Lipids: Emerging Players of Microglial Biology

Abstract

Lipids are small molecule immunomodulators that play critical roles in maintaining cellular health and function. Microglia, the resident immune cells of the central nervous system, regulate lipid metabolism both in the extracellular environment and within intracellular compartments through various mechanisms. For instance, glycerophospholipids and fatty acids interact with protein receptors on the microglial surface, such as the Triggering Receptor Expressed on Myeloid Cells 2, influencing cellular functions like phagocytosis and migration. Moreover, cholesterol is essential not only for microglial survival but, along with other lipids such as fatty acids, is crucial for the formation, function, and accumulation of lipid droplets, which modulate microglial activity in inflammatory diseases. Other lipids, including acylcarnitines and ceramides, participate in various signaling pathways within microglia. Despite the complexity of the microglial lipidome, only a few studies have investigated the effects of specific lipid classes on microglial biology. In this review, we focus on major lipid classes and their roles in modulating microglial function. We also discuss novel analytical techniques for characterizing the microglial lipidome and highlight gaps in current knowledge, suggesting new directions for future research on microglial lipid biology.

Keywords: fatty acids; inflammation; lipid droplets; lipidomics; lipids; microglia; phospholipids.

FIGURE 1

Overview of lipid classification and structural diversity. Lipids are broadly categorized into eight categories per the International Lipid Classification and Nomenclature Committee: Fatty acyls (FA—shown in turquoise), glycerolipids (GL—shown in pink), glycerophospholipids (GP—shown in purple), sphingolipids (SP—shown in red), sterols (ST—shown in yellow), prenol lipids (PR), saccharolipids (SL), and polyketides (PK). Within each main lipid category exist additional lipid classes. For example, the glycerolipid class (highlighted in pink) contains the triacylglycerol, diacylglycerol, and monoacylglycerol lipid subclasses. Similarly, glycerophospholipids (GPs) contain a number of classes characterized by polar head group composition. In the purple panel (bottom left), example sn‐1 radyl chains are portrayed, noting that the nature of the sn‐1 linkage dictates GP subclass. Explicitly, GP contain either an acyl, 1‐O‐alkyl, or a 1‐O‐alk‐1′‐enyl group at the sn‐1 position, indicating the diacyl, plasmanyl, or plasmenyl subclasses, respectively. Noting that lipid species within each major lipid class and subclass can exhibit hundreds, if not thousands, of structural features dictated by the presence and position of double bonds, functional groups, length of acyl chains, and so on, the lipidome is highly complex and diverse.

FIGURE 2

Major lipid pathways and regulation in microglia. Select pathways and mechanisms (dark gray) mediated by lipids (yellow) in microglia. The microglial lipidome can be altered by external triggers such as dying cells, lipoproteins, and misfolded proteins. Lipids from the extracellular space interact with key membrane proteins on the microglial cell surface and are subsequently metabolized within the cells. For instance, free fatty acids can be metabolized by fatty acyl‐CoA within mitochondria or stored in lipid droplets via the acylglycerol pathway. Several species of phosphatidylinositols (PIs) influence microglial endolysosomal function and the phagocytic clearance of debris. Cholesterol is transported out of the cell via ABCA1/7 transporters. Certain lipids also modulate the microglial inflammatory response through the TLR4 and NF‐kB pathway. Phosphatidylcholines, phosphatidylinositols, phosphatidylglycerols, and phosphatidylethanolamines embedded in the microglial cell membrane regulate membrane fluidity and remodeling, thereby influencing cellular integrity, migration, and response to stimuli. It is important to note that this is a broad and simplified overview of lipid‐mediated pathways in microglia. In reality, these molecules and pathways are far more complex, intertwined, and susceptible to changes even from subtle environmental shifts.