Simvastatin Inhibits Brucella abortus Invasion into RAW 264.7 Cells through Suppression of the Mevalonate Pathway and Promotes Host Immunity during Infection in a Mouse Model.
Trang Thi NguyenHeejin KimTran Xuan Ngoc HuyWongi MinHu Jang LeeAlisha Wehdnesday Bernardo ReyesJohnhwa LeeSuk KimPublished in: International journal of molecular sciences (2022)
Simvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase and has been found to have protective effects against several bacterial infections. In this study, we investigate the effects of simvastatin treatment on RAW 264.7 macrophage cells and ICR mice against Brucella ( B. ) abortus infections. The invasion assay revealed that simvastatin inhibited the Brucella invasion into macrophage cells by blocking the mevalonic pathway. The treatment of simvastatin enhanced the trafficking of Toll-like receptor 4 in membrane lipid raft microdomains, accompanied by the increased phosphorylation of its downstream signaling pathways, including JAK2 and MAPKs, upon = Brucella infection. Notably, the suppressive effect of simvastatin treatment on Brucella invasion was not dependent on the reduction of cholesterol synthesis but probably on the decline of farnesyl pyrophosphate and geranylgeranyl pyrophosphate synthesis. In addition to a direct brucellacidal ability, simvastatin administration showed increased cytokine TNF-α and differentiation of CD8 + T cells, accompanied by reduced bacterial survival in spleens of ICR mice. These data suggested the involvement of the mevalonate pathway in the phagocytosis of B. abortus into RAW 264.7 macrophage cells and the regulation of simvastatin on the host immune system against Brucella infections. Therefore, simvastatin is a potential candidate for studying alternative therapy against animal brucellosis.
Keyphrases
- induced apoptosis
- toll like receptor
- cell cycle arrest
- mouse model
- signaling pathway
- adipose tissue
- rheumatoid arthritis
- endoplasmic reticulum stress
- inflammatory response
- stem cells
- metabolic syndrome
- type diabetes
- high throughput
- pi k akt
- insulin resistance
- mesenchymal stem cells
- machine learning
- single cell
- fatty acid
- deep learning
- big data
- electronic health record
- human health