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Neuroinflammation

Neuroinflammation is an inflammatory response within the (CNS) that involves the activation of resident immune cells, particularly and , and the production of inflammatory mediators such as cytokines (e.g., TNF-α, IL-1β, IL-6) and (e.g., MCP-1/). This process is triggered by endogenous factors like neuronal damage or protein aggregates, or exogenous insults including , , ischemia, or toxins, leading to a coordinated but potentially dysregulated immune reaction aimed at restoring . While initially adaptive, neuroinflammation can become chronic and detrimental, contributing to neuronal injury and synaptic dysfunction. Key cellular players in neuroinflammation include , the primary resident immune cells of the CNS, which rapidly respond to disturbances by shifting from a surveillant to an activated state, releasing pro-inflammatory signals via pathways like the inflammasome. Astrocytes support this response by modulating blood-brain barrier integrity and amplifying production, while oligodendrocytes may contribute to myelin repair or exacerbate damage under prolonged . Infiltrating peripheral immune cells, such as T cells and macrophages, can also enter the CNS during severe breaches, further intensifying the reaction through adaptive immunity. These interactions are influenced by environmental factors like , which upregulates hypoxia-inducible factor-1α (HIF-1α) to enhance inflammatory . Neuroinflammation exhibits a dual role: protective in acute phases, where it facilitates pathogen clearance, debris removal, and tissue repair through mechanisms like and neurotrophic factor release, but harmful in chronic states, promoting , blood-brain barrier disruption, and progressive neurodegeneration. For instance, microglial toward an M2-like supports resolution, whereas persistent M1-like activation drives . This balance is critical, as dysregulation is implicated in various CNS disorders. The process is prominently linked to neurodegenerative diseases, including Alzheimer's disease (where amyloid-β plaques and tau tangles trigger sustained microglial activation), Parkinson's disease (involving α-synuclein-induced inflammation), multiple sclerosis (characterized by autoimmune-mediated demyelination), amyotrophic lateral sclerosis (ALS), and Huntington's disease. Emerging evidence also connects neuroinflammation to psychiatric conditions, traumatic brain injury, and stroke, highlighting its broad pathophysiological impact. Therapeutic strategies increasingly target inflammatory pathways, such as NLRP3 inhibitors or anti-cytokine therapies, with ongoing clinical trials exploring their potential to mitigate disease progression.

Fundamentals

Definition and Characteristics

Neuroinflammation is defined as an inflammatory response localized within the central nervous system (CNS), encompassing the brain and spinal cord, characterized by the activation of immune processes, which primarily affect the CNS but can induce systemic effects such as fever through cytokine-mediated signaling, without the typical peripheral manifestations like widespread swelling. This response is primarily mediated by the production of cytokines, chemokines, reactive oxygen species, and other secondary messengers released by resident CNS cells, including glia and endothelial cells, as well as potential peripheral immune infiltrates in pathological states. Unlike systemic inflammation, which involves widespread peripheral immune activation, neuroinflammation is tightly regulated by the blood-brain barrier (BBB), which limits the influx of immune cells and soluble factors, thereby confining the process to the CNS and altering its physiological impact. A hallmark of neuroinflammation is its dual nature, serving both protective and deleterious functions. In its protective role, it facilitates the clearance of pathogens and cellular debris through and promotes tissue repair and maintenance, enabling adaptive responses to or . However, when dysregulated or persistent, it becomes harmful, contributing to neuronal damage through mechanisms such as , , and excessive release of pro-inflammatory signals, which can exacerbate CNS pathologies. Key physiological features include the predominant involvement of CNS-resident immune cells, such as and , which orchestrate the response, alongside the balanced release of pro-inflammatory (e.g., IL-1β, TNF-α) and mediators to modulate intensity. This process affects multiple CNS components, including neurons, , and vasculature, and can manifest in acute phases as a rapid defense or evolve into chronic states with broader implications for neural function.

