Category: disease_cascade
Microglia are the resident innate immune cells of the CNS, originating from yolk-sac erythromyeloid progenitors during embryogenesis. Step 1: homeostatic state — surveillance of synaptic + parenchymal space; phagocytosis of debris + apoptotic cells; complement-tagged synaptic pruning (developmental and adult). Step 2: activation trigger — pathogen exposure, sterile injury, protein aggregates (Aβ, α-synuclein, mutant huntingtin), DAMPs (HMGB1, ATP, mitochondrial DNA). Step 3: priming — chronic low-grade stimulation lowers the activation threshold without producing full activation; primed microglia hyper-respond to subsequent triggers ("microglial reactivity hypersensitivity"). Step 4: activation phenotypes — historically M1 (pro-inflammatory: TNF-α, IL-1β, IL-6, NO, ROS) vs M2 (anti-inflammatory: IL-10, TGF-β, arginase, debris clearance); modern view recognizes continuum + disease-associated microglia (DAM) signature (Trem2-high). Step 5: chronic activation pathology — sustained pro-inflammatory output → bystander neuronal damage; complement-mediated synaptic pruning excess → cognitive decline (Alzheimer, schizophrenia, lupus-CNS); NLRP3 inflammasome → IL-1β + pyroptosis. Step 6: cross-talk — astrocyte reactivity (A1 neurotoxic vs A2 reparative); blood-brain barrier disruption recruits peripheral myeloid cells; chronic neuroinflammation contributes to AD, PD, MS, traumatic brain injury, depression. Therapeutic targets: NLRP3 (canakinumab, MCC950), microglial CSF1R (pexidartinib — preclinical CNS), TREM2 agonists (early clinical), classical anti-inflammatories (corticosteroids, minocycline — modest CNS penetration), psychobiotics + omega-3 + curcumin (chronic anti-inflammatory). Cross-links: [[tlr_innate_signaling]] (TLR4 + microglia), [[cgas_sting_type1_ifn]] (cytosolic DNA → IFN), [[nlrp3_inflammasome]] (canonical microglial inflammasome), [[alzheimer_amyloid_tau_cascade]], [[parkinson_alpha_synuclein_aggregation]].