Immunoproteasome subunit ß5i regulates diet-induced atherosclerosis through altering MERTK-mediated efferocytosis in Apoe knockout mice.

ABSTRACT

The immunoproteasome contains three catalytic subunits (ß1i, ß2i and ß5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between ß5i and human atherosclerotic plaque instability; however, the causative role of ß5i 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 ß5i. We found that ß5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). ß5i/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 ß5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that ß5i deletion reduced IκBα degradation and inhibited NF-κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that ß5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. ß5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.