Inflammation-induced mTORC2-Akt-mTORC1 signaling promotes macrophage foam cell formation
| Autor: | Durba Pal, Dipanjan Banerjee, Arvind K. Rathore, Alak Kumar Buragohain, Anindhya Sundar Das, Archana Sinha, Sudeshna Saikia, Bhaskarjyoti Gogoi, Suman Dasgupta |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
THP-1 Cells Mechanistic Target of Rapamycin Complex 2 mTORC1 Mechanistic Target of Rapamycin Complex 1 030204 cardiovascular system & hematology Biochemistry mTORC2 Phosphatidylinositol 3-Kinases 03 medical and health sciences 0302 clinical medicine Humans Phosphorylation Scavenger receptor Protein kinase B PI3K/AKT/mTOR pathway Foam cell Inflammation Chemistry General Medicine Cell biology Toll-Like Receptor 4 030104 developmental biology lipids (amino acids peptides and proteins) Signal transduction Proto-Oncogene Proteins c-akt Foam Cells Signal Transduction |
| Zdroj: | Biochimie. 151:139-149 |
| ISSN: | 0300-9084 |
| Popis: | The transformation of macrophages into lipid-loaded foam cells is a critical and early event in the pathogenesis of atherosclerosis. Several recent reports highlighted that induction of TLR4 signaling promotes macrophage foam cell formation; however, the underlying molecular mechanisms have not been clearly elucidated. Here, we found that the TLR4 mediated inflammatory signaling communicated with mTORC2-Akt-mTORC1 metabolic cascade in macrophage and thereby promoting lipid uptake and foam cell formation. Mechanistically, LPS treatment markedly upregulates TLR4 mediated inflammatory pathway which by activating mTORC2 induces Akt phosphorylation at serine 473 and that aggravate mTORC1 dependent scavenger receptors expression and consequent lipid accumulation in THP-1 macrophages. Inhibition of mTORC2 either by silencing Rictor expression or inhibiting its association with mTOR notably prevents LPS induced Akt activation, scavenger receptors expression, and macrophage lipid accumulation. Although suppression of mTORC1 expression by genetic knockdown of Raptor did not produce any significant change in Akt S473 phosphorylation, however, incubation with Akt activator in Rictor silenced cells failed to promote scavenger receptors expression and macrophage foam cell formation. Thus, present research explored the signaling pathway involved in inflammation-induced macrophage foam cells formation and therefore, targeting this pathway might be useful for preventing macrophage foam cell formation. |
| Databáze: | OpenAIRE |
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