Figure 1.

Microglial cell activation signaling pathways. Pathogen-associated and damage-associated molecular patterns (PAMPs and DAMPs, respectively) are recognized by membrane receptors such as Toll-like receptors (TLR1–9), C-type lectin receptors (CLRs), and cytoplasmic sensors like nucleotide-binding oligomerization domain (NOD)–like receptors (NRLs). PAMPs and DAMPs include RNA, DNA, proteins, bacterial and fungal cell wall components, and microbial antigens such as lipopolysaccharides, lipoproteins, peptidoglycan, glycolipids, α- and β-mannan, β-glucan, fucose, and glycosylphosphatidylinositol. (1) Ligand binding to TLRs triggers events dependent on myeloid differentiation primary response protein 88 (MyD88) and TIR domain-containing adaptor protein inducing interferon β (TRIF). MyD88 activates nuclear factor–κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, inducing transcriptional activation of proinflammatory genes such as interleukin (IL)–1 β, tumor necrosis factor–α (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2). (2) Glutaminase (Glnase) levels and activity have been shown to be increased during inflammatory responses in a NF-κB–dependent manner. (3) Reactive oxygen species (ROS)/nitric oxide (NO) released by activated microglia induce increased expression levels and activity of cystine/glutamate antiporter (xCT) on nearby microglial cells.