🟢 Strong Evidence
The nervous system and immune system function as a single, integrated biological network rather than separate entities, according to research published in Nature Reviews Immunology (2025). Neurons actively regulate immune cell behavior through neurotransmitters and electrical signals, while immune cells directly influence brain function and behavior through cytokine signaling, establishing a bidirectional communication system that coordinates defense and maintains homeostasis across the entire body.
Key takeaways
- Neurons use neurotransmitters, neuropeptides, and electrical signals to directly regulate immune cell migration, activation, and suppression
- Immune cells release cytokines and chemokines that alter synaptic function, mood, cognition, and pain perception in the brain
- Psychological stress activates neural circuits that mobilize immune cells, shifting systemic inflammation through coordinated neuro-immune signaling
- Microglia—brain-resident immune cells—integrate neural and immune signals to shape learning, memory, and neurodegeneration vulnerability
Study at a Glance
| Source | Nature Reviews Immunology |
| Article type | Narrative review of neuroimmunology research |
| Focus | Bidirectional communication between nervous and immune systems |
| Key mechanism | Neurotransmitter, cytokine, and microglia-mediated signaling |
| Publication year | 2025 |
Neuro-Immune Communication Pathways
Five major mechanisms by which the nervous and immune systems regulate each other
Adapted from Leuning et al., Nature Reviews Immunology (2025) | Georgian Medical Journal News
Neural Signals Directly Control Immune Cell Behavior
Neurons do not merely sense the immune system passively; they actively sculpt immune responses through multiple molecular mechanisms. According to the research by Leuning, Gianeselli, Russo, and Swirski published in Nature Reviews Immunology (2025), neurotransmitters including norepinephrine, acetylcholine, and dopamine bind to receptors on monocytes, neutrophils, and T cells, directly regulating their migration to sites of infection or injury. Neuropeptides such as substance P and neuropeptide Y further fine-tune immune cell activation states, while electrical signals from sympathetic nerve terminals coordinate the timing of immune responses across tissues.
This neural control extends beyond simple on-off switching. The vagus nerve, a major parasympathetic pathway, dampens inflammation in the gut and peripheral organs through acetylcholine signaling, establishing a built-in brake on excessive immune activation. See our Clinical Updates section for emerging therapeutic applications of neuro-immune targeting.
Immune Cells Reshape Brain Function and Behavior
The reverse communication is equally profound. When immune cells encounter pathogens or tissue damage, they secrete cytokines—signaling molecules including interleukin-6, tumor necrosis factor-alpha, and interleukin-1beta—that cross the blood-brain barrier and directly alter neuronal function. According to Leuning and colleagues’ review, these cytokines modify synaptic plasticity (the brain’s ability to strengthen or weaken connections), disrupt neurotransmitter balance, and alter mood, motivation, and pain perception. Chemokines released by activated immune cells guide lymphocytes to the brain and meninges, where they influence learning and memory consolidation.
This mechanism explains why infection or immune activation commonly produces behavioral changes: fever, fatigue, anhedonia (loss of pleasure), and cognitive dulling are not merely side effects but coordinated outputs of the neuro-immune system responding to perceived threat. Understanding these pathways may inform treatment strategies for neuropsychiatric conditions triggered or worsened by immune activation, as covered in our New Studies section.
Psychological Stress Mobilizes Immune Cells Through Neural Pathways
Stress does not merely “feel bad”—it rewires the immune system in real time through defined neural circuits. The amygdala and prefrontal cortex sense psychological and social stress, activating the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis. According to the Nature Reviews Immunology analysis by Leuning, Gianeselli, Russo, and Swirski, these neural pathways release catecholamines (epinephrine and norepinephrine) and glucocorticoids that mobilize monocytes and neutrophils from the bone marrow into the bloodstream, shifting systemic inflammation. This process, termed “emergency hematopoiesis,” allows the immune system to mount rapid defense but, when chronically activated by sustained psychological stress, contributes to pathological inflammation in the brain and periphery.
Neurons and immune cells form a single, integrated network that senses stress, injury, infection, and social cues in real time, with neural signals directly shaping immune behavior and immune signals directly altering synaptic function, mood, and cognition.
— Leuning, Gianeselli, Russo, and Swirski, Nature Reviews Immunology (2025)
Microglia Bridge Neural and Immune Worlds
Microglia—the brain’s resident immune cells—occupy a unique position as integrators of both neural and immune signals. According to the Leuning review, microglia receive direct input from neurons through synaptic contact, neurotransmitter receptors, and neuropeptide signaling while simultaneously responding to immune signals including cytokines and danger-associated molecular patterns. This dual sensing allows microglia to regulate synaptic pruning (the elimination of weak or unnecessary connections), support learning and memory, and modulate vulnerability to neurodegeneration. When neuro-immune communication breaks down—such as during chronic inflammation, aging, or autoimmune disease—microglial dysfunction contributes to cognitive decline and neuropsychiatric symptoms.
What this means
Frequently asked questions
Can stress directly cause inflammation?
Yes. According to Leuning and colleagues’ Nature Reviews Immunology article, psychological stress activates neural pathways that release catecholamines and glucocorticoids, mobilizing immune cells and shifting systemic inflammation. Chronic stress maintains this inflammatory state, contributing to autoimmune disease, infection susceptibility, and neurodegenerative disease.
What are microglia and why do they matter?
Microglia are brain-resident immune cells that integrate both neural and immune signals. According to the review, microglia regulate synaptic pruning, support learning and memory, and prevent neurodegeneration. Microglial dysfunction is implicated in Alzheimer’s disease, depression, and cognitive decline.
How might understanding neuro-immune communication lead to new treatments?
By targeting specific communication pathways—such as vagal signaling, microglia activation, or stress-induced immune mobilization—researchers may develop therapies for conditions ranging from depression and anxiety to autoimmune disease and neurodegeneration. Several neuro-immune-targeted drugs are currently in clinical development.
The recognition that the brain and immune system form a unified, bidirectional network fundamentally reshapes how we understand health and disease. Future clinical practice will likely integrate assessment of both neural and immune function, with therapeutic interventions targeting the communication pathways that connect them. This represents a paradigm shift from treating the brain and immune system as separate biological domains toward viewing them as co-authors of physiology. Further research into the specificity and plasticity of neuro-immune signaling will be essential for translating these insights into precision interventions that address the root causes of complex diseases affecting both cognition and immunity.
Source: Leuning A, Gianeselli M, Russo SJ, Swirski FK. Connection and communication between the nervous and immune systems. Nature Reviews Immunology (2025)
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