Neuroimmune interactions: from molecular mechanisms to therapeutic targets

Abstract Neuroimmune interactions reveal that the central nervous system (CNS) is dynamically integrated with peripheral immunity. This bidirectional communication is mediated by microglia, astrocytes, peripheral immune cells, and the neurovascular unit through cytokines, chemokines, complement proteins, neurotransmitters, and neuropeptides. At the molecular level, pattern-recognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain-like receptors, activate NF-κB, MAPK, and JAK–STAT signaling. These pathways regulate cytokine production, oxidative stress, cellular metabolism, and glial phenotypes. NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation induces caspase-1-dependent maturation of IL-1β and IL-18 and promotes pyroptosis, thereby amplifying neuroinflammation. Complement C1q/C3–CR3 signaling mediates synaptic pruning, whereas C–C motif chemokine ligand 2 (CCL2)–CCR2 signaling promotes leukocyte recruitment and microglial activation. Cytokines and matrix metalloproteinases disrupt endothelial tight junctions and compromise blood–brain barrier integrity. In addition, calcitonin gene-related peptide (CGRP) and substance P activate neuropeptide receptors to drive neurogenic inflammation. Together, these molecular circuits regulate glial activation, immune-cell trafficking, synaptic remodeling, neuronal excitability, vascular function, and cell survival. Their dysregulation contributes to neurodegenerative, neuroinflammatory, psychiatric, neurodevelopmental, and peripheral diseases through the blood–brain barrier, gut–brain axis, and vagus nerve. This Review summarizes how molecular neuroimmune mechanisms drive disease initiation, progression, and heterogeneity, and discusses emerging therapies targeting inflammasomes, complement, chemokine receptors, neuropeptide signaling, and microbiota to advance biomarker-guided, personalized neuroimmune medicine.