Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MerTK‐mediated efferocytosis in Apoe knockout mice

The immunoproteasome contains three catalytic subunits (beta1i, beta2i and beta5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between beta5i and human atherosclerotic plaque instability; however, the causative role of beta5i 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 beta5i. We found that beta5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). beta5i/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 beta5i-specific inhibitor PR-957. Mechanistic studies in vitro revealed that beta5i deletion reduced IkappaBalpha degradation and inhibited NF-kappaB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that beta5i plays an important role in diet-induced atherosclerosis by altering MERTK-mediated efferocytosis. beta5i might be a potential pharmaceutical target against atherosclerosis. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.