BACKGROUND
Microglia are essential regulators of central nervous system homeostasis and participate in immune surveillance, inflammatory regulation, phagocytosis, metabolic adaptation, and tissue repair. Recent single cell and spatial omics studies have revealed extensive microglial heterogeneity, challenging the traditional M1/M2 classification. However, the functional significance and therapeutic potential of distinct microglial states remain highly context dependent.
METHODS
This review summarizes recent advances in microglial biology across acute brain injury, neurodegenerative and demyelinating disorders, central nervous system infections, and psychiatric and neurodevelopmental diseases. Evidence from multiomics studies, genetic approaches, functional experiments, and emerging therapeutic strategies was integrated to evaluate mechanisms and translational challenges.
RESULTS
Microglial responses represent dynamic functional programs rather than fixed beneficial or detrimental phenotypes. Their effects on inflammation, phagocytosis, immune regulation, and tissue repair are determined by disease stage, anatomical location, and local microenvironment. Although microglia targeted therapies, including signaling modulation, depletion and repopulation, replacement strategies, and targeted delivery systems, show promise, clinical translation remains limited by insufficient human validation, model differences, and incomplete understanding of spatiotemporal regulation.
CONCLUSIONS
Microglial function should be interpreted within a context dependent framework integrating cellular state, functional outcome, disease stage, and therapeutic timing. Future studies should focus on cell specific validation and human translational approaches to develop precise microglia directed therapies.
HIGHLIGHT
Microglial responses are dynamic functional programs shaped by disease context, anatomical location, and temporal progression rather than fixed phenotypes. Single cell and spatial omics reveal extensive microglial heterogeneity, but functional validation remains essential to distinguish molecular states from biological outcomes. Context guided microglial modulation, including targeted delivery, immune regulation, depletion, and replacement strategies, provides new opportunities for precision therapy.
Jie Chen, Wangzheqi Zhang, Li-Zhou Song et al.· Clinical and Translational M...· 0 citations
Neuroinflammation represents a common pathological mechanism underlying a wide range of central nervous system (CNS) disorders, encompassing neurodegenerative disorders (NDDs), ischemic stroke (IS), traumatic brain injury (TBI), and demyelinating diseases such as multiple sclerosis (MS). This process is initiated by the orchestrated responses of microglia, astrocytes, oligodendrocyte-lineage cells, neurons, brain endothelial cells, and infiltrating peripheral immune cells. Neuroinflammation can facilitate tissue repair or, conversely, perpetuate chronic inflammation and neural damage. Post-translational modifications (PTMs) serve as critical mediators linking extracellular danger signals and intracellular metabolic conditions to alterations in protein activity, stability, localization, interactions, and degradation. Notably, the biological impact of a PTM cannot be solely deduced from its classification; rather, it is contingent upon factors such as the specific enzyme responsible for its addition or removal, the identity of the substrate, the modified residue or ubiquitin-chain architecture, the subcellular localization, the cellular context, and the stage of the disease. In this review, we synthesize evidence on various PTMs such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, glycosylation, S-nitrosylation (SNO), and metabolite-coupled modifications, including lactylation and succinylation. We analyze their convergent and divergent roles across different neuroimmune cell types, disease-related stimuli, and temporal contexts, and investigate the mechanisms by which intercellular communication propagates PTM-dependent inflammatory signals. Special emphasis is placed on the ordered and competitive crosstalk among PTMs that modulate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor protein 3 (NLRP3) inflammasome, and JAK-STAT signaling pathways, as well as the integrity of the blood-brain barrier (BBB), oligodendrocyte differentiation, and remyelination processes. Additionally, we assess PTM-regulating enzymes as potential therapeutic targets, while highlighting current limitations such as uneven cell-specific evidence, extrapolation from non-neural systems, low modification stoichiometry, rapid turnover, tissue-processing artifacts, and the insufficiency of transcriptomic data alone to demonstrate site-specific protein modifications. The integration of single-cell and spatial multi-omics with PTM-enrichment proteomics, quantitative site-occupancy assessments, and orthogonal mechanistic validation is anticipated to facilitate the generation of PTM maps that are resolved at the cellular, site-specific, and developmental stage levels. This evidence-based framework has the potential to enhance biomarker-guided disease stratification and inform the development of more selective, brain-targeted therapeutic interventions for neuroinflammatory disorders. Not applicable