Historical Development

The concept of neuroinflammation emerged in the early through histological observations of glial responses in the . In 1919, Spanish neurohistologist Pío del Río-Hortega published a seminal series of papers identifying as distinct resident immune cells, describing their morphology, distribution, and phagocytic function as "brain macrophages" capable of responding to pathological insults in neural tissue. These findings, built on staining techniques developed in the 1910s and expanded through the 1930s, marked the initial recognition of innate immune surveillance within the (CNS), shifting focus from neurons to supportive glial elements in . By the mid-20th century, research challenged the long-held view of the as an "immune-privileged" site isolated from systemic immunity. Pioneering experiments in the by demonstrated that allogeneic skin grafts implanted into rabbit brain parenchyma were rejected more slowly than in peripheral sites but not indefinitely, indicating active immune monitoring rather than complete isolation. This was further propelled in the and by studies on experimental allergic encephalomyelitis (EAE), an animal model of induced by antigens, which revealed T-cell infiltration and inflammatory demyelination in the CNS, underscoring the brain's capacity for adaptive immune responses under certain conditions. In the late 20th century, the identification of soluble inflammatory mediators in the CNS advanced understanding of neuroinflammation's biochemical basis. During the 1980s, proinflammatory cytokines such as interleukin-1 (IL-1) and (TNF) were detected in brain tissue and , linking peripheral immune signals to central neural functions like fever and neuroendocrine regulation. The 1990s highlighted neuroinflammation's role in infectious contexts, particularly HIV-associated neurocognitive disorders (HAND), where chronic microglial activation and cytokine release contributed to in up to 50% of infected individuals, even as antiretroviral therapies reduced overt . Entering the 21st century, neuroinflammation was increasingly recognized for its dual nature—protective in acute phases but detrimental when chronic. In the 2000s, studies elucidated this ambivalence, showing how initial microglial responses aid debris clearance but prolonged activation exacerbates neuronal damage via oxidative stress and excitotoxicity. A key milestone was the 2004 description of microglial priming, where prior insults sensitize microglia to exaggerated responses, amplifying inflammation in aging or diseased states. The 2010s integrated neuroimaging techniques, such as positron emission tomography (PET) with TSPO ligands, to visualize microglial activation in vivo, linking it to neurodegeneration in conditions like Alzheimer's disease. Recent advances in the have emphasized endogenous triggers of neuroinflammation, particularly damage-associated molecular patterns (DAMPs) from misfolded proteins that propagate glial activation and sterile inflammation. Post-2020 reviews have synthesized these insights, highlighting DAMPs like amyloid-β aggregates as amplifiers of storms in proteinopathies. Concurrently, 2023–2025 syntheses across neurodegenerative diseases have prioritized biomarkers, such as CSF YKL-40 and sTREM2, for tracking neuroinflammatory progression and evaluating therapeutic modulation.

