Post-translational modifications in Neuroimmune cells during neuroinflammation: integrated regulatory networks and therapeutic opportunities

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