Polybrominated Diphenyl Ether Quinone Exposure Induces Atherosclerosis Progression via CD36-Mediated Lipid Accumulation, NLRP3 Inflammasome Activation, and Pyroptosis

Abstract

Polybrominated diphenyl ethers (PBDEs) are used worldwide in brominated flame retardants. Although due to the forbiddance of their application, PBDEs continuously exist in the environment due to their persistence. Therefore, it is important to expand the understanding of their potential toxicities and human risks. The underlying cardiovascular toxicological mechanisms of PBDEs are still largely unknown. Our previous studies indicated that PBDE quinone-type metabolite (PBDEQ) exposure causes reactive oxygen species (ROS)-driven cytotoxicity and various types of programmed cell death. Here, we first reported PBDEQ exposure induces atherosclerosis progression in bone marrow-derived macrophages (BMDMs) isolated from wild-type C57BL/6 or CD36 −/− mice and J774A.1 macrophage models. First, we found that PBDEQ exposure induced lipid accumulation in oxidized low-density lipid (Ox-LDL)-treated J774A.1 macrophages. Consistently, in J774A.1 macrophages, PBDEQ exposure resulted in NLR family pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis. CD36, a scavenger receptor responsible for the mediation of Ox-LDL uptake, was upregulated upon PBDEQ treatment. On the contrary, genetic knockout of CD36 or CD36 silencing by small interfering RNA efficiently attenuates PBDEQ-promoted lipid accumulation in BMDMs and J774A.1 macrophages. These findings highlight the effect of CD36 on the cardiovascular toxicity of PBDEs, which provides a better understanding of the pro-atherosclerosis effect of PBDEs.

Chlojaponilactone B Attenuates THP-1 Macrophage Pyroptosis by Inhibiting the TLR/MyD88/NF-κB Pathway

“…The activation of inflammation and pyroptosis exacerbates the progression of viral myocarditis [ 24 ]. Similarly, exposure to polybrominated diphenyl ethers promotes atherosclerosis through lipid accumulation, NLRP3 inflammasome activation, and pyroptosis [ 12 ]. These findings suggest that inhibiting pyroptosis may be an effective strategy to alleviate inflammatory conditions.…”

“…Of particular interest, macrophages, as central players in inflammation and immune processes, exhibit a significant impact on the progression of these diseases through their pyroptotic state. For instance, in atherosclerotic disease [ 12 , 13 ], a type of inflammatory disease affecting the arterial wall, nicotine can induce macrophage pyroptosis, thereby promoting disease progression [ 14 ]. Furthermore, GSDME-mediated macrophage pyroptosis has also been found to be closely associated with the development of atherosclerosis [ 15 ].…”

2,2′,4,4′-Tetrabromodiphenyl Ether (PBDE 47) Selectively Stimulates Proatherogenic PPARγ Signatures in Human THP-1 Macrophages to Contribute to Foam Cell Formation

“…Foam cells, primarily derived from macrophages, are closely correlated with the development of atherosclerosis, which is the etiology of many fatal cardiovascular diseases such as stroke and coronary disease . PBDE 209 and PBDE quinone-type metabolite 2-(2′,4′-Bromophenoxyl)­benzoquinone were reported to induce foam cell formation by stimulating inflammation-associated toll like receptor 4 (TLR4) or NLRP3 inflammasome activation in macrophages. , On the contrary, PBDE 47 was reported to impair the innate inflammatory response in macrophages, and the effects of PBDE 47 on foam cell formation are still unknown. In this study, we proposed to analyze the toxic outcome of PBDE 47 on foam cell formation from the viewpoint of activation of PPARγ first.…”

CD36: The Bridge between Lipids and Tumors

“…In this chronic inflammatory disease, lipids in the blood are deposited in the intima of arteries, causing the fibrous thickening of the intima, necrosis, and the disintegration of deep tissue in order to form atheromatous material that hardens the arterial wall and narrows the lumen [ 91 ]. CD36 is involved in this process by augmenting lipid accumulation and inflammatory vesicle activation [ 92 ]. OxLDL, a key molecule [ 93 ], binds to CD36 and stimulates macrophages to take themselves up.…”