Mechanisms of Neuroinflammation

Glial Cell Activation

Glial cells, particularly and , serve as the primary orchestrators of neuroinflammation within the (CNS), responding to injury or pathology by undergoing activation that shapes the inflammatory environment. , the resident macrophages of the CNS, maintain under normal conditions but rapidly activate in response to threats, adopting distinct phenotypes that influence . , meanwhile, contribute through reactive , a process involving morphological and functional changes that can either contain or propagate inflammatory signals. play a more indirect role, primarily through the release of debris that signals to other , amplifying the response. Microglia activation is characterized by a shift from a ramified, state to amoeboid morphologies, enabling and release. The describes -like pro-inflammatory states, which promote of debris, production of (ROS), and secretion of pro-inflammatory mediators, contrasting with M2-like states focused on tissue repair and debris clearance. However, this binary model oversimplifies the spectrum, as single-cell analyses reveal diverse, context-dependent states beyond M1/M2. In aging and chronic disease, become "primed," exhibiting exaggerated responses to stimuli, which heightens neuroinflammatory output and impairs resolution. For instance, primed in aged brains show upregulated pro-inflammatory , contributing to a sustained inflammatory milieu. Astrocytes undergo reactive upon , marked by upregulation of (GFAP) and proliferation, forming glial scars that isolate damaged areas. This process involves the release of such as and , which recruit immune cells and modulate the response. Reactive astrocytes exhibit dual roles: they can resolve by promoting barrier integrity and neurotrophic support, yet in chronic contexts, they may exacerbate neuro through excessive production and impaired functions. Oligodendrocytes contribute indirectly by generating myelin debris during injury, which contains immunogenic components like and sulfatides; this debris signals to and macrophages, triggering their and perpetuating while inhibiting remyelination. Activation of these glia is primarily triggered by damage-associated molecular patterns (DAMPs), such as high-mobility group box 1 () released from necrotic cells, which bind receptors (PRRs) like Toll-like receptors (TLRs) on glial surfaces. TLR engagement, particularly TLR4 by , initiates downstream signaling via the pathway, leading to nuclear translocation and transcription of inflammatory genes in and . Recent advances in single-cell sequencing (scRNA-seq) have illuminated microglial heterogeneity in the CNS, identifying subsets like disease-associated (DAMs) with pro-inflammatory signatures enriched in conditions involving neuroinflammation. The Human Microglia Atlas, integrating over 90,000 cells from diverse pathologies, reveals nine distinct subpopulations, including lipid-associated DAMs expanded in Alzheimer's and , underscoring the nuanced, disease-specific activation states beyond traditional classifications.

Inflammatory Mediators

Inflammatory mediators are soluble signaling molecules that orchestrate neuroinflammatory responses within the (CNS), primarily produced by resident glial cells and neurons. These molecules include cytokines, , and other bioactive compounds that amplify or resolve , influencing neuronal survival, synaptic function, and tissue repair. Their dysregulation can perpetuate chronic neuroinflammation, contributing to neurodegeneration without direct involvement in specific disease pathologies. Cytokines represent a core class of inflammatory mediators, with pro-inflammatory subtypes such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) driving acute responses. TNF-α, primarily secreted by activated , induces through glutamate release and promotes in neurons while eliciting fever-like systemic effects that manifest as hypothalamic responses in the CNS. IL-1β, also predominantly from , triggers similar fever induction, suppression, and impairments in learning and , alongside stimulating further production of TNF-α and IL-6 to amplify and . IL-6, produced by , , and neurons, fosters and microglial activation, exhibiting a dual role that can extend to in acute phases but often exacerbates chronic . In contrast, cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) promote resolution and . IL-10, derived from , suppresses pro-inflammatory cytokine release (e.g., IL-6, TNF-α, ) and enhances microglial of debris, thereby mitigating and supporting tissue repair. TGF-β, expressed by and neurons, inhibits signaling to downregulate immune responses, facilitates , and induces neuroprotective glial states that limit neuronal damage during . The balance between pro- and cytokines critically determines neuroinflammatory outcomes, with shifts toward pro-inflammatory dominance leading to persistent damage and impaired resolution. Chemokines, such as C-C motif ligand 2 (), facilitate the recruitment of peripheral immune cells into the CNS and modulate local . acts as a potent chemoattractant for monocytes and T cells across the blood-brain barrier, promoting their infiltration to sites of while also activating resident to contribute to reactive and sustained inflammatory signaling. Other mediators include components of the , eicosanoids, (ROS), and (NO), which collectively drive oxidative and anaphylactic responses. Anaphylatoxins C3a and C5a, generated from complement activation, bind G-protein-coupled receptors on and neurons to enhance microglial activation, induce neuronal , and amplify sensitization and neuro. Eicosanoids, particularly prostaglandins like (PGE2), are lipid-derived signals produced via enzymes in and ; PGE2 exacerbates by promoting release and amyloid precursor processing, though some derivatives like 15d-PGJ2 inhibit pro-inflammatory pathways via (PPARγ). ROS and NO contribute to , with excessive NO from inducible in activated promoting and neuronal death, while ROS disrupts and activates downstream inflammatory cascades. Key regulatory pathways underpin mediator production and action, including nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT). , activated by cytokines and Toll-like receptors in astrocytes and microglia, translocates to the nucleus to transcribe genes encoding pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6, thereby amplifying neuroinflammatory loops. The MAPK pathway, particularly p38-MAPK, integrates stress signals to phosphorylate transcription factors, enhancing cytokine production and tau hyperphosphorylation in inflammatory contexts. JAK/STAT signaling, triggered by cytokines such as IL-6, amplifies responses through phosphorylation and nuclear translocation, promoting glial polarization toward pro-inflammatory states, while negative feedback via suppressors of cytokine signaling (SOCS) and protein tyrosine phosphatases (PTPs) enables resolution. Recent insights from 2023–2025 highlight damage-associated molecular patterns (DAMPs) derived from misfolded proteins, such as amyloid-β, as potent activators of the . Amyloid-β aggregates function as DAMPs to prime in via Toll-like receptors and ROS, leading to caspase-1 activation and subsequent IL-1β release, which perpetuates neuroinflammation and neuronal damage independent of peripheral immune contributions. Inhibition of in preclinical models reduces this IL-1β-driven cycle, underscoring its role in chronic mediator dysregulation.

