Cytokines as Neuromodulators: Insights From Experimental Studies With Humans and Nonhuman Primates

Beyond their role in immune signaling, cytokines have emerged as key neuromodulators that influence processes including neurotransmitter function, neuronal excitability, synaptic plasticity, neurogenesis, myelination, and cortical sleep state. These roles are observed in the healthy brain and during infections when they reorient motivational, cognitive, and emotional responses. Experimental evidence from human and nonhuman primate immune challenge studies has been pivotal to understanding these effects. By showing that elevated cytokines readily induce transdiagnostic symptoms, including anhedonia, social withdrawal, psychomotor slowing, and cognitive impairment, these studies have also helped demonstrate that inflammation contributes to the shared neural dysfunction observed across psychiatric and neurological disorders. Cytokines modulate glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurotransmission, impair dopaminergic and serotonergic signaling, and regulate homeostatic synaptic scaling, leading to altered network connectivity and behavioral deficits. While research has often focused on single cytokines in isolation, neuroimmune signaling occurs through combinatorial cytokine codes, requiring systems-level approaches to understand their interactive effects. Advances in neuroimaging, molecular neuroscience, and biophysical modeling offer opportunities to link cellular cytokine action with macroscale network dysfunction, enabling mechanistic insights into cytokine-mediated neuromodulation. Clinically, cytokine-targeting therapies hold promise for treating inflammation-driven cognitive and mood disorders, but their long-term impact on neuroplasticity remains uncertain. Future research should characterize immune signatures predictive of neuropsychiatric symptoms, identify cell type-specific cytokine effects, and integrate multiscale modeling to refine understanding of neuroimmune interactions. Reconceptualizing cytokines as fundamental regulators of neural function rather than merely inflammatory mediators is crucial for developing precision medicine to mitigate immune-driven brain dysfunction and improve mental health outcomes.