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Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis

ABSTRACT: Chronic cadmium (Cd) exposure contributes to the progression of cardiovascular disease (CVD), especially atherosclerosis (AS), but the underlying mechanism is unclear. Since mitochondrial homeostasis is emerging as a core player in the development of CVD, it might serve as a potential mechanism linking Cd exposure and AS. In this study, we aimed to investigate Cd-mediated AS through macrophage polarization and know the mechanisms of Cd-caused mitochondrial homeostasis imbalance. In vitro, flow cytometry shows that Cd exposure promotes M1-type polarization of macrophages, manifested as the increasing expressions of nuclear Factor kappa-light-chain-enhancer of activated B (NF-kB) and NLR family pyrin domain containing 3 (NLRP3). Mitochondrial homeostasis tests revealed that decreasing mitochondrial membrane potential and mitophage, increasing the mitochondrial superoxide (mROS), and mitochondrial fission are involved in the Cd-induced macrophage polarization. The upregulated expressions of receptor-interacting protein kinase 3 (RIPK3) and pseudokinase-mixed lineage kinase domain-like protein (p-MLKL) were observed. Knocking out RIPK3, followed by decreasing the expression of p-MLKL, improves the mitochondrial homeostasis imbalance which effectively reverses macrophage polarization. In vivo, the oil red O staining showed that Cd with higher blood significantly aggravates AS. Besides, M1-type polarization of macrophages and mitochondrial homeostasis imbalance were observed in the aortic roots of the mice through immunofluorescence and western blot. Knocking out RIPK3 restored the changes above. Finally, the administered N-acetyl cysteine (NAC) or mitochondrial division inhibitor-1 (Mdivi-1), which decreased the mROS or mitochondrial fission, inhibited the expressions of RIPK3 and p-MLKL, attenuating AS and macrophage M1-type polarization in the Cd-treated group. Consequently, the Cd exposure activated the RIPK3 pathway and impaired the mitochondrial homeostasis, resulting in pro-inflammatory macrophage polarization and subsequent AS. Knocking out RIPK3 provided a potential therapeutic target for Cd-caused macrophage polarization and subsequent AS.

SUBMITTER: Zhang J

PROVIDER: S-EPMC8606644 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionResveratrol is an immune modulator that can reduce M1 macrophage polarization in vitro. Reducing macrophage recruitment and M1 polarization can prevent corneal allograft rejection (CGR). In this study, rat corneal allograft rejection models were established to explore the effects of resveratrol on CGR and macrophages and the underlying mechanisms after corneal transplantation.MethodsCorneal allograft models were established, and 100 mg/kg resveratrol was injected intraperitoneally. The corneal allografts were assessed clinically using the Holland rejection scoring system, anterior segment photography, and anterior segment optical coherence tomography. Corneal macrophages, pro-inflammatory cytokines, and corneal lymphatic vessels were detected using hematoxylin and eosin staining, immunofluorescence staining, and real-time quantitative polymerase chain reaction (qRT-PCR). Dendritic cells (DCs) in cervical lymph nodes were explored using flow cytometry. RNA sequencing experiments were conducted to identify the mechanisms through which resveratrol affected CGR. The results were verified using Simple Western analysis. Pro-inflammatory cytokines by macrophages in vitro were measured using qRT-PCR and enzyme-linked immunosorbent assays.ResultsResveratrol significantly prolonged the survival of corneal grafts and reduced graft edema and central corneal thickness. Corneal macrophage recruitment and M1 macrophage polarization decreased significantly after corneal transplantation in the resveratrol group. Resveratrol also reduced pro-inflammatory cytokines in corneal grafts and suppressed the early generation of cornea lymphatic vessels and the recruitment of cornea inflammatory cells 14 days after surgery. Resveratrol decreased the proportion of DCs in ipsilateral cervical lymph nodes. The effect of resveratrol on CGR was related to the phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) pathway. Resveratrol reduced the secretion of pro-inflammatory cytokines by M1 macrophages in vitro.ConclusionOur findings suggest that resveratrol can reduce corneal macrophage recruitment and M1 macrophage polarization after corneal transplantation in rats and prevent CGR. The PI3K/Akt pathway may be an important mechanism that warrants further research.

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Receptor-Interacting Protein Kinase 3 Inhibition Prevents Cadmium-Mediated Macrophage Polarization and Subsequent Atherosclerosis via Maintaining Mitochondrial Homeostasis

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