Meningeal immune signaling supports emotional adaptation following threat

Social creatures must attend to threat signals from conspecifics and respond appropriately, both behaviorally and physiologically. In this work, we show a threat-sensitive immune signaling that orchestrates psychological processes and is amenable to social modulation. Repeated encounters with socially-cued threats triggered neutrophil priming preferentially in males. Meningeal niche-specific neutrophil activity was correlated with attenuated defensive responses to cues. The neutrophil-specific membrane protein CD177 responded to threat-predicting social cues, and its genetic ablation abrogated male behavioral phenotypes. Neutrophil CD177 signaling facilitated optimal meningeal IFN-γ production, which blunted neural response to threatening stimuli by enhancing intrinsic GABAergic inhibition within the prelimbic cortex. Initiation of meningeal neutrophil-mediated IFN-γ signaling was sensitized by negative emotional states and governed by socially dependent androgen release. This male-biased hormone/neutrophil regulatory axis is seemingly conserved in humans. Our findings provide insights into how immune responses influence behavioral responses to threats, suggesting a possible neuroimmune basis of emotional regulation.