A Novel Role for CETP as Immunological Gatekeeper: Raising HDL to Cure Sepsis?

Raising HDL using cholesteryl ester transfer protein (CETP) inhibitors failed to show a clinically relevant risk reduction of cardiovascular disease in clinical trials, inviting reconsideration of the role of CETP and HDL in human physiology. Based on solid evidence from studies with isolated macrophages, rodents, and humans, we propose that a major function of CETP may be to modulate HDL in order to help resolve bacterial infections. When gram-negative bacteria invade the blood, as occurs in sepsis, Kupffer cells lose their expression of CETP to increase HDL levels. This rise in HDL prevents systemic endotoxemia by binding lipopolysaccharide and induces a systemic proinflammatory response in macrophages to mediate bacterial clearance. This raises the interesting possibility to repurpose CETP inhibitors for the treatment of sepsis.