Spirulina and Microglial Activation: TLR4/NF-kB, M1/M2 Polarisation, and Neuroinflammation

Microglia: CNS Immune Surveillance

Microglia are yolk-sac-derived myeloid cells that populate the brain during embryogenesis and are maintained by CSF1R (colony-stimulating factor 1 receptor) signalling and local proliferation without monocyte replacement under steady state. Resting microglia continuously survey the parenchyma with branched processes, sampling for pathogens, debris, and synaptic activity via P2RY12 (ADP sensor), CX3CR1 (fractalkine receptor), and TREM2 (phosphatidylserine/lipid debris receptor). TREM2 signalling (via DAP12-Syk) promotes microglial lipid phagocytosis and suppresses inflammatory activation.

TLR4-NF-kB: M1 Microglial Activation

Classical (M1) activation by LPS/TLR4, IFN-gamma/IFNGR, or ATP/P2RX7 drives NF-kB, AP-1, and IRF-5 to produce: iNOS (NO-mediated neurotoxicity), TNF-alpha, IL-1beta (NLRP3-processed), IL-6, IL-12, MHC class II, and CD68. Chronic M1 activation drives excitotoxicity (iNOS-derived NO + superoxide → peroxynitrite → NMDAR potentiation), synaptic pruning excess (C1q/C3 complement tagging, CR3-mediated phagocytosis of synapses), and phagocytic impairment of amyloid-beta. PCB suppresses LPS-induced NF-kB and iNOS in BV-2 microglial cell lines and primary microglia with IC50 values consistent with physiologically achievable concentrations.

M2 Microglial Polarisation: IL-4/IL-13/IL-10 Axis

Alternative (M2) activation by IL-4 (STAT6), IL-13 (STAT6), IL-10 (STAT3), and TGF-beta promotes: arginase-1 (ARG1, competing with iNOS for arginine), CD206 (mannose receptor), FIZZ1 (RETNLA), YM1 (CHI3L3), and anti-inflammatory cytokines. M2 microglia phagocytose debris and amyloid, produce BDNF/IGF-1 for neuroprotection, and resolve neuroinflammation. The M1/M2 binary is oversimplified (multiple M2 subtypes and disease-associated microglia/DAM phenotypes exist), but mechanistically illustrates the bidirectional modulation spirulina achieves: suppressing M1 NF-kB/iNOS while Nrf2-HO-1 promotes anti-inflammatory HO-1+ phenotype overlap with M2.

TREM2 and Disease-Associated Microglia (DAM)

In neurodegeneration (Alzheimer, ALS, MS), microglia transition to a disease-associated microglial (DAM) phenotype: downregulating homeostatic genes (P2RY12, CX3CR1, TMEM119) and upregulating phagocytic/inflammatory genes (TREM2, ApoE, CTSD, LPL). DAM polarisation requires TREM2 signalling and is APOE-dependent. Nrf2 activation promotes microglial phagocytic capacity (via NRF2-NQO1/HO-1 reduction of phagosomal oxidative burst damage) while attenuating inflammatory DAM-like NF-kB gene expression. Spirulina supplementation reduces amyloid-beta burden in APP/PS1 transgenic mice, consistent with enhanced microglial phagocytosis and reduced neuroinflammation.

Glutamate Excitotoxicity and Microglial Contribution

Activated microglia release glutamate via the cystine-glutamate antiporter (System Xc-/ SLC7A11) and vesicular glutamate (VGLUT1/2), contributing to excitotoxic NMDAR overstimulation. Microglial System Xc- is paradoxically both a source of oxidative stress (glutamate → neuronal excitotoxicity → ROS) and a route for cystine import for GSH synthesis (anti-inflammatory). Spirulina's NF-kB suppression reduces microglial SLC7A11 induction under inflammatory conditions, attenuating the excitotoxic glutamate-release arm while EAAT2 (astrocytic glutamate transporter, Nrf2 target) induction clears synaptically-released glutamate.

Neuroinflammation and Spirulina Preclinical Evidence

Multiple animal models show spirulina attenuates neuroinflammation: (1) MPTP Parkinson model: reduced nigral NF-kB, TNF-alpha, and microglial CD11b density; (2) LPS-induced neuroinflammation: reduced hypothalamic IL-1beta and iNOS; (3) focal ischaemia: reduced infarct volume correlating with microglial NF-kB suppression and Nrf2-HO-1 induction. The convergent mechanistic explanation (PCB→NF-kB and Nrf2/HO-1) explains the consistent multi-model neuroprotective phenotype.