Neuroinflammation and Glial Activation Module

This is a mechanism module, not a specific disease. Disorder entries reference the central node via conforms_to (e.g., "neuroinflammation_glial_activation#Reactive Microglial and Astrocytic Activation"). The module was created to close AOP-Wiki gap KE 188 ("brain inflammation") per dismech issue #10368: around 20 disorder entries and 4 modules (glaucoma_optic_neuropathy, mps_gag_storage, glymphatic_dysfunction, lysosomal_substrate_accumulation) carry a neuroinflammation node fused into a disorder- or module-specific composite name, but until now no standalone module node existed for microglial and astrocytic activation on its own, so nothing could conform to it and the same process was re-derived in each entry. AOP-Wiki's own Event Components for KE 188 list two rows - "brain inflammation -> microglial cell -> pathological" and "brain inflammation -> astrocyte -> pathological" - i.e. AOP-Wiki itself treats microglial and astrocytic activation as one Key Event with two cell-type components, not two separate events, which is why this module's central_effector node binds both CL:0000129 (microglial cell) and CL:0000127 (astrocyte) on a single node rather than splitting them. Governance decision recorded here (dismech issue #6189, item 3 of the autophagy_senescence_inflammasome_axis reconciliation). A 2026-07-30 curation-scanner comment on #6189 identified a "glial-mediation gap" and posed it as an open question: should a senescent or reactive glial cell be modelled as a new node, or handled by substituting glial cell_types on an existing cellular_senescence conformance in CNS disorder entries, with a tentative (unexecuted) guess toward the latter? This module decides that question in favour of a new, standalone module, for three reasons. First, AOP-Wiki treats brain inflammation (KE 188) as its own Key Event, not as a cellular-senescence Key Event or a component of one - the two are indexed and evidenced separately in the adverse outcome pathway literature this module draws on, which is the strongest single argument for not routing this mechanism through cellular_senescence's conformance surface. Second, and consistent with that framing, Escartin et al. (PMID:33589835), the field's own consensus nomenclature paper, explicitly cautions against extending the concept of senescence to astrocytes, because the core definition of senescence - irreversible cell-cycle arrest in a proliferative cell - does not straightforwardly apply to astrocytes, which are largely post-mitotic in healthy tissue; reactive astrogliosis and microglial activation are their own molecularly defined programs, not an instance of the arrest-and-SASP program cellular_senescence models. Third, mechanically, several of the disorder entries this module was built to conform (Huntington_Disease, Pick_Disease, Alzheimer_Disease) already carry a bare, standalone "Neuroinflammation" pathophysiology node with real cell-type bindings and evidence; conforming those nodes directly, rather than asking curators to first reclassify them as cellular_senescence conformers with substituted glial cell types, is the lower-friction and more mechanistically honest wiring. What this module explicitly does NOT claim, and where the next boundary sits. The chain modelled here ends at cytokine/chemokine release and bystander injury from an acutely or subacutely activated glial cell. Whether, and under what conditions, a persistently reactive microglion or astrocyte additionally senesces - acquiring a senescence-associated secretory phenotype in the cellular_senescence or inflammaging sense, on top of or instead of the acute reactive program modelled here - is a live and unresolved question in the glial-senescence literature and is NOT decided by this module. A conforming disorder entry whose evidence supports that further transition should curate a distinct node conforming to cellular_senescence or inflammaging's SASP/accumulation nodes as well, substituting the glial cell type there, rather than treating conformance to this module as satisfying that separate claim. This module also does not model the specific disorder-level hypothesis that reactive glia and their trigger form a self-sustaining feedback cycle (the "self-sustaining cycle" claim raised in #6189's original ASI-axis proposal) as a settled mechanism; where an entry's own evidence supports a reciprocal edge (for example, Alzheimer_Disease already curates microglial ASC specks reinforcing amyloid-beta aggregation, PMID:29293211, as a downstream edge with hypothesis_groups), that belongs on the disorder entry's own pathograph and mechanistic_hypotheses, not folded into this module's causal chain. Relationship to nlrp3_inflammasome_activation. That module's "Priming Signal and NLRP3 Transcriptional Upregulation" node and this module's amplifier node both describe pattern-recognition-receptor-driven NF-kappaB priming, but at different resolutions: nlrp3_inflammasome_activation's priming node is scoped to what licenses the NLRP3 sensor itself (NLRP3 and pro-IL-1 beta transcription), while this module's amplifier node is the broader glial danger-signal-sensing step that precedes any specific inflammasome. A conforming disorder entry whose evidence traces all the way to an assembled, caspase-1-activating NLRP3 complex should additionally conform the relevant downstream node to nlrp3_inflammasome_activation's central_effector node rather than treating this module's effector (cytokine release) node as satisfying that separate, more specific claim; this module does not re-derive inflammasome assembly, caspase-1 cleavage, or gasdermin D pyroptosis. Relationship to glutamate_excitotoxicity. That module's trigger node, "Excessive Glutamatergic Stimulation and Impaired Glutamate Clearance", already owns astrocytic failure to clear synaptic glutamate as a distinct mechanistic claim. A conforming entry whose evidence includes reactive astrocytes losing glutamate-buffering capacity (for example, Pick_Disease's own Neuroinflammation node already describes "reduced astrocytic glutamate-cycling markers") should curate that as a separate downstream edge or a separate conforming node against glutamate_excitotoxicity, not inside this module's chain. Modules bind GO and CL terms only; the identity of the disorder-specific danger signal (a particular aggregated protein, pathogen, or xenobiotic) is described in prose rather than bound to a CHEBI or MONDO term. Worked conformers: Huntington_Disease, Pick_Disease, and Alzheimer_Disease each already carried a bare, standalone "Neuroinflammation" pathophysiology node with real microglia/astrocyte cell-type bindings and PMID-cited evidence before this module existed; all three now conform their node to this module's central_effector node. Pick_Disease's own node and evidence describe astrocyte-dominant reactivity with "remarkably little activation of microglia" relative to Alzheimer disease; this still satisfies the node, whose criterion is a reactive microglial and/or astrocytic state, not both in equal measure, but is recorded here so the conformance does not read as a mismatch to a reader who has not read Pick_Disease's own text. Other disorder entries carrying a similar bare Neuroinflammation node (Bipolar_Disorder, Major_Depressive_Disorder, Parkinsons_Disease, Gerstmann-Straussler-Scheinker_Syndrome, Long_COVID, Amyotrophic_Lateral_Sclerosis, Gaucher_Disease, Multiple_System_Atrophy, Fibromyalgia) are natural further conformers and are deliberately left unwired here; wiring them is future curation, not a defect of this module. The 6 existing module-level composite neuroinflammation nodes identified in issue #10368 (glaucoma_optic_neuropathy#Optic Nerve Degeneration and Neuroinflammation, mps_gag_storage#Heparan Sulfate-Driven Neuroinflammation, glymphatic_dysfunction#Neuroinflammation and Progressive Neurodegeneration, lysosomal_substrate_accumulation#Storage-Cell Cytotoxicity and Neuroinflammation) are also left untouched: retargeting an existing module-to-module conformance pattern is a further governance question this module does not decide unilaterally. This module does not carry a treatments block. Microglial-modulating candidates such as minocycline are described in the review literature surveyed here only as a named example of a neuroprotective-polarization candidate, with no robust clinical-outcome evidence in the diseases surveyed for this module; the drug-target pattern is deliberately deferred rather than forced onto weak evidence.