Meningeal neutrophil immune signaling influences behavioral adaptation following threat

Area of Science:

• Neuroimmunology
• Behavioral Neuroscience
• Immunology

Background:

• Social animals must detect and respond to threats from others.
• Immune mechanisms can influence psychological processes and behavior.
• The role of the immune system in social threat detection is not fully understood.

Purpose of the Study:

• To investigate a threat-sensitive immune mechanism in mice.
• To explore the role of meningeal neutrophils (MNs) in social threat responses.
• To elucidate the neuroimmune pathways modulating behavioral and physiological reactions to threats.

Main Methods:

• Inducing social threat cues in mice.
• Analyzing meningeal neutrophil activity and CD177 expression.
• Utilizing genetic ablation of CD177.
• Measuring behavioral defensive responses.
• Investigating the role of interferon-gamma (IFN-γ) and GABAergic inhibition.

Main Results:

• Repeated social threat cues led to preferential meningeal neutrophil (MN) priming in males.
• MN activity correlated with reduced defensive responses to threat cues.
• CD177 upregulation was observed after social threat cueing; its absence abolished male behavioral changes.
• CD177 signaling promoted a T helper 1 (Th1)-like immune bias, enhancing GABAergic inhibition in the prelimbic cortex via IFN-γ, thus blunting neural responses.
• Hormonal factors, including androgens, and negative emotional states modulated MN signaling.

Conclusions:

• A male-biased, hormone- and neutrophil-dependent immune mechanism influences behavioral and physiological responses to social threats.
• This neuroimmune axis, involving CD177 and IFN-γ, modulates threat perception and defensive behaviors.
• The findings suggest a conserved neuroimmune basis for emotional regulation and threat processing in mammals, potentially including humans.