
• Main Authors: Nair, P. M., Starkey, M. R., Haw, T. J., Liu, G., Horvat, J. C., Morris, J. C., Verrills, N. M., Clark, A. R., Ammit, A. J., Hansbro, P. M.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.12.2017
• Subjects: Airway Remodeling; Allergens; allergic airway disease; Alveoli; Animals; Anti-Asthmatic Agents - pharmacology; Anti-inflammatory agents; Asthma; Biomarkers; Bortezomib; Bronchus; Combined treatment; Cytokines; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Eosinophils; Exposure; Female; FTY720; Gene Expression; House dust; Immune response; Immunoglobulin E; Inflammation; Inflammation Mediators - metabolism; Inhibitor drugs; Interleukin 13; Interleukin 5; Leukocytes (eosinophilic); Mice; Mucus; Ovalbumin; Phosphatase; Phosphoprotein phosphatase; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; Proteasomes; Protein phosphatase; Protein Phosphatase 2 - antagonists & inhibitors; protein phosphatase 2A; Protein-serine/threonine phosphatase; Respiratory Hypersensitivity - drug therapy; Respiratory Hypersensitivity - etiology; Respiratory Hypersensitivity - metabolism; Respiratory Hypersensitivity - pathology; Respiratory tract diseases; RNA, Messenger - genetics; RNA, Messenger - metabolism; Serine; Threonine phosphatase; Thymic stromal lymphopoietin; Thymus; Ubiquitin; ubiquitin proteasome system; allergic airway disease; ubiquitin proteasome system; asthma; inflammation; protein phosphatase 2A
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.13212

Background Asthma is an allergic airway disease (AAD) caused by aberrant immune responses to allergens. Protein phosphatase‐2A (PP2A) is an abundant serine/threonine phosphatase with anti‐inflammatory activity. The ubiquitin proteasome system (UPS) controls many cellular processes, including the initiation of inflammatory responses by protein degradation. We assessed whether enhancing PP2A activity with fingolimod (FTY720) or 2‐amino‐4‐(4‐(heptyloxy) phenyl)‐2‐methylbutan‐1‐ol (AAL(S)), or inhibiting proteasome activity with bortezomib (BORT), could suppress experimental AAD. Methods Acute AAD was induced in C57BL/6 mice by intraperitoneal sensitization with ovalbumin (OVA) in combination with intranasal (i.n) exposure to OVA. Chronic AAD was induced in mice with prolonged i.n exposure to crude house dust mite (HDM) extract. Mice were treated with vehicle, FTY720, AAL(S), BORT or AAL(S)+BORT and hallmark features of AAD assessed. Results AAL(S) reduced the severity of acute AAD by suppressing tissue eosinophils and inflammation, mucus‐secreting cell (MSC) numbers, type 2‐associated cytokines (interleukin (IL)‐33, thymic stromal lymphopoietin, IL‐5 and IL‐13), serum immunoglobulin (Ig)E and airway hyper‐responsiveness (AHR). FTY720 only suppressed tissue inflammation and IgE. BORT reduced bronchoalveolar lavage fluid (BALF) and tissue eosinophils and inflammation, IL‐5, IL‐13 and AHR. Combined treatment with AAL(S)+BORT had complementary effects and suppressed BALF and tissue eosinophils and inflammation, MSC numbers, reduced the production of type 2 cytokines and AHR. AAL(S), BORT and AAL(S)+BORT also reduced airway remodelling in chronic AAD. Conclusion These findings highlight the potential of combination therapies that enhance PP2A and inhibit proteasome activity as novel therapeutic strategies for asthma.