Peripheral Immune Interactions

During neuroinflammation, the blood-brain barrier (BBB) undergoes increased permeability, enabling the entry of peripheral immune cells such as T-cells and monocytes into the central nervous system (CNS). This disruption is mediated by upregulated adhesion molecules on endothelial cells, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), which facilitate leukocyte adhesion and transmigration across the BBB. Infiltrating peripheral immune cells include both adaptive and innate components, with CD4+ and CD8+ T-cells, B-cells, neutrophils, and macrophages crossing into the CNS . Adaptive immune cells like T- and B-cells contribute to autoimmune responses by promoting pro-inflammatory release and , potentially exacerbating tissue damage, while innate cells such as neutrophils provide rapid antimicrobial defense and macrophages offer dual roles in and repair. In certain contexts, monocyte-derived macrophages can limit pathological progression by clearing debris, highlighting their protective potential against unchecked inflammation. Peripheral-CNS crosstalk occurs through various signaling pathways, including influences from the gut microbiome, which modulates CNS inflammation via the by altering microbial metabolites that affect neural and immune signaling. The serve as a critical gateway for this interaction, housing lymphatic vessels that allow immune surveillance and the trafficking of peripheral leukocytes into the CNS while draining antigens and immune cells to . Cytokines from peripheral sources can briefly enhance this infiltration by chemoattracting cells to breach the . Regulatory T-cells (Tregs), particularly +Foxp3+ subsets, suppress excessive neuroinflammatory responses by inhibiting effector T-cell proliferation and production within the CNS. These cells maintain immune and prevent by promoting tolerance at the BBB interface. Studies on indicate sustained dysregulation of the peripheral-CNS immune axis, with persistent T-cell activation and impaired Treg function contributing to prolonged low-grade inflammation and neurological symptoms. Unlike peripheral inflammation, which benefits from robust lymphatic drainage for efficient immune , the CNS exhibits limited conventional lymphatic infrastructure, relying instead on meningeal and glymphatic pathways that can prolong inflammatory states if impaired. This structural difference alters the clearance of inflammatory mediators and immune cells, potentially leading to neuroinflammation due to delayed .

