NMDA Receptor Subunit NMR-2 Regulates Pathogen-Induced Immune Responses via the Nervous System in C. elegans

Neural control of innate immunity must balance restraint of basal immune activity with rapid activation upon pathogen encounter. Glutamate, the primary excitatory neurotransmitter in the nervous system, has been implicated in several neurological disorders associated with inflammation, suggesting a potential link to immune regulation. However, how glutamatergic signaling contributes to immune balance remains unknown. Here, we demonstrated that the NMDA-type ionotropic glutamate receptor subunit NMR-2, a component of the NMDA receptor complex, acts in the C. elegans nervous system as a key regulator of pathogen-induced immune responses. Loss of nmr-2 enhanced resistance to Staphylococcus aureus and Pseudomonas aeruginosa, without elevating basal immune gene expression. The pathogen-induced response controlled by NMR-2 required the conserved PMK-1/p38 MAPK, DAF-16/FOXO, and HLH-30/TFEB pathways. We identified the AVD interneuron as the site of action of NMR-2, where it integrates inputs from upstream sensory neurons ASE, ASK, AQR, and PQR. These findings uncover a neural circuit in which glutamatergic signaling distinguishes basal immune gene expression from pathogen-induced immune responses, revealing a mechanism that promotes effective defense without altering baseline immunity.