Hypothalamic lipid‐laden astrocytes induce microglia migration and activation

Abstract

Obesity-induced hypothalamic inflammation is closely associated with various metabolic complications and neurodegenerative disorders. Astrocytes, the most abundant glial cells in the central nervous system, play a crucial role in pathological hypothalamic inflammatory processes. Here, we demonstrate that hypothalamic astrocytes accumulate lipid droplets under saturated fatty acid-rich conditions, such as obese environment, and that the lipid-laden astrocytes increase astrogliosis markers and inflammatory cytokines (TNFα, IL-1β, IL-6, MCP-1) at the transcript and/or protein level. Medium conditioned by the lipid-laden astrocytes stimulate microglial chemotactic activity and upregulate transcripts of the microglia activation marker Iba-1 and inflammatory cytokines. These findings indicate that the lipid-laden astrocytes formed in free fatty acid-rich obese condition may participate in obesity-induced hypothalamic inflammation through promoting microglia migration and activation.

Lipid Droplets in Neurodegenerative Disorders

“…Another study found that palmitate treatment of isolated primary astrocytes increased inflammatory markers including TNF-alpha, IL-1 beta, IL-6, and MCP-1 in addition to Oil Red O (a fat-soluble dye) staining and PLIN1 and PLIN2 transcription. Interestingly, treatment of microglia with conditioned media from lipid-loaded astrocytes enhanced microglial chemotaxis through a CCR2-MCP1 mechanism (Kwon et al, 2017). These data suggest that LD-associated astrocyte inflammation may subsequently signal to microglia to augment the inflammatory response.…”

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…The monocyte chemoattractant protein (MCP‐1, also known as chemokine ligand 2 [CCL2]) is a central chemokine in mononuclear cell recruitment . In different models such as saturated fatty acid‐ or oxLDL‐rich conditions, leptin stimuli in tumor cells, polymicrobial infection, or LPS‐driven inflammatory responses, the increase in MCP‐1/CCL2 production occurs in parallel to LD formation. Indeed, MCP‐1/CCL2 directly induces a dose‐dependent increase in the numbers of cytoplasmic LDs in vitro within resident peritoneal macrophages isolated from naive mice, indicating that its effect occurs through cell migration independent pathways.…”

“…36,78,81,82 The monocyte chemoattractant protein (MCP-1, also known as chemokine ligand 2 [CCL2]) is a central chemokine in mononuclear cell recruitment. 83 In different models such as saturated fatty acid- 84,85 or oxLDL-rich conditions, 66 leptin stimuli in tumor cells, 86 polymicrobial infection, or LPS-driven inflammatory responses, 37 the increase in MCP-1/CCL2 production occurs in parallel to LD formation.…”

Microglial distribution, branching, and clearance activity in aged rat hippocampus are affected by astrocyte meshwork integrity: evidence of a novel cell‐cell interglial interaction

“…Little is known about the possible mechanical interactions of microglia and astrocytes. Astrocytes contribute to homeostasis of neuronal networks, regulate nerve cell maturation and synapse formation, modulate neurotransmission, act as a bridge among all cell types in the CNS, influence microglial phagocytosis (37)(38)(39)(40)(41), assist the movement of microglia branches from a random scanning of the microenvironment to extension toward injury sites (6) and promote microglia migration in vitro (42). In the gray matter, astrocytes display a star-shaped morphology due to numerous cytoplasmic astrocyte projections (APJs) extending in all direction from the soma (39).…”