Causes and Triggers

Traumatic Injuries

(TBI) represents a major trigger of neuroinflammation, with a global annual incidence estimated at approximately 21 million cases as of 2021. The injury unfolds in two phases: primary damage from direct mechanical forces, such as impact or acceleration-deceleration, which causes immediate neuronal and vascular disruption, and secondary damage driven by ensuing inflammatory processes that exacerbate tissue loss. Microglial activation, as initial responders among glial cells, begins within hours of the insult, rapidly proliferating and adopting an amoeboid morphology to phagocytose debris. This activation coincides with release, culminating in a storm of proinflammatory signals that peaks between 1 and 3 days post-injury, contributing to widespread cellular dysfunction. Spinal cord injury (SCI), typically arising from contusion or compression mechanisms, similarly elicits robust neuroinflammation centered at the core, where necrotic tissue and disrupted vasculature amplify local immune responses. Inflammatory mediators released by activated and infiltrating leukocytes promote axonal die-back, wherein regenerating axons retract from the injury site over distances of several millimeters, hindering functional recovery. The inflammatory profile in SCI varies by spinal level; injuries, for example, show reduced systemic expression of both pro- and proteins compared to thoracic lesions, potentially due to greater autonomic dysregulation and broader physiological impact. The progression of neuroinflammation after traumatic CNS injuries follows a distinct temporal sequence, initiating with hemorrhage from ruptured vessels, which seeds the inflammatory milieu. This is rapidly followed by formation and blood-brain barrier breakdown, allowing peripheral infiltration and further mediator diffusion that sustains acute damage over hours to days. In the chronic phase, evolving over weeks to months, formation emerges as a fibrotic barrier, accompanied by persistent that maintains low-grade and impedes axonal regrowth. Recent investigations as of 2025 underscore the perpetuating role of damage-associated molecular patterns (DAMPs) from necrotic , which act as endogenous alarms to prolong microglial priming and production beyond the initial .

Infections and Autoimmunity

Neuroinflammation can be triggered by various infectious agents that invade the (CNS), leading to the activation of innate immune pathways. Viruses such as () and severe acute respiratory syndrome coronavirus 2 () are prominent examples, often causing or through direct neuronal infection or indirect immune-mediated damage. -1, in particular, establishes latent infections in sensory neurons and can reactivate to induce acute inflammation characterized by cytokine storms and glial activation. Bacterial infections, such as those caused by in , cross the blood-brain barrier to provoke , resulting in , cranial , or radiculoneuritis with persistent microglial activation even after bacterial clearance. Parasitic infections like , induced by , lead to chronic CNS cysts that sustain low-grade inflammation, altering neuronal function and promoting cytokine release from infected . These pathogens are primarily recognized by Toll-like receptors (TLRs) on and , which detect pathogen-associated molecular patterns (PAMPs) such as viral or bacterial lipopolysaccharides, initiating signaling cascades that amplify inflammatory responses. Autoimmune processes in neuroinflammation arise from a breakdown in , where the erroneously targets CNS self-antigens, often following an infectious trigger. This loss of tolerance can manifest as autoreactive T cells or autoantibodies attacking neural components, such as sheaths, leading to demyelination and persistent inflammation. A key mechanism is molecular mimicry, where microbial antigens structurally resemble CNS proteins, prompting cross-reactive immune responses; for instance, post-infectious Guillain-Barré syndrome involves antibodies against bacterial glycolipids that mimic gangliosides on peripheral nerves, with similar principles applying to CNS . In the CNS, this self-reactivity is exacerbated by infections that disrupt the blood-brain barrier, allowing peripheral immune cells to infiltrate and sustain neuroinflammatory cascades. The dynamics of neuroinflammatory responses to infections vary between acute and chronic phases. In acute scenarios, such as viral encephalitis from HSV, rapid cytokine production— including interferons and interleukins—facilitates pathogen clearance by recruiting immune effectors and activating glial cells, often resolving with minimal long-term damage if treated promptly. Conversely, chronic infections like HIV establish viral reservoirs in microglia and macrophages, leading to persistent low-level inflammation driven by ongoing viral replication and incomplete immune suppression, even under antiretroviral therapy. This chronic state promotes neuronal loss and cognitive deficits through sustained release of pro-inflammatory mediators. Studies on highlight specific neuroinflammatory patterns, with the virus entering the CNS via the , infecting sustentacular cells and triggering mucosal inflammation that extends to . Research from 2020 to 2025 has shown regionally heterogeneous microglial morphological changes in COVID-19 cases, including activated states in the associated with and long-term sequelae like and . Autoimmune CNS disorders, encompassing conditions like neuromyelitis optica and , are rare, with prevalence rates typically under 10 per 100,000 in high-income regions, potentially linked to increased post-infectious . Emerging 2025 insights underscore the role of the gut-brain axis in infection-triggered , where microbial from pathogens like or alters gut permeability, promoting systemic inflammation that breaches CNS tolerance via vagal and immune pathways. This axis facilitates neuroinflammation by enhancing signaling from the periphery to , potentially amplifying autoimmune responses in susceptible individuals.

