The immunoproteasome as a neuroimmune hub in the central nervous system: from proteostasis stress to inflammatory pathology

The immunoproteasome (IP) is a stress-inducible specialization of the ubiquitin-proteasome system that integrates immune activation with cellular homeostasis in the central nervous system (CNS). Incorporation of the inducible β1i, β2i, and β5i subunits enhances proteolytic capacity under inflammatory, oxidative, and metabolic stress, thereby supporting redox balance, mitochondrial integrity, and proteostasis. IP expression is highly dynamic and cell type-specific, varying across astrocytes, microglia, endothelial cells, and neurons in response to local microenvironmental cues. Functionally, IP activation exhibits a dual nature: transient induction facilitates the clearance of damaged proteins and fine-tunes inflammatory signaling, whereas sustained or dysregulated activation reinforces NF-κB- and STAT-dependent inflammatory programs, disrupts proteostatic equilibrium, and increases neuronal and vascular vulnerability. Across neurological disorders, the IP acts as a context-dependent regulator, shaping post-ischemic inflammation and blood-brain barrier (BBB) integrity, contributing to maladaptive responses in Alzheimer’s and Parkinson’s disease, and amplifying immune-mediated injury in multiple sclerosis, neuromyelitis optica spectrum disorder, epilepsy, and infectious encephalitis. Elucidating the spatiotemporal regulation of the IP and its therapeutic selectivity may enable precision immunomodulatory strategies for CNS diseases.