Stimulus-Driven Remodeling of Microglial Endocannabinoid Metabolism Illuminates ABHD12 Function in Immunity

Area of Science:

• Neuroscience
• Immunology
• Biochemistry

Background:

• Microglia, the brain's immune cells, modulate neuroinflammation through metabolic reprogramming.
• Lipid metabolism, particularly endocannabinoid signaling, is vital for microglial state regulation.
• Enzymatic activities governing microglial lipid metabolism are not well understood.

Purpose of the Study:

• To map lipid metabolism in distinct microglial states using activity-based protein profiling (ABPP) and lipidomics.
• To identify key enzymes involved in endocannabinoid metabolism within microglia.
• To investigate the role of ABHD12 in microglial immune function.

Main Methods:

• Combined activity-based protein profiling (ABPP) with targeted lipidomics.
• Developed a novel ABHD12 activity probe (LEI-612).
• Utilized pharmacological inhibition of ABHD12 (DO264) and analyzed cytokine release.

Main Results:

• Identified DAGLβ and ABHD12 as key enzymes with opposing activity patterns in microglial lipid metabolism.
• Demonstrated that ABHD12 activity is post-translationally regulated and inversely correlates with 2-AG levels.
• Showed that ABHD12 inhibition modulates cytokine release (TNF-α and IL-6) via CB2R and PGE2 pathways.

Conclusions:

• Activity-based profiling is crucial for understanding microglial metabolic states.
• ABHD12 is a significant regulator of 2-AG metabolism and microglial immune responses.
• Targeting ABHD12 offers a potential strategy for modulating neuroinflammation.