Aging and Environmental Factors

Aging is a primary driver of neuroinflammatory priming in the , characterized by microglial , which involves reduced phagocytic capacity and a shift toward a pro-inflammatory . Senescent exhibit impaired clearance of debris and pathogens, leading to persistent activation and secretion of pro-inflammatory cytokines such as IL-1β and TNF-α. This is marked by morphological changes, including shortened processes and increased expression of (SASP) factors, contributing to a cycle of chronic low-grade known as inflammaging. Inflammaging arises from the accumulation of senescent cells, including neurons and , which release SASP components that perpetuate systemic and central , exacerbating age-related cognitive decline. Key mechanisms underlying aging-related neuroinflammation include the accumulation of damage-associated molecular patterns (DAMPs), such as oxidized , which act as endogenous triggers for glial . Oxidized phospholipids, generated through during , bind to receptors on and , promoting the release of inflammatory mediators and contributing to neuronal damage. Additionally, telomere shortening in glial cells, particularly , accelerates replicative and enhances pro-inflammatory responses to secondary stimuli, with aged showing heightened sensitivity to inflammatory cues compared to younger counterparts. Recent studies as of 2025 have also linked climate-related heat stress to neuroinflammation, where elevated temperatures induce glial and release, potentially worsening vulnerability in aging populations through mechanisms like blood-brain barrier disruption. Inflammaging is associated with elevated levels in the elderly , with pro-inflammatory markers such as IL-6 and TNF-α showing sustained increases that correlate with . Environmental factors further amplify neuroinflammatory processes in the . Exposure to , particularly fine (PM2.5), activates (TLR4) on , leading to pathway upregulation and increased production of pro-inflammatory cytokines like IL-6 and COX-2. Chronic dysregulates the hypothalamic-pituitary-adrenal () axis, resulting in elevated glucocorticoids that paradoxically prime for exaggerated inflammatory responses despite their intent. High-fat diets induce metabolic by promoting hypothalamic and , with lipid overload impairing mitochondrial function in and , thereby fostering a pro-inflammatory milieu. emerges as a modifiable environmental risk factor, with 2024 analyses indicating that prolonged obesity duration heightens brain across regions like the and , independent of age at onset. These aging and environmental influences interact synergistically with genetic factors, such as the APOE4 allele, which enhances susceptibility to neuroinflammation. APOE4 carriers exhibit exacerbated microglial activation and impaired in the , leading to greater amyloid-β accumulation and inflammatory signaling compared to non-carriers. This genetic-environmental interplay underscores how APOE4 amplifies the pro-inflammatory bias of senescent glia in response to stressors like or , accelerating neurodegenerative .

