Cholesterol & innate immunity
Cholesterol may initiate or inhibit inflammatory reactions depending on its location and physical state. Cholesterol forms cellular membrane lipid bilayers together with phospholipids and sphingolipids, regulating membrane fluidity and membrane functions such as endocytosis. By being central for membrane lipid microdomains or rafts, cholesterol also modulates signal transduction of a range of receptors.
High cholesterol levels in blood constitute the most prominent risk factor for atherosclerotic coronary artery disease. In a study published in Nature (2010), we demonstrated that cholesterol itself can cause inflammation in its crystalline form by activating NLRP3 (Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.) Thus, it is possible that the phase-transition of cholesterol from soluble to crystalline is sensed by immune cells, which would provide a fairly simple molecular explanation for the pronounced pro-inflammatory effects of excessive levels of cholesterol in blood and tissue.
We wish to clarify how the cholesterol content in cells affects signalling by PRR. In addition, we hope to uncover in detail how the various arms of the innate immune system contribute to inflammation mediated by cholesterol crystals.