Neuroinflammation and immune-brain interactions

Current State

Neuroinflammation is recognized as a central player in the pathogenesis and progression of a wide array of neurological disorders, extending beyond traditional neurodegenerative diseases to include stroke, traumatic brain injury (TBI), and even psychiatric conditions like depression (Zhang et al., 2023; Candelario‐Jalil et al., 2022; Wu et al., 2023; Dinet et al., 2019). It involves complex interactions between resident CNS immune cells (microglia, astrocytes), peripheral immune cells, and the neurovascular unit (Jayaraj et al., 2019; Candelario‐Jalil et al., 2022). The gut-immune-brain axis is also emerging as a significant modulator of neuroinflammation and brain function (O’Riordan et al., 2025; Park et al., 2025).

Strongest Evidence

Compelling evidence demonstrates that protein aggregates, common in neurodegenerative diseases like Alzheimer's and Parkinson's, induce neuroinflammation, which in turn exacerbates aggregation and neurodegeneration (Zhang et al., 2023; Ransohoff et al., 2016). In ischemic stroke, acute neuroinflammation, while initially protective, can become detrimental, contributing to blood-brain barrier dysfunction and secondary brain injury (Candelario‐Jalil et al., 2022; Jayaraj et al., 2019). Microglia, the brain's resident immune cells, are consistently implicated across these conditions, with their activation states and functions being critical determinants of disease outcome (Luo et al., 2024; Walter et al., 2017).

Unresolved Uncertainties

Distinguishing between beneficial and detrimental aspects of neuroinflammation remains a key challenge (DiSabato et al., 2016). The precise mechanisms by which the gut microbiota influences CNS immunity and neuroinflammation are still being elucidated (O’Riordan et al., 2025; Park et al., 2025). Furthermore, developing targeted therapies that modulate specific inflammatory pathways without compromising essential immune functions or causing systemic side effects is complex. The optimal timing and duration of anti-inflammatory interventions are also unclear, as inflammation can be both a cause and a consequence of pathology.

Why the Topic Matters

Understanding neuroinflammation and immune-brain interactions is crucial for developing effective treatments for debilitating neurological diseases. Modulating these pathways offers promising therapeutic avenues, from targeting specific immune cell functions (Luo et al., 2024) to leveraging lifestyle interventions like exercise mimetics to restore immune homeostasis (Zhao et al., 2024). Given the high societal burden of neurodegenerative diseases, stroke, and mental health disorders, advancements in this field have the potential to significantly improve patient outcomes and quality of life.

Points of Agreement

• Neuroinflammation, characterized by the activation of resident immune cells like microglia and astrocytes, is a fundamental process in the central nervous system (CNS) and plays a crucial role in the pathogenesis of various neurological conditions, including neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, ALS), stroke, and traumatic brain injury (TBI) (Zhang et al., 2023; Ransohoff et al., 2016; Candelario‐Jalil et al., 2022; Dinet et al., 2019).
• Protein aggregates, a common feature in neurodegenerative diseases, can induce neuroinflammation, which in turn exacerbates further protein aggregation and neurodegeneration (Zhang et al., 2023).
• The gut microbiota-immune-brain axis is a significant modulator of neuroinflammation and overall brain function, with disruptions implicated in neurological and psychiatric disorders (O’Riordan et al., 2025; Park et al., 2025).
• Microglia, as the CNS-resident immune cells, are central to neuroinflammatory responses and are considered key therapeutic targets for neurological diseases due to their ability to influence the brain's immune microenvironment and interact with other glial cells and neurons (DiSabato et al., 2016; Luo et al., 2024).

Active Disagreements

• There is an ongoing debate regarding the precise balance between the detrimental and beneficial aspects of neuroinflammation. While often associated with neuronal injury and worse outcomes, particularly in chronic conditions, neuroinflammation also plays a role in tissue repair and removal of damaged cells, especially in acute phases like stroke (Jayaraj et al., 2019; Candelario‐Jalil et al., 2022).

Uncertain Claims

• The exact mechanisms by which genetic variations in CNS cells or peripheral inflammation initiate neuroinflammation earlier than protein aggregation in neurodegeneration are not fully elucidated (Zhang et al., 2023).
• While exercise is known to improve brain function and protect against neuroinflammation, the specific 'exercise mimetics' and their precise mechanisms for managing neuroinflammation in conditions like Alzheimer's disease require further investigation (Zhao et al., 2024).

