Immunoproteasome subunit β5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice.

The immunoproteasome contains three catalytic subunits (β1i, β2i and β5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between β5i and human atherosclerotic plaque instability; however, the causative role of β5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of β5i. We found that β5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). β5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase-3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with β5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that β5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that β5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. β5i might be a potential pharmaceutical target against atherosclerosis.