Kapka MITEVA, Switzerland
Foundation for the Medical Research University of Geneva Division of CardiologyPresenter of 1 Presentation
Effect of Monocytes on NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells Phenotypic Switch and Foam Cells Formation in Atherosclerosis
Abstract
Background and Aims
Atherosclerosis is a lipid driven, chronic inflammatory disease. The monocytes expansion is causally linked to the enlargement of the atherosclerotic lesion, while NLRP3 inflammasome activation has a major role in atherogenesis progression. We aim to reveal the effect of monocytes/macrophages on NLRP3 inflammasome activation in vascular smooth cells (VSMCs) and their phenotypic switch/foam cells formation.
Methods
Flow cytometry, qPCR, caspase 1 and pyroptosis assay showed the effect of oxLDL activated monocytes on VSMCs NLRP3 inflammasome activation and phenotypic switch in a co-culture system. Immunofluorescence quantification and ELISA illustrated the NLRP3 inflammasome activation in VSMCs in aortic roots of Apoe-/- mice on normal or high cholesterol diet (HCD).
Results
In the presence of oxLDL activated monocytes VSMCs contractile proteins - α-SMA and SM22α and the transcription factor Oct-4 preserving VSMCs contractile phenotype were downregulated, while the expression of the macrophages markers - MAC2, F4/80 and CD68 and KLF4 promoting atherosclerotic plaque pathogenesis were upregulated in VSMCs. In parallel, oxLDL activated monocytes conditioned medium promoted VSMCs caspase 1 activation and pyroptosis, programmed cell death. In vivo Apoe-/- mice fed HCD exhibited in the aortic roots an increased in α-SMA cells expressing CD68 in addition to NLRP3 and Caspase 1, Apoe-/- mice derived VSMCs secreted IL-1b (Figure 1).
Conclusions
These results show that oxLDL activated monocytes trigger VSMCs phenotypic switch, NLRP3 inflammasome activation, which in hypercholesteremia is linked to VSMCs phenotypic transformation in atherosclerosis. In conclusion, monocytes are a potent trigger of NLRP3 inflammasome activation, VSMCs phenotypic switch and atherosclerotic disease progression.