Immunoproteasome deficiency promotes airway type 2 inflammation in allergen challenged mice

Allergic asthma is an inflammatory respiratory disease associated with airway type 2 inflammation that is characterized by high levels of eosinophils and type 2 cytokines (IL-13). The immunoproteasome (IP) is proteolytic machinery that is induced by pro-inflammatory stimuli such as interferons and tumor necrosis factor-alpha. IP has been implicated in reducing viral burden during infections, but little is known about the role of IP in airway allergic inflammation. IP expression has been found to be reduced in subjects suffering from respiratory diseases such as asthma, but the underlying mechanisms remain unclear. The aim of this study was to determine if IP deficiency exaggerates airway type 2 inflammation induced by allergen exposure. Wild-type (WT) and IP (either IP subunit LMP2 or LMP7) knockout (KO) mice were challenged with house dust mite (HDM) or PBS as a control. After 72 hours of the last HDM challenge, mice were sacrificed to collect bronchoalveolar lavage (BAL) and lung tissue. LMP2/LMP7 KO mice exposed to HDM had significantly more eosinophils present in BAL fluid compared to WT mice. Eotaxin-2, an eosinophil chemokine, was also increased in the KO mice compared to WT mice. Interestingly, IL-4Ra, the receptor shared by IL-13 and IL-4, was significantly upregulated in HDM-challenged KO (vs. WT) mouse lung tissue. Our data suggests that IP deficiency increases IL-4Ra protein levels, leading to excessive airway eosinophilic inflammation. Enhancement of IP expression or activity may serve as an alternative approach to attenuate airway type 2 inflammation.