Atheroprotective effects of sphingosine 1-phosphate (S1P) in macrophages and T-cells

• Applicants: Professor Dr. Ralph Burkhardt; Professor Dr. Jerzy-Roch Nofer
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271378789

Atherosclerosis is an inflammatory disease leading to coronary heart disease and stroke. High density lipoprotein (HDL) is a lipid-protein complex and the most potent plasma-born anti-atherogenic factor in humans. Increasing evidence suggests that atheroprotective effects of HDL are related to their capacity to interrupt macrophage- and T-cell-mediated inflammatory processes in the arterial wall. The investigations of the applicant revealed that HDL serves as a carrier of biologically active lysosphingolipids such as sphingosine 1-phosphate (S1P) and that S1P is a major contributor to anti-atherogenic and anti-inflammatory effects of HDL in vitro. However, mechanisms underlying the anti-atherogenic potential of S1P in vivo are poorly understood. The objective of the proposed project is to investigate the effects of S1P on the development of atherosclerosis in mouse models with amplified signalling through S1P receptors and to gain insights into molecular mechanisms underlying anti-inflammatory effects of free and HDL-associated S1P relevant for protection against atherosclerosis. For this purpose, atherosclerosis-prone murine lines will be generated, which selectively overexpress S1P receptors type 1 and 3 (S1P1 or S1P3) in macrophages or T-cells. In each murine line, the development of atherosclerosis will be assessed along with the examination of inflammatory responses. In addition, functional characterization of macrophages and T-cells overexpressing S1P1 or S1P3 with respect to molecular processes relevant to the development of atherosclerosis (cholesterol handling, apoptosis, efferocytosis, inflammatory activation, polarization) will be performed under in vitro conditions. The resulting insights of the project proposed here may form the fundament for the development of novel diagnostic and therapeutic strategies for the prevention and treatment of atherosclerotic cardiovascular disease.

• DFG Programme: Research Grants
• International Connection: Denmark
• Cooperation Partner: Professor Dr. Lars Bo Nielsen