Cytokine-mediated immune-to-brain signaling in neural circuit disorders

Abstract

Neuroinflammation has emerged as a fundamental driver of neural circuit dysfunctions across a spectrum of neurodevelopmental and psychiatric disorders. Beyond classical neuroimmune pathologies, accumulating evidence indicates that systemic inflammatory states — including those elicited by infection, metabolic dysfunction, stress, or peripheral immune activation — induce profound and long-lasting alterations in brain development and function. Cytokines act as critical molecular mediators of this peripheral-to-central immune communication, precisely orchestrating microglial activation in a spatiotemporally restricted manner. Inflammasome-dependent signaling, particularly NLRP3 activation and subsequent cytokine release, has a central role in shaping microglial states during neuroinflammation. Here, we integrate current evidence linking systemic inflammation to microglial cytokine signaling programs and discuss how these cascades shape synaptic development, refinement, and circuit function. Although synapse pruning and cytokine-mediated microglial signaling jointly contribute to circuit remodeling, we highlight cytokine-driven microglial state amplification as a central mechanism linking systemic inflammation to neural circuit instability. We also highlight that specific cytokines can exert direct effects on neuronal populations — independent of microglial intermediates — to context-dependently modulate synaptic efficacy and circuit excitability. Finally, we evaluate the mechanisms linking systemic inflammation to brain dysfunction and highlight emerging translational opportunities, including the therapeutic repurposing of cytokine-targeting and immunomodulatory agents for neuropsychiatric interventions. This Review explores how systemic inflammation impacts brain development and function, emphasizing the role of cytokines in modulating synaptic organization and neural circuits. The authors argue for a shift from brain-centric models to an integrative approach that considers peripheral immune signals. They highlight microglia, the brain’s resident immune cells, as key players in translating systemic inflammation into local cytokine signaling programs and synaptic changes. Using representative cytokine signaling pathways as example, this Review discusses how these signals can lead to synaptic pruning, altered synaptic function, and circuit dysfunction, contributing to conditions such as depression and schizophrenia. The authors propose that cytokines act as circuit-integrated amplification nodes, influencing synaptic gain and circuit stability. This understanding opens avenues for targeted immunomodulatory therapies, suggesting that precision interventions could mitigate immune-driven neural dysfunctions, potentially transforming treatment strategies for neurodevelopmental and psychiatric disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.