Crosstalk between neurotransmitters and NLRP3 inflammasome pathway: A narrative review

Neurotransmitters (NTs) are endogenous chemical messengers that critically shape daily functions, influencing emotion, cognition, behavior, and motor activity. The NLRP3 inflammasome bridges innate immunity and neural function. Accumulating evidence indicates that its crosstalk with NT signaling affects both neuroinflammatory processes and the activity of neuronal and glial cells. In this review, we summarize the current evidence on the crosstalk between neurotransmitters (NTs) and the NLRP3 inflammasome under pathological conditions affecting the central nervous system (CNS), where neurotransmitter dysregulation and chronic NLRP3 inflammasome activation coexist. Our review does not support a single, uniform pattern for this interaction; instead, outcomes vary according to the neurotransmitter involved, receptor subtype, cell type, and underlying pathology. Most available studies assess how NTs regulate NLRP3 priming or activation, whereas the reverse influence of NLRP3 signaling on NT release, receptor function, and synaptic plasticity remains less studied. Further investigation of this bidirectional relationship may help inform the development of therapeutic strategies that target NLRP3-NT crosstalk. Given the complex interconnectivity among neurotransmitter systems, integrating their mutual interactions with NLRP3 activity is likely to yield a more comprehensive view of neuroimmune regulation in health and disease. The emerging evidence of dual and context-specific actions for example, biphasic effects of dopamine on neuroinflammation under different experimental conditions underscores the need for mechanistically oriented, disease-specific, and cautiously interpreted studies. Finally, systematic investigation of less-studied neurotransmitters and receptor subtypes may uncover additional regulatory mechanisms within the NLRP3 network and identify potential targets for future therapeutic investigation in neuroinflammatory and neurological disorders.