Role in Disease

Alzheimer's Disease

Neuroinflammation plays a central role in (AD) pathogenesis, contributing to neuronal damage and cognitive decline through interactions with core pathological hallmarks such as amyloid-β (Aβ) plaques and tangles. In AD, chronic activation of the innate immune response in the brain exacerbates neurodegeneration, with and as primary effectors. This inflammatory milieu not only amplifies plaque and tangle formation but also impairs synaptic function and promotes neuronal loss, distinguishing AD from other tauopathies by its dual amyloid-driven and sterile inflammatory components. Aβ plaques serve as damage-associated molecular patterns (DAMPs) that trigger activation via the , leading to the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β). This activation forms a vicious cycle where dysfunctional fail to efficiently phagocytose Aβ aggregates, resulting in persistent plaque accumulation and further priming. Studies in AD mouse models demonstrate that knockout reduces Aβ deposition and improves cognitive outcomes, underscoring the 's role in perpetuating this cycle. Similarly, hyperphosphorylated tangles induce sterile by acting as endogenous DAMPs, activating receptors on and promoting hyperphosphorylation and propagation through inflammatory signaling pathways like . Experimental evidence shows that sustained IL-1β overexpression exacerbates pathology independently of Aβ, linking to tangle spread and neuronal toxicity. Microglia in AD often become primed and adopt a disease-associated state, characterized by impaired Aβ clearance and the release of neurotoxic factors that induce dystrophic neurites around plaques. Genetic variants in TREM2, a microglial receptor essential for and survival, heighten AD risk by 2-4 fold and impair the transition to this protective yet dysregulated state, leading to unchecked inflammation. contribute through polarization into neurotoxic A1 phenotypes, which secrete complement factors and cytokines that amplify microglial , or neuroprotective A2 states that are diminished in AD brains. This glial dysfunction correlates with synaptic loss and hippocampal atrophy observed in postmortem AD tissue. In disease progression, neuroinflammation acts as an early driver before plaque formation, with upregulated cytokines detectable in preclinical stages, and later as an exacerbator that accelerates cognitive decline. Elevated (CSF) biomarkers, such as sTREM2 and cytokines including IL-1β and YKL-40, predict faster progression from to AD dementia, reflecting microglial and astrocytic activation. As of 2025, anti- therapies like , which targets Aβ protofibrils, have shown modulation of this inflammation by enhancing microglial-mediated clearance and reducing activity in clinical trials, offering potential to alter disease trajectories in early AD. TREM2 variants continue to be implicated in these responses, with heterozygous linked to diminished therapeutic efficacy in amyloid clearance.

Parkinson's Disease

Neuroinflammation plays a central role in (PD) pathogenesis, particularly through the involvement of misfolded α-synuclein aggregates in Lewy bodies, which function as damage-associated molecular patterns (DAMPs) to trigger l activation in the . These extracellular α-synuclein oligomers bind to receptors such as (TLR2) on , initiating a sterile inflammatory response that leads to the release of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α, as well as (ROS). This activation exacerbates loss in the , where general glial responses amplify the neurotoxic milieu. Furthermore, the prion-like propagation of α-synuclein pathology, involving cell-to-cell transmission of aggregates, is enhanced by this inflammatory environment, as activated fail to efficiently clear misfolded proteins and instead promote their spread across regions. In the , chronic inflammation driven by pro-inflammatory such as TNF-α directly contributes to toxicity and neuronal degeneration. Elevated TNF-α levels in brains activate TNF receptors on neurons, inducing and that impair synthesis and release. Concurrently, dysfunction disrupts their supportive role, as reactive shift from neuroprotective to pro-inflammatory states, failing to regulate glutamate uptake and defenses, thereby worsening and inflammation in the . This glial interplay in the accelerates the selective vulnerability of neurons, linking sustained signaling to motor deficits. The gut-brain axis provides a key peripheral entry point for inflammation in PD, where microbiome dysbiosis fosters intestinal barrier dysfunction and systemic immune activation that seeds central nervous system (CNS) events. Alterations in gut microbiota composition, characterized by reduced short-chain fatty acid-producing bacteria, promote ileal inflammation and elevated pro-inflammatory cytokines like IL-17 and IL-6, which permeabilize the blood-brain barrier and facilitate α-synuclein aggregation in the enteric nervous system before propagating to the brainstem. Fecal microbiota from PD patients transplanted into mouse models induces peripheral Th17 cell dysregulation and subsequent CNS microglial activation, underscoring how gut-derived inflammation initiates or amplifies synucleinopathy. Neuroinflammation in PD progresses through distinct stages, beginning in the prodromal phase with subtle glial changes detectable in at-risk individuals, such as those with or /GBA mutations, where early microglial priming in the precedes overt neuronal loss. In advanced stages, systemic elevation, including TNF-α and IL-6, correlates strongly with motor symptom severity, as measured by Unified Rating Scale scores, reflecting widespread immune dysregulation that drives disease progression. Recent 2025 insights highlight () imaging of (TSPO) as a non-invasive microglial marker for early detection, with increased TSPO binding in prodromal PD indicating subclinical inflammation in the before motor onset. Additionally, mutations, such as G2019S, enhance and NLRC4 activity in and peripheral immune cells, amplifying IL-1β production and linking genetic risk to heightened neuroinflammatory responses.

