Regulation of Inflammasome Activation by Cholesterol Trafficking and Oxysterol-binding Protein-related Proteins (ORPs)

Abstract

Inflammasomes are multimeric protein structures that assemble in response to various pathogenic stimuli, as well as endogenous host molecules. They play critical roles in enhancing the innate immune response by activating and releasing pro-inflammatory cytokines, e.g. IL-1β and IL-18, and activating Gasdermin D which results in pyroptosis, an inflammatory form of cell death. However, inflammasomes are also implicated in the development of numerous inflammatory and metabolic disorders as a consequence of unwanted exaggerated inflammation. Current advances have enhanced our understanding of the various activators and regulators of different inflammasomes, including the most-well studied NLRP3 inflammasome. Recently, cholesterol trafficking to the endoplasmic reticulum (ER) was found to be essential for the activation of the NLRP3 inflammasome. However, there is limited knowledge as to how cholesterol is transported intracellularly and precisely which molecules mediate cholesterol transport to the ER. A family of lipid-binding proteins known as ORPs (oxysterol-binding protein-related proteins) have been associated with transporting cholesterol between organelles. While the precise roles of each ORP family member is yet to be deciphered, previous reports have suggested key functions for OSBP, ORP9, ORP5, and ORP1L in either cholesterol trafficking to the ER or mediating other functions in association with the ER. This review will introduce the major types of inflammasomes and how they are regulated before discussing the current findings on how cellular cholesterol trafficking modulates the NLRP3 inflammasome. Improved understanding of this area may lead to novel therapeutics to temper inflammasome activity in inflammatory and autoimmune diseases.