Evidence Gaps

• More detailed understanding is needed on how different contexts (disease, injury, infection, stress) specifically alter the course and duration of neuroinflammatory responses and their corresponding physiological, biochemical, and behavioral consequences (DiSabato et al., 2016).
• Further research is required to fully characterize the effects of ethanol on microglial functioning and how microglial depletion precisely changes the brain's neuroimmune response to acute binge ethanol withdrawal (Walter et al., 2017).
• There is a need for more interdisciplinary research to advance the therapeutic implications of the gut microbiota-immune-brain axis in modulating neuroinflammation and treating related disorders (O’Riordan et al., 2025; Park et al., 2025).

Neuroinflammation, the inflammatory response within the CNS, is a complex process involving resident immune cells like microglia and astrocytes, as well as infiltrating peripheral immune cells, and is mediated by molecular factors such as cytokines and chemokines (DiSabato et al., 2016). This process is not merely a consequence but a crucial driver of various neurological conditions.

Neurodegenerative Diseases: Neuroinflammation is strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (Zhang et al., 2023; Ransohoff et al., 2016). Protein aggregates, a common pathological feature in these diseases, can induce neuroinflammation, which in turn exacerbates protein aggregation and neurodegeneration. Genetic variations in CNS cells or peripheral immune cells can also initiate neuroinflammation, leading to protein deposition (Zhang et al., 2023). In AD, neuroinflammation is a pathological hallmark, characterized by the stimulation of resident immune cells and the penetration of peripheral immune cells, facilitating amyloid-beta plaque deposition and tau hyperphosphorylation (Zhao et al., 2024).

Stroke: In ischemic stroke, neuroinflammation plays a dual role: it promotes further injury and neuronal cell death in the acute phase, but also contributes to recovery (Jayaraj et al., 2019; Candelario‐Jalil et al., 2022). Intense neuroinflammation during acute stroke is associated with blood-brain barrier (BBB) breakdown, neuronal injury, and worse neurological outcomes (Candelario‐Jalil et al., 2022).

Traumatic Brain Injury (TBI): TBI induces significant neuroinflammation that contributes to long-lasting sequelae, including cognitive decline, sensory-motor dysfunction, and psychiatric disorders, weeks, months, or even years after the initial injury (Dinet et al., 2019).

Psychiatric Disorders: Neuroinflammation is increasingly recognized in major depressive disorder (MDD), where it is involved through mechanisms such as dysregulation of neurogenesis in the dentate gyrus of the hippocampus (Wu et al., 2023).

Gut-Immune-Brain Axis: The gut microbiota-immune-brain axis is a key communication pathway where the microbiome influences neuroinflammation, brain function, and behavior (O’Riordan et al., 2025; Park et al., 2025). Disruptions in gut microbiota composition and barrier integrity are linked to various neurological and psychiatric disorders (Park et al., 2025).

Role of Microglia: Microglia, the CNS-resident immune cells, are central mediators of neuroinflammatory responses (DiSabato et al., 2016). They are implicated in many neurological diseases, becoming phagocytic and secreting immune molecules that shape the brain's immune microenvironment (Luo et al., 2024). Microglial dysfunction is also observed in conditions like alcoholism (Walter et al., 2017).

Therapeutic Implications: Modulating neuroinflammation is a promising therapeutic approach. Strategies include managing neuroinflammation to restore immune homeostasis and decrease neuronal damage in AD (Zhao et al., 2024), and leveraging engineered microglia as therapeutic delivery vehicles (Luo et al., 2024). Exercise mimetics are also being explored for their potential to combat neuroinflammation in AD (Zhao et al., 2024).

Evidence Strength: The evidence for the role of neuroinflammation in neurodegenerative diseases, stroke, TBI, and psychiatric disorders is strong, primarily supported by numerous review syntheses and clinical/translational studies. The involvement of microglia and the gut-immune-brain axis is also strongly supported. Limitations often involve the complexity of neuroinflammatory responses, which can be both detrimental and beneficial depending on context, course, and duration (DiSabato et al., 2016; Jayaraj et al., 2019).

Recent research underscores a significant shift in understanding neuroinflammation, moving beyond its traditional role as a mere consequence of neurological damage to recognizing it as a crucial, early, and active participant in disease progression. This evolving perspective highlights several key trends and emerging areas:

1. Early Onset and Causal Role in Neurodegeneration: Studies increasingly suggest that neuroinflammation can precede and even induce protein aggregation, a hallmark of neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic Lateral Sclerosis (ALS). This indicates that inflammation is not just a result but a critical player in the development of neurodegeneration (Zhang et al., 2023; Ransohoff, 2016).

