Fig. 3
NL3P3 inflammasome activation. (1) Increased cellular stress causes the release of toxic metabolites (ATP, uric acid, glutamate, DAMPs, PAMPs, and others), increasing influx of extracellular calcium through P2X7, NMDA, and L-type calcium channels (LTCCs). ATP-P2X7 upregulation independently induces neuroinflammation (via NLRP3 activation, NF-kB, NFAT, GSK3β and VEGF signaling—not shown here), increases NMDA-excitotoxicity, and has been associated with rapid cycling in BD. (2) Mitochondrial dysfunction (decreased complex I activity) results in decreased oxidative phosphorylation and increased generation of ROS, Ca2+, as well as oxidized lipids and mtDNA. Intracellular Ca2+ imbalance can overwhelm deficient mitochondrial buffering capacity in BD, leading to fragmentation, morphological abnormalities, and eventually apoptosis. By any means, apoptotic signals (especially release of oxidized mtDNA), which potently upregulate NLRP3 activity [55]. (3) Damage signals activate the NLRP3 inflammasome, which (via caspase-1 cleavage) causes the elaboration of mature IL-1β and IL-18 as well as pore formation in the cell membrane (pyropoptosis), and ultimately the release of these deleterious intracellular molecules into the extracellular space. DAMPs/PAMPs also upregulate proinflammatory gene expression (NF-kB) and subsequent release of IL-1β, IL-6, IL-18, TNF-α, and other cytokines. (4) Once in the extracellular space, these agents act to amplify inflammation, activating surrounding microglia, increasing BBB permeability, recruiting peripheral immune cells, and upregulating the complement cascade (via Hmgb-1 and S100a9—MBL binding), causing sustained, sterile inflammation in the brain. Sublytic membrane attack complex (MAC) stimulation can also lead to increased mitochondrial calcium influx and loss of mitochondrial membrane potential, resulting in NLRP3 activation (not shown here) [54]. (5) In healthy individuals, these signals serve as repair mechanisms, and are deactivated by anti-inflammatory feedback (mainly from microglia and T regulatory cells), restoring homeostasis. In BD, chronic mitochondrial dysfunction and lack of proper feedback signaling results in amplification of inflammation and chronic neurodegeneration