Neuroinflammation is an inflammatory response formed in the nervous system under conditions such as infection, injury, metabolic stress, abnormal protein deposition, or immune imbalance. Its core lies in the dynamic imbalance among microglia, astrocytes, peripheral immune cells, the blood-brain barrier, inflammatory mediators, and neuronal function.

Keywords: neuroinflammation; acute neuroinflammation; chronic neuroinflammation; primary neuroinflammation; secondary neuroinflammation; microglia; astrocytes; blood-brain barrier; inflammasome; neurodegenerative diseases

1 Research Entry Points for Neuroinflammation

1.1 Basic Concept of Neuroinflammation

Neuroinflammation is an immune-inflammatory response that occurs within the central nervous system or peripheral nervous system. In the central nervous system, microglia, astrocytes, oligodendrocytes, neurons, vascular endothelial cells, and peripheral infiltrating immune cells can all participate in this process. In the peripheral nervous system, Schwann cells, macrophages, sensory neurons, and immune cells can also form a local inflammatory microenvironment.

Neuroinflammation has dual effects. A short-term and controlled inflammatory response helps clear pathogens, necrotic cells, and injury debris, and promotes tissue repair. However, persistent, uncontrolled, or repeatedly activated inflammation may lead to synaptic dysfunction, myelin injury, axonal degeneration, neuronal death, and abnormal neural network remodeling.

1.2 Classification Requires Distinguishing the Time Axis from the Etiological Axis

“Acute, chronic, primary, and secondary” are not completely parallel and mutually exclusive classifications, but describe neuroinflammation from different perspectives. Acute and chronic emphasize inflammatory duration and dynamic process; primary and secondary emphasize inflammatory origin and etiological background. In actual diseases, these dimensions often overlap. For example, ischemic brain injury may first present as acute secondary neuroinflammation and later develop into chronic low-grade inflammation. Multiple sclerosis is a primary immune-mediated neuroinflammatory disease, but it can also show repeated acute attacks and chronic progression.

2 Four Major Classifications of Neuroinflammation

2.1 Acute Neuroinflammation

Acute neuroinflammation is usually caused by infection, trauma, ischemia-reperfusion, hemorrhage, toxic stimulation, or acute immune activation. It is characterized by rapid onset, high inflammatory intensity, rapid increases in cytokines and chemokines, and accompanying microglial activation, astrocytic response, altered blood-brain barrier permeability, and recruitment of peripheral immune cells.

Acute inflammation is not necessarily harmful. Moderate acute inflammation can clear necrotic cells, pathogens, and myelin/cellular debris, creating conditions for tissue repair. However, if the inflammatory response is too strong or continues to amplify, it can lead to cerebral edema, oxidative stress, excitotoxicity, neuronal death, and neurological deficits.

2.2 Chronic Neuroinflammation

Chronic neuroinflammation is a persistent low-grade or repeatedly activated inflammatory state that can last for months or even years. Its typical features include long-term reactive states of microglia and astrocytes, persistent elevation of TNF-α, IL-1β, IL-6, complement factors, ROS, and chemokines, and prolonged exposure of neurons and synapses to inflammatory stress.

Chronic neuroinflammation is commonly seen in Alzheimer’s disease, Parkinson’s disease, the progressive phase of multiple sclerosis, amyotrophic lateral sclerosis, chronic pain, diabetes-related neuropathy, and some neuropsychiatric disorders. Long-term inflammation interferes with synaptic plasticity, myelin stability, neurogenesis, and neural network activity, and serves as an important amplifying factor in the progression of neurodegenerative disease. In Alzheimer’s disease, neuroinflammation is considered closely associated with Aβ, Tau pathology, microglial responses, and complement-mediated synaptic changes [1].

