Intracellular cholesterol trafficking and its impact on inflammatory processes

Inflammation is a fundamental physiological response to infection and cellular damage, initiated by pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) through pattern recognition receptors located at the plasma membrane and within intracellular compartments. Increasing evidence highlights that inflammatory signaling is closely linked to membrane cholesterol and its intracellular distribution and trafficking. Cholesterol homeostasis is maintained through tightly controlled biosynthesis, uptake, and efflux pathways, and is further shaped by complex intracellular trafficking routes involving vesicular transport and non-vesicular transfer at membrane contact sites. In particular, cholesterol-rich membrane domains, i.e. lipid rafts, have been implicated in toll-like receptor (TLR) signaling, while an activation of this signaling pathway in turn can lead to increased cellular cholesterol levels. Furthermore, cholesterol biosynthesis, intracellular cholesterol trafficking as well as accumulation can promote activation of the nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This review summarizes the current understanding of cholesterol sensing, distribution, and trafficking pathways and discusses how these processes regulate innate immune signaling. We further highlight the role of cholesterol-mediated modulation of TLR4 signaling and NLRP3 inflammasome activation and explore implications for diseases.