Systemic and innate immunity in neurodegenerative disease - inflammasomes, microglial states and clonal hematopoiesis from mechanism to biomarker

Neurodegenerative diseases are increasingly recognized as disorders of persistent neuroinflammation in which microglia and other immune cells act both as sentinels and effectors of tissue damage or repair. Microglia integrate systemic inflammatory cues and local danger signals, with inflammasomes orchestrating IL-1 family cytokine release and inflammatory cell death in response to misfolded proteins and metabolic stressors. In parallel, aging of the hematopoietic system, clonal hematopoiesis of indeterminate potential, and somatic mutations in myeloid lineages have emerged as candidate modulators of CNS innate immunity, microglial composition, and resilience or susceptibility to neurodegeneration. These converging lines of evidence highlight the need to study systemic and brain-intrinsic innate immunity as an integrated axis, moving beyond traditional dichotomies between “central” and “peripheral” inflammation to better understand disease heterogeneity and trajectories.This Research Topic aims to dissect how systemic and innate immune mechanisms converge to shape neurodegenerative disease onset and progression, with a particular focus on clonal hematopoiesis, inflammasome signaling, and microglial state transitions. Recent work suggests that age-related somatic mutations in hematopoietic stem and progenitor cells, as well as somatic variants within brain-resident microglia, can modulate neuroinflammatory tone and vulnerability to diseases such as Alzheimer’s disease and related dementias. In parallel, dysregulated inflammasome activity, especially within microglia and other glial cells, emerges as a central hub linking protein aggregation, cellular stress, and pyroptotic cell death. By bringing together studies that span mechanistic models, multi-omics, advanced imaging, and biomarker discovery, this Research Topic seeks to define how systemic immune alterations and innate immune pathways reprogram microglial states and brain homeostasis. Ultimately, our goal is to foster the translation of these mechanistic insights into novel biomarkers, stratification tools, and immunomodulatory therapeutic concepts in neurodegenerative disease.We welcome contributions that investigate systemic and innate immune mechanisms in neurodegenerative diseases, spanning Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia/ALS, prion diseases, and — where the focus is on the neurodegenerative component — multiple sclerosis, as well as other conditions in which neuroinflammation drives neurodegeneration.Topics of interest include, but are not limited to:- clonal hematopoiesis and somatic mosaicism in myeloid and microglial lineages, and their impact on CNS innate immunity and neurodegeneration;- mechanisms and consequences of inflammasome activation in CNS cells;- microglial states and trajectories defined by single-cell and spatial multi-omics;- systemic–brain immune crosstalk as it shapes neurodegenerative disease onset and progression;- and fluid or imaging biomarkers reporting on microglial activation, inflammasome activity, or hematopoietic clones in the context of neurodegeneration.We encourage submissions ranging from original mechanistic and translational research, multi-omics and computational studies, and biomarker development, to translational and clinically informative studies that clarify the underlying neurodegenerative or neuroinflammatory mechanisms of action, as well as Reviews, Mini-Reviews, Hypothesis and Theory articles, and Perspectives that synthesize emerging concepts and outline future directions.Contributions should provide in-depth molecular, cellular, or systems-level insight — ideally supported by in vivo or patient-derived models — and clarify neurodegenerative mechanisms; standalone clinical reports, or studies of general cell death without mechanistic neuro-immune relevance, fall outside the scope. Topic editors: Sergio Castro-Gomez, Marina Trombetta Lima Source: https://www.frontiersin.org/research-topics/86269/systemic-and-innate-immunity-in-neurodegenerative-disease---inflammasomes-microglial-states-and-clonal-hematopoiesis-from-mechanism-to-biomarker