2.3 Primary Neuroinflammation

Primary neuroinflammation refers to inflammatory responses mainly driven by immune abnormalities within the nervous system, exposure of neural tissue antigens, or local pathological processes in neural tissue. Representative diseases include multiple sclerosis, neuromyelitis optica spectrum disorder, autoimmune encephalitis, and some autoimmune peripheral neuropathies.

In primary neuroinflammation, T cells, B cells, antibodies, complement, microglia, and astrocytes can jointly participate in neural tissue injury. Pathological outcomes may include demyelination, axonal injury, synaptic dysfunction, neuronal death, or nerve conduction impairment. The key to this type of inflammation is not merely the “presence of inflammation,” but abnormal immune recognition or persistent attack against components of neural tissue.

2.4 Secondary Neuroinflammation

Secondary neuroinflammation is triggered by factors outside the nervous system. Common triggers include systemic infection, sepsis, metabolic disorders, obesity, diabetes, cardiovascular disease, tumor-related inflammation, excessive peripheral immune activation, and chronic stress. Peripheral inflammation can affect the nervous system through blood circulation, blood-brain barrier changes, vagus nerve-immune pathways, cytokine signaling, and neuroendocrine routes.

Secondary neuroinflammation is easily underestimated in experimental research. Even when peripheral infection or chronic metabolic inflammation does not directly invade brain tissue, it can still affect microglial status, synaptic function, and behavioral performance through IL-1β, TNF-α, IL-6, complement, and endothelial inflammatory signals.

3 Seven Key Mechanisms of Neuroinflammation

3.1 Immune Cell Activation and Recruitment

After neuroinflammation is initiated, microglia are among the first cells to sense damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), abnormal protein deposition, ATP release, ion homeostasis changes, and cellular debris signals. When microglia shift from a homeostatic surveillance state to a reactive state, they can release inflammatory factors, chemokines, ROS, and phagocytosis-related molecules, participating in pathogen clearance, debris engulfment, and inflammatory amplification.

Peripheral immune cells can also enter neural tissue through a damaged blood-brain barrier or blood-nerve barrier. Monocytes/macrophages participate in phagocytosis and inflammatory amplification. T cells and B cells participate in antigen recognition, cytotoxic injury, antibody production, and complement activation in autoimmune neuroinflammation. Microglia-mediated neurotoxicity is an important research direction in neuroinflammatory injury [2].

3.2 Release of Inflammatory Mediators

Activated immune cells and glial cells can release inflammatory mediators such as TNF-α, IL-1β, IL-6, IL-17, IFN-γ, CCL2, CXCL1, PGE2, NO, and ROS. These mediators can promote further immune cell recruitment, enhance inflammatory signal transduction, alter neuronal ion channels and synaptic transmission, and induce oxidative stress.

Inflammatory mediators do not act in isolation, but form a cascade network. IL-1β and TNF-α can enhance astrocytic and microglial reactivity. CCL2 can promote monocyte recruitment. ROS and NO can damage mitochondria, proteins, and lipid structures. PGE2 participates in pain sensitization and maintenance of inflammatory responses. If inflammatory mediator release is not terminated in time, neuroinflammation shifts from a defensive response to a chronic damaging factor.

3.3 Glial Cell Activation

Glial cell activation is a core component of neuroinflammation. Microglia are responsible for immune surveillance, phagocytosis, and inflammatory regulation. Astrocytes participate in ion homeostasis, neurotransmitter clearance, blood-brain barrier support, and metabolic coupling. Under inflammatory conditions, the two cell types can activate each other and jointly shape the inflammatory microenvironment.

After activation, astrocytes can release cytokines, chemokines, and complement-related molecules, and can also limit inflammatory spread and injury expansion through glial scar formation. However, excessive or long-term reactive astrocytes can affect synaptic homeostasis, neural regeneration, and local metabolic support. The role of astrocytes in nervous system pathology is not simply protective or damaging, but depends on stimulus type, disease stage, and tissue microenvironment [3].

