This review synthesizes evidence that the histamine H4 receptor (H4R) exerts context-dependent, dual roles in neuroinflammation—promoting NF-κB/MAPK-driven pro-inflammatory microglial and T-cell responses that worsen MS and PD pathology while under some conditions engaging JAK/STAT/PI3K-Akt…

H4R is a druggable GPCR with existing ligands, so resolving its cell- and disease-stage specific signaling bias could enable repurposing or development of H4R-targeted therapies to modulate neuroinflammation and potentially protect dopaminergic neurons in Parkinson's disease.

Neuroinflammation plays a pivotal role in the progression of neurodegenerative disorders such as multiple sclerosis (MS) and Parkinson's disease (PD), primarily through a self-amplifying positive feedback loop between inflammation and neurodegeneration. The histamine H4 receptor (H4R), expressed on both peripheral immune cells and central microglia, serves as a critical molecular interface linking peripheral immunity to central nervous system inflammation. This review provides a systematic analysis of the context-dependent, dual roles of H4R in neuroinflammatory processes underlying MS and PD. In the context of MS and its experimental autoimmune encephalomyelitis (EAE) model, H4R activation promotes NF-κB signaling and upregulates pro-inflammatory mediators including TNF-α and IL-6, thereby driving the differentiation of pathogenic T-helper subsets (Th1, Th9, and Th17) and exacerbating disease pathology. Paradoxically, H4R signaling may also support early immune homeostasis by facilitating the expansion and functional maturation of regulatory T cells. In PD, elevated H4R expression correlates with increased disease severity. H4R activation drives microglial polarization toward a pro-inflammatory phenotype and stimulates the release of inflammatory cytokines via NF-κB and MAPK signaling pathways, ultimately contributing to dopaminergic neuron loss. Conversely, under specific physiological or pharmacological conditions, H4R engagement can promote anti-inflammatory microglial polarization through the JAK/STAT/PI3K/Akt signaling cascade. The functional complexity of H4R arises from factors such as cell-type specificity, disease stage, ligand-biased signaling, and variations across experimental models. A deeper understanding of the dual regulatory mechanisms of H4R and its therapeutic potential will offer valuable insights for the development of novel strategies targeting neuroinflammatory pathways.