2. The Gut-Immune-Brain Axis: A prominent emerging trend is the recognition of the gut microbiota-immune-brain axis as a major pathway influencing neuroinflammation. The microbiome's interaction with innate and adaptive immunity is implicated in neuroinflammation in both health and disease, suggesting therapeutic implications for gut-brain axis disorders (O’Riordan et al., 2025; Park et al., 2025). This bidirectional communication system is gaining significant attention for its profound effects on immune and neurological homeostasis.

3. Dual Nature of Neuroinflammation in Stroke: In ischemic stroke, neuroinflammation is increasingly viewed as a "friend and foe." While it plays a role in removing damaged tissue and preparing for repair, intense acute neuroinflammation can lead to blood-brain barrier (BBB) breakdown, neuronal injury, and worse outcomes (Candelario‐Jalil et al., 2022; Jayaraj et al., 2019). Understanding this delicate balance is crucial for therapeutic strategies.

4. Therapeutic Modulation of Microglia: Microglia, the CNS-resident immune cells, are central to neuroinflammation. Emerging methods focus on "taming" microglia, with engineered microglia showing promise in treating neurological diseases by modulating the brain's immune microenvironment (Luo et al., 2024). This includes strategies like microglial depletion to investigate their role in conditions like acute binge ethanol withdrawal (Walter et al., 2017).

5. Exercise Mimetics and Lifestyle Interventions: Exercise is recognized for its ability to improve brain function and protect against neuroinflammation. A novel strategy involves "exercise mimetics" to combat neuroinflammation and neurodegenerative conditions like Alzheimer's disease, aiming to restore immune homeostasis and reduce neuronal damage (Zhao et al., 2024).

6. Neuroinflammation in Mental Health and TBI: The correlation between neuroinflammation and major depressive disorder (MDD) is receiving increasing attention, particularly concerning its involvement in dysregulation of neurogenesis in the hippocampus (Wu et al., 2023). Furthermore, traumatic brain injury (TBI) is understood to cause long-lasting neuroinflammation, contributing to significant morbidity weeks, months, or years after the initial injury (Dinet et al., 2019).

7. Advanced Imaging Modalities: The importance of maintaining BBB integrity in CNS homeostasis is highlighted, with imaging modalities playing a crucial role in visualizing BBB dysfunction and neuroinflammatory responses, particularly in conditions like stroke (Candelario‐Jalil et al., 2022).

Overall, the trend is towards a more nuanced understanding of neuroinflammation, recognizing its context-dependent nature and exploring diverse therapeutic avenues, from gut microbiome modulation to direct cellular interventions and lifestyle-mimicking strategies (DiSabato et al., 2016).

Synthesis

Neuroinflammation is a complex immune response within the central nervous system (CNS) that plays a dual role in brain health and disease. While acute inflammation is a protective mechanism for tissue repair, chronic or dysregulated neuroinflammation is a key pathological driver in a wide range of neurological conditions (DiSabato et al., 2016). It is increasingly recognized not just as a consequence of neurodegeneration but as a crucial instigator, potentially preceding hallmark pathologies like protein aggregation in diseases such as Alzheimer's and Parkinson's (Zhang et al., 2023; Ransohoff et al., 2016). This process involves resident immune cells like microglia and astrocytes, as well as infiltrating peripheral immune cells, which together orchestrate a response that can either promote recovery or exacerbate injury (Jayaraj et al., 2019). The context, duration, and specific mediators of the inflammatory response determine its ultimate effect. In ischemic stroke, for instance, intense acute neuroinflammation is linked to blood-brain barrier (BBB) breakdown and worse outcomes (Candelario‐Jalil et al., 2022). Similarly, it is implicated in the pathophysiology of major depressive disorder by dysregulating hippocampal neurogenesis (Wu et al., 2023) and contributes to long-term cognitive decline after traumatic brain injury (Dinet et al., 2019).

Methods/Materials

Research in this field employs a variety of methods. Preclinical studies utilize animal models, such as acute binge ethanol administration in mice, to study microglial responses and the effects of their depletion (Walter et al., 2017). Models of Alzheimer's disease are used to test the efficacy of interventions like exercise mimetics in reducing neuroinflammation and synaptic dysfunction (Zhao et al., 2024). Imaging modalities are critical for visualizing BBB dysfunction and neuroinflammatory processes in vivo, particularly in the context of stroke research (Candelario‐Jalil et al., 2022). A significant emerging area involves genetic and cellular engineering, with researchers developing methods to create engineered microglia as potential therapeutic delivery vehicles to modulate the brain's immune microenvironment (Luo et al., 2024).