3.4 Blood-Brain Barrier Disruption

The blood-brain barrier (BBB) is composed of brain microvascular endothelial cells, tight junctions, pericytes, astrocytic end-feet, and the basement membrane. It is an important structure for maintaining central nervous system homeostasis. Inflammatory factors, oxidative stress, matrix metalloproteinases, and endothelial activation can disrupt BBB integrity, allowing peripheral immune cells, antibodies, complement, and inflammatory mediators to enter the central nervous system more easily.

BBB disruption has two major consequences. First, peripheral inflammatory signals enter neural tissue and aggravate local inflammation. Second, the ionic, water, and protein environment in the brain changes, triggering cerebral edema, abnormal neuronal excitability, and neurological dysfunction. In multiple sclerosis, cerebral ischemia, infectious encephalitis, traumatic brain injury, and some neurodegenerative diseases, BBB abnormality is a key node of inflammatory amplification.

3.5 Neuronal Injury and Cell Death

Neuroinflammation can cause neuronal dysfunction and death through multiple pathways. TNF-α, IL-1β, ROS, NO, and complement can affect synaptic structure, mitochondrial function, membrane potential stability, and protein homeostasis. Impaired glutamate uptake and excitotoxicity can induce Ca²⁺ overload. Mitochondrial injury can cause ATP decline and further ROS elevation. Under long-term inflammatory stress, neurons may undergo apoptosis, necrosis-like death, pyroptosis-related injury, or other forms of cell death.

Neuronal injury can also amplify neuroinflammation in return. Injured neurons release ATP, HMGB1, mitochondrial DNA, abnormal proteins, and other DAMP signals, which can continue to activate microglia and astrocytes, forming a positive feedback loop of “neuronal injury-glial activation-inflammatory amplification.”

3.6 Imbalanced Glia-Neuron Interaction

Under homeostatic conditions, glial cells provide metabolic support, ion buffering, neurotransmitter clearance, and synaptic pruning for neurons. In neuroinflammatory states, this supportive interaction is disrupted. Activated microglia can affect synaptic structure through inflammatory factors, ROS, complement, and phagocytic signals. Reactive astrocytes can reduce glutamate clearance capacity, alter potassium buffering and metabolic support, and thereby affect neuronal excitability and synaptic plasticity.

Imbalanced glia-neuron interaction is a key step through which neuroinflammation shifts from an “immune response” to “neural network dysfunction.” In many neurodegenerative and neuropsychiatric diseases, even before large-scale neuronal death occurs, synaptic function and neural network activity may already be affected by the inflammatory microenvironment.

3.7 Neuroendocrine and Systemic Immune Regulation

Neuroinflammation is not only a local tissue event, but is also regulated by the neuroendocrine system. The hypothalamic-pituitary-adrenal (HPA) axis can regulate immune cell activation and inflammatory factor release through glucocorticoids. Short-term glucocorticoid elevation helps limit inflammation, whereas chronic stress, HPA axis abnormalities, or imbalanced glucocorticoid responses may lead to immunosuppression, inflammatory rebound, or maintenance of chronic low-grade inflammation.

The autonomic nervous system also participates in neuroinflammatory regulation. Sympathetic nerves can affect peripheral immune cells and vascular responses through norepinephrine. The vagus nerve-related cholinergic anti-inflammatory pathway can inhibit the release of some pro-inflammatory factors. Neuroendocrine and autonomic regulation connects local neuroinflammation with systemic immune status and represents an important mechanistic basis of chronic inflammation, stress-related neurological dysfunction, and neuropsychiatric symptoms.

4 Roles of Neuroinflammation in Disease Development

4.1 Neurodegenerative Diseases

In diseases such as Alzheimer’s disease, Parkinson’s disease, ALS, and Huntington’s disease, abnormal protein deposition, mitochondrial injury, oxidative stress, and neuronal death can all induce chronic neuroinflammation. Long-term activation of microglia and astrocytes can affect synaptic structure and neuronal survival through inflammatory factors, complement, and ROS. This type of inflammation is usually not a single initiating factor, but a key amplification step during disease progression.

