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

Abstract

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. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Deficiency of LMP10 Attenuates Diet-Induced Atherosclerosis by Inhibiting Macrophage Polarization and Inflammation in Apolipoprotein E Deficient Mice

“…These studies indicated that LMP10 targets NF-κB activation possibly through PTEN/AKT/IKK signaling. Interestingly, our recent study on experimental atherosclerosis also supports LMP7mediated transcriptional regulation of efferocytosis through oxidized LDL-induced IκBα degradation and subsequent NF-κB activation (Liao et al, 2020a). In the current study, we observed that oxidized LDL-induced degradation of IκBα and activation of NF-κB pathway was also reduced in LMP10deleted macrophages (Figures 6F,G), suggesting that LMP10 deletion inhibited NF-κB activation partially through blocking IκBα degradation.…”

“…Previous research has shown that LMP7 expression is increased in the shoulder areas of symptomatic carotid plaques and in correlation with inflammatory cell infiltration, but the causative roles and potential mechanisms of immunoproteasomes in atherosclerosis remain unclear (Herrmann et al, 2012). Recently, we demonstrated in ApoE ko mice that ATD feeding significantly induced LMP7 expression in plaque macrophages, and that genetic and pharmaceutical inhibition of LMP7 attenuated diet-induced atherosclerosis (Liao et al, 2020a). Furthermore, we identified in isolated macrophages that LMP7-mediated regulation of atherosclerosis was associated with efferocytosis of apoptotic cells during foam cell formation (Liao et al, 2020a).…”

“…Recently, we demonstrated in ApoE ko mice that ATD feeding significantly induced LMP7 expression in plaque macrophages, and that genetic and pharmaceutical inhibition of LMP7 attenuated diet-induced atherosclerosis (Liao et al, 2020a). Furthermore, we identified in isolated macrophages that LMP7-mediated regulation of atherosclerosis was associated with efferocytosis of apoptotic cells during foam cell formation (Liao et al, 2020a). In the current study, we explored whether another immunoproteasome catalytic subunit LMP10 contributed to experimental atherosclerosis in ApoE ko mice.…”

“…Recently, we uncovered a pro-atherogenic role of the immunoproteasome catalytic subunit LMP7 in apolipoprotein Abbreviations: UPS, ubiquitin-proteasome system; ApoE, apolipoprotein E; ko, knockout; dko, double knockout; ATD, atherogenic diet; FPLC, fast protein liquid chromatography; BM, bone marrow; ox-LDL, oxidized low density lipoprotein; NF-κB, nuclear factor kappa B; IκB, inhibitor of NF-κB; Ang II, angiotensin II; SMC, smooth muscle cell; DOCA, deoxycorticosterone acetate. E (ApoE) knockout (ko) mice (Liao et al, 2020a). Here, we explored whether another subunit, LMP10, also contributes to diet-induced atherosclerosis.…”

Inhibition of the Ubiquitin-Activating Enzyme UBA1 Suppresses Diet-Induced Atherosclerosis in Apolipoprotein E-Knockout Mice

“…Previous studies from our group have showed that PYR-41 is able to prevent the degradation of a wide range of target proteins, such as IκBα and MKP-1 [15,22]. Among them, IκBα is an inhibitory protein for NF-κB signaling pathway, which is known to play a critical role in regulating inflammatory cytokine and NADPH oxidase expression during cardiac remodeling and atherosclerosis [15,23]. Interestingly, our recent data indicate that PYR-41 might suppress inflammation and oxidative stress possibly through stabilization of IκBα and inhibition of Journal of Immunology Research NF-κB activation in several cell and disease models [15,22].…”