What Is the Role of Microglial Metabolism in Inflammation and Neurodegeneration?

Microglia constitute the brain innate immune system and are epigenetically and transcriptionally distinct from other tissue-resident and bone marrow–derived macrophages.1,2 Under physiologic conditions, microglia actively survey their environment and maintain a unique gene expression signature characteristic of homeostatic microglia.3 Microglia express a wide variety of receptors for a large range of environmental stimuli. They include pattern recognition receptors such as Toll-like receptors (TLRs); chemokine receptors; receptors for proinflammatory and anti-inflammatory cytokines; scavenger receptors; and receptors for neurotransmitters and neuromodulators, including purinergic adenosine triphosphate (ATP) receptors (e.g., P2X7 and P2Y12), adenosine A2a and cannabinoid CB2 receptors, and receptors for glutamate, -aminobutyric acid, acetylcholine, monoamines, and neuropeptides.4-7 The triggering receptor expressed on myeloid cells (TREM2) is exclusively expressed in microglia and binds multiple ligands that regulate microglial activation.8,9 In response to environmental stimuli, microglia switch into a reactive state, altering their transcriptome programming and acquiring different activation subtypes.10-15 For example, lipopolysaccharides acting via TLR4 receptors or interferon (IFN)- induce a proinflammatory microglia phenotype,5 whereas interleukin (IL)-4 (IL-4) induces an anti-inflammatory/regenerative phenotype.16 Activated microglia are functionally heterogeneous and highly plastic, and their phenotype can be reprogrammed according to their microenvironment.17 The transformation from the homeostatic state to the different reactive states is associated with profound changes in metabolism in microglia18-25 (Figure).

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