Applications

Understanding neuroinflammation opens several therapeutic avenues. Modulating microglial activity is a primary target, with strategies ranging from pharmacological inhibition to advanced cell-based therapies using engineered microglia to treat neurodegenerative and neuroautoimmune diseases (Luo et al., 2024). The gut-immune-brain axis represents another major therapeutic frontier; manipulating the gut microbiota could offer a novel way to control neuroinflammation and manage neurological and psychiatric disorders (O’Riordan et al., 2025; Park et al., 2025). Furthermore, lifestyle interventions are gaining traction, with 'exercise mimetics' being explored as a strategy to confer the neuroprotective and anti-inflammatory benefits of physical activity to combat conditions like Alzheimer's disease (Zhao et al., 2024).

Limitations

The primary limitation is the dual nature of neuroinflammation; therapeutic strategies must selectively inhibit detrimental inflammatory pathways without compromising the beneficial, reparative functions of the immune response (Jayaraj et al., 2019). The complexity of the gut-immune-brain axis, involving countless microbial species and metabolites, makes it difficult to pinpoint specific targets for consistent therapeutic outcomes (O’Riordan et al., 2025). Furthermore, translating findings from animal models to human patients remains a significant hurdle, as does overcoming the blood-brain barrier for effective drug delivery.

Update Triggers

This review should be updated upon the publication of clinical trial results for therapies targeting microglial modulation or the gut-brain axis. The development of novel, non-invasive imaging techniques capable of precisely tracking neuroinflammatory states in humans would also warrant a significant update. Additionally, breakthroughs in understanding the specific molecular switches that determine whether an inflammatory response is beneficial or detrimental will be critical.

Near-Term Work

• Mechanism Elucidation: Delineate the specific roles of microglia, astrocytes, and infiltrating immune cells in different disease contexts (e.g., stroke vs. Alzheimer's). Focus on distinguishing between beneficial (e.g., debris clearance) and detrimental (e.g., chronic inflammation) immune activities (Jayaraj et al., 2019).
• Gut-Brain Axis: Investigate how gut microbiota metabolites modulate neuroinflammatory pathways and blood-brain barrier (BBB) integrity, building on the concept of the microbiota-immune-brain axis (O’Riordan et al., 2025).
• Biomarker Development: Identify and validate fluid and imaging biomarkers for early detection and monitoring of neuroinflammation and BBB dysfunction post-stroke and in neurodegeneration (Candelario‐Jalil et al., 2022).

Validation Needs

• Model Systems: Validate findings from animal models in human-derived systems (e.g., iPSC-derived organoids, post-mortem tissue) to ensure clinical relevance.
• Therapeutic Timing: Establish the optimal therapeutic window for anti-inflammatory interventions, as the role of inflammation changes over the course of diseases like ischemic stroke.

Datasets and Benchmarks

• Integrated Datasets: Create multi-modal datasets combining imaging (MRI, PET), CSF/blood biomarkers, and clinical data from patients with stroke, MS, and neurodegenerative diseases.
• Standardized Assays: Develop benchmarked assays for quantifying key inflammatory mediators (cytokines, chemokines) and cell populations across different research labs.

Translational Barriers

• BBB Penetration: Overcoming the BBB remains a major hurdle for delivering targeted anti-inflammatory therapeutics to the CNS.
• Target Specificity: Many anti-inflammatory drugs have broad effects, risking immunosuppression. Developing therapies that specifically target detrimental pathways while preserving beneficial immune functions is critical.
• Disease Heterogeneity: The inflammatory profile varies significantly between patients and diseases, complicating a one-size-fits-all therapeutic approach (Zhang et al., 2023).

High-Value Experiments

• Longitudinal Studies: Conduct longitudinal studies in patient cohorts to map the temporal evolution of neuroinflammation using advanced imaging and fluid biomarkers, correlating these with disease progression.
• Targeted Modulation: Use genetic (e.g., CRISPR) or pharmacological tools in preclinical models to selectively inhibit or activate specific immune pathways (e.g., microglial phenotypes) to causally link them to neuroprotection or neurodegeneration.