Figure 1. Schematic illustration of glial activation and neuronal injury in Alzheimer’s disease-associated chronic neuroinflammation

4.2 Neuroimmune Diseases

Diseases such as multiple sclerosis, neuromyelitis optica spectrum disorder, and autoimmune encephalitis are centered on abnormal immune attack against neural tissue. T cells, B cells, antibodies, complement, and glial cells jointly participate in lesion formation, causing demyelination, axonal injury, synaptic dysfunction, or neuronal injury. These diseases are closer to the category of primary neuroinflammation.

4.3 Acute Nervous System Injury

In stroke, traumatic brain injury, spinal cord injury, and infectious encephalitis, acute neuroinflammation can participate in injury clearance at early stages, but excessive inflammatory amplification can cause secondary injury. BBB disruption, peripheral immune cell infiltration, oxidative stress, and cell death signaling are important mechanisms of neurological deterioration after acute injury.

4.4 Neuropsychiatric Diseases and Chronic Stress

In depression, schizophrenia, chronic stress-related disorders, and some cognitive dysfunctions, systemic low-grade inflammation, neuroendocrine abnormalities, and altered glial cell function can be observed. Inflammatory factors can affect neurotransmitter metabolism, synaptic plasticity, and neural network function, thereby participating in behavioral and cognitive abnormalities.

5 Product Selection Related to the Four Classifications and Seven Mechanisms of Neuroinflammation

6 Common Misinterpretations in Neuroinflammation Research

6.1 Treating All Inflammatory Responses as Harmful

Neuroinflammation has stage-dependent and functionally diverse effects. Early controlled inflammation can participate in clearance and repair, whereas persistent or excessive inflammation is more likely to cause neural injury. Research should distinguish inflammatory initiation, inflammatory amplification, inflammatory resolution, and repair stages.

6.2 Simply Dividing Microglia into M1/M2

The M1/M2 classification can be used for a preliminary description of inflammatory tendencies, but it cannot fully reflect the complex states of microglia in vivo. In actual neuroinflammation, microglia may simultaneously express molecules related to pro-inflammatory responses, phagocytosis, metabolic remodeling, antigen presentation, and repair. A more reasonable approach is to determine microglial state by combining time window, transcriptomic profile, spatial localization, and functional experiments.

6.3 Detecting Only Inflammatory Factors While Ignoring the Barrier and Cellular Source

Elevation of TNF-α, IL-1β, or IL-6 only indicates enhanced inflammatory signaling and cannot directly determine the source of inflammation or pathological outcome. Neuroinflammation research should also focus on cellular source, BBB status, glial activation, peripheral immune cell infiltration, and changes in neuronal function.

6.4 Equating Chronic Neuroinflammation with Prolonged Acute Inflammation

Chronic neuroinflammation is not simply an extension of acute inflammation. It results from the combined effects of sustained glial reactivity, immune-metabolic changes, abnormal synaptic homeostasis, and systemic inflammatory input. Its treatment and intervention strategies are also different from those for acute inflammation control.

Neuroinflammation can be classified into acute, chronic, primary, and secondary types according to temporal process and etiological source. Its mechanisms involve immune cell recruitment, inflammatory mediator release, glial cell activation, blood-brain barrier disruption, neuronal injury, imbalanced glia-neuron interaction, and abnormal neuroendocrine regulation. Accurate distinction of inflammation type, stage, and functional outcome is an important foundation for understanding neurodegenerative diseases, neuroimmune diseases, and nervous system injury.

References

[1] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol. 2015;14(4):388-405.

[2] Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci. 2007;8(1):57-69.

[3] Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7-35.

For more related articles, please see below:

[1] Cytokines and Inflammation

[2] Lipid Regulatory Mechanisms in Inflammation and Immune Responses