NLRP3 Inflammasome and Microglial Innate-Immune Signalling in Neurodegeneration

Microglia are the resident innate immune cells of the central nervous system and act as key sensors of tissue damage, protein aggregation, and metabolic stress. In response to these cues, microglia undergo profound molecular state transitions, shifting from homeostatic profiles toward disease-associated and inflammatory states governed by defined signalling programs. Central among these are TREM2-DAP12/TYROBP signalling, which shapes microglial activation, survival, phagocytosis, and lipid handling, and assembly of the NLRP3 inflammasome, which drives caspase-1 activation, gasdermin D-dependent pyroptosis, and the release of IL-1β and other pro-inflammatory mediators. Together with APOE, complement, and interferon signalling, these pathways determine how microglia respond to amyloid, tau, myelin debris, and lipid stress, positioning microglial innate immunity at the center of neurodegenerative disease mechanisms.A rapidly expanding body of work has established that dysregulated microglial signalling is not only a consequence but an active driver of neurodegeneration. Aberrant NLRP3 inflammasome activation, altered TREM2 function, and the emergence of disease-associated and lipid-droplet-accumulating microglia have been implicated in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and responses to CNS injury. These processes intersect with lipid metabolism, mitochondrial dysfunction, cGAS-STING and other innate immune pathways, and impaired proteostasis, yet the molecular events controlling microglial state transitions, inflammasome assembly, and the balance between protective and pathological responses remain incompletely defined. Clarifying these mechanisms is increasingly urgent as inflammasome inhibitors and TREM2-directed therapies advance toward the clinic.This Research Topic aims to bring together studies that dissect the molecular signalling controlling microglial innate immunity in the nervous system and that connect pathway-specific mechanisms to defined neuropathological outcomes. By integrating molecular, genetic, and pharmacological perspectives, this collection seeks to clarify how microglia sense damage, assemble the inflammasome, handle lipids, and transition between functional states, and how these mechanisms can be targeted for therapeutic benefit while preserving homeostatic immune function.We welcome submissions employing biochemical, genetic, and imaging approaches, as well as metabolomic and multi-omic methods at single-cell or spatial resolution, including work in genetically engineered animal models, human iPSC-derived microglia and neural systems, and organoids. Studies dissecting TREM2 or inflammasome signalling, defining microglial states and their molecular drivers, or evaluating pathway-selective biomarkers and small-molecule modulators are particularly encouraged.Topics of interest include, but are not limited to:- Molecular signalling governing microglial activation, priming, and state transitions - TREM2-DAP12/TYROBP signalling and its roles in microglial survival, phagocytosis, and lipid handling- NLRP3 inflammasome assembly, caspase-1 activation, gasdermin D, and pyroptosis in neural cells- Emergence and regulation of disease-associated and lipid-droplet-accumulating microglia- Microglial lipid metabolism, APOE signalling, and immunometabolic control of innate immunity- Crosstalk between inflammasome signalling and cGAS–STING, complement, interferon, and cell death pathways- Microglial responses to amyloid, tau, α-synuclein, myelin debris, and other disease-relevant stimuli- Contributions of microglial innate-immune signalling to Alzheimer’s disease, Parkinson’s disease, ALS, and multiple sclerosis- Microglial signalling in acute CNS injury, stroke, and neuroinflammatory conditions- Single-cell and spatial transcriptomic, metabolomic, and other omics approaches to define microglial states and their signalling drivers- Pharmacological and gene-based strategies targeting inflammasome or TREM2 signalling for neuroprotection Topic editors: Brian M Polster, Ruili Xie, Danny Galleguillos Source: https://www.frontiersin.org/research-topics/83740/nlrp3-inflammasome-and-microglial-innate-immune-signalling-in-neurodegeneration