Targeting Immunoproteasome in Macrophages Suppresses M1 Polarization and Ameliorates Experimental Emphysema via Activating NRF1 and NRF2-P62 Axis

Chronic obstructive pulmonary disease (COPD) stands as the prevailing chronic airway ailment, characterized by chronic bronchitis and emphysema. Current medications fall short in treatment of these diseases, underscoring the urgent need for effective therapy. Prior research indicated immunoproteasome inhibition can alleviate various inflammatory diseases by modulating immune cell functions. However, its therapeutic potential in COPD remains largely unexplored. Here, we observed elevated expression of immunoproteasome subunits LMP2 and LMP7 in bronchoalveolar lavage (BAL) macrophages collected from mouse with LPS/elastase-induced emphysema and M1 polarized macrophages in vitro. Subsequently, intranasal administration of the immunoproteasome-specific inhibitor ONX-0914 significantly mitigated emphysema-associated airway inflammation and improved lung function in mice, by suppressing M1 macrophage polarization. Mechanistically, ONX-0914 activated autophagy, and endoplasmic reticulum (ER) stress was not necessary for ONX- 0914-induced M1 suppression. Intriguingly, ONX-0914 upregulated the autophagy receptor p62/SQSTM1, which proved vital for the inhibitory effect of ONX-0914 on M1 polarization. Additionally, our research identified that the nuclear factor erythroid 2-related factor-2 (NRF2), but not NRF1, was responsible for the induction of p62. Finally, silencing both NRF1 and NRF2 partially counteracted ONX-0914-mediated M1 polarization inhibition. In summary, our findings suggest that targeting the immunoproteasome in macrophages holds promise as a therapeutic strategy for emphysema.