The inhibitor of autophagy SBI‑0206965 aggravates atherosclerosis through decreasing myeloid‑derived suppressor cells

Abstract

Atherosclerosis (AS) is currently the leading cause of mortality worldwide, with the development of new strategies to prevent the formation and rupture of atherosclerotic plaques being a paramount area of research. Amounting evidence suggests autophagy has an important role in the pathogenesis of AS and may be a potential therapeutic target. In this study, the effect of SBI-0206965(6965), a novel inhibitor of autophagy, was tested on the development of AS in apolipoprotein E deficient (ApoE-/-) mice. Systemic application of 6965 was found to aggravate AS, with increased plaque size and decreased plaque stability in comparison with the control. Of note, it was observed that 6965 decreased the proportion of myeloid-derived suppressor cells (MDSCs). Further investigation demonstrated MDSCs markedly alleviated AS in ApoE-/mice; while 6965 reduced the viability and promoted apoptosis of MDSCs in vitro. This is the first study describing an association between autophagy and MDSCs in AS models, providing a novel mechanism to potentially target in the management of this condition.

Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway

“…Based on our finding that DMF induced autophagy in microglia, we next determined whether DMF-induced autophagy regulated the anti-inflammatory response in microglia by pretreatment of cultures with bafilomycin A1 (Mauvezin and Neufeld, 2015;Redmann et al, 2017) or SBI-0206965 (Martin et al, 2018;Wang et al, 2020), both potent inhibitors of cellular autophagy, for 1 h followed by treatment with DMF for 6 h. As expected, the mRNA levels of the anti-inflammatory cytokines TNF-α and IL-6, which were significantly increased by LPS treatment, were reduced by DMF treatment. Importantly, bafilomycin A1 and SBI-0206965 completely abrogated the DMF-induced reduction in proinflammatory cytokine production in primary MGC (Figures 5A,B).…”

Emerging Roles of Myeloid-Derived Suppressor Cells in Diabetes

“…The opposing effects of the two subgroups of MDSC remind us to observe the role of MDSC in AS and score clear subgroups. In the LDLr -/- model ( Foks et al, 2016 ) and the ApoE -/- murine model ( Wang et al, 2020 ) fed on the Western-type diet (WTD, containing 0.25% cholesterol and 15% cocoa butter) diet (0.25% cholesterol and 15% cocoa butter), MDSC were shown to significantly slow down the disease process of AS after adoptive transfer. Also, the therapy for MDSC was regarded as one of the hopes for the treatment of atherosclerosis.…”

“…It was proved that oral HSP60 reduced the development of AS by increasing the number of M-MDSC and enhancing its function, while subcutaneous HSP60 caused the opposite response ( Hu et al, 2018 ). In addition, SBI-0206965, an inhibitor of autophagy, rapidly reduced MDSC and promoted the development of atherosclerosis ( Wang et al, 2020 ). Therefore, the immunomodulation of MDSC and its subgroups may be regarded as a potential treatment of atherosclerosis.…”

A novel interleukin-2-based fusion molecule, HCW9302, differentially promotes regulatory T cell expansion to treat atherosclerosis in mice

“…Expression of five genes ( Itgb6 , Vtcn1, Rnf128/Grail, Tgfb2 , and Neurl1a ) related to Treg cell activation and expansion ( 57 – 62 ) were elevated and one gene ( Bach2 ) related to inhibition of Treg cell activation ( 63 – 65 ) was reduced ( Figure 6G ). In contrast, the expression of four genes ( Ly6g6c , Retnla/Fizz1, Alox15 , and Abca12 ) associated with MDSCs ( 66 , 67 ), M2 macrophage polarization ( 68 ), macrophage efferocytosis ( 69 , 70 ), and macrophage cholesterol efflux ( 71 ) were upregulated ( Figure 6G ) .…”

“…Atherosclerosis is a chronic inflammatory disease and both the innate and adaptive immune systems have been shown to play a role in either accelerating or curbing this disease ( 72 ). CD8 + T cells, Th1 cells, type 1 innate lymphoid cells (ILC1), and M1 macrophages have been implicated as pro-atherogenic ( 72 – 76 ), whereas Tregs, type 1 regulatory T cells (Tr1), M2 macrophages, MDSCs, and ILC2 have been demonstrated to be antiatherogenic ( 66 , 67 , 75 – 77 ). In contrast, NK cells were shown to have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis ( 78 ).…”