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

Abstract

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 if 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 sensitisation 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.

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