Amyotrophic Lateral Sclerosis

Neuroinflammation plays a pivotal role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder characterized by the selective degeneration of motor neurons. In ALS, microglia, the resident immune cells of the central nervous system, undergo a phenotypic shift toward a pro-inflammatory M1-like state, which exacerbates motor neuron vulnerability. This activation is prominently triggered by genetic mutations such as those in SOD1 and C9orf72, where mutant SOD1 induces microglial proliferation and release of pro-inflammatory cytokines like TNF-α and IL-1β, leading to non-cell-autonomous toxicity on motor neurons. Similarly, C9orf72 mutations, the most common genetic cause of ALS, result in dysregulated microglial lysosomes and heightened expression of inflammatory genes, promoting a neurotoxic environment. TDP-43 protein aggregates, a hallmark pathological feature in over 95% of ALS cases, further drive this microglial response by stimulating extracellular release that activates pro-inflammatory signaling pathways in microglia, thereby accelerating motor neuron loss. Astrocytes, another key glial cell type, contribute significantly to neuroinflammation in ALS through dysfunction that amplifies and cytokine-mediated damage. A critical aspect is the loss of excitatory transporter 2 (EAAT2), the primary glutamate in , which leads to elevated extracellular glutamate levels and subsequent overactivation of neuronal glutamate receptors, culminating in calcium overload and death. This EAAT2 downregulation is observed in both sporadic and familial ALS cases, correlating with disease severity and progression. Additionally, activated in ALS secrete pro-inflammatory cytokines such as TNF-α, which not only impair glutamate but also induce direct toxicity on s by disrupting mitochondrial function and promoting . These astrocytic changes highlight a non-cell-autonomous where glial dysfunction sustains a vicious cycle of and neurodegeneration. The inflammatory milieu in extends beyond the , incorporating a systemic component characterized by peripheral T-cell infiltration, particularly into the where degeneration is most pronounced. + and + T cells infiltrate the parenchyma in models and patients, contributing to hyperinflammation that is more severe in the compared to the , reflecting the disease's motor-specific . These infiltrating T cells, often in a pro-inflammatory state, interact with resident to amplify production and exacerbate neuronal damage, though their role can be context-dependent. This peripheral-central immune crosstalk underscores the broader immune dysregulation in , with elevated T-cell activation detectable in both blood and . Neuroinflammation in ALS exhibits a biphasic progression, initially protective through microglial clearance of debris and aggregates, but eventually turning deleterious as chronic activation predominates. In early disease stages, microglia adopt an M2-like that aids in of TDP-43 aggregates and mutant proteins, potentially delaying onset; however, as ALS advances, this shifts to sustained M1-like inflammation, promoting and demise. Biomarkers such as neurofilament light chain (), a marker of axonal damage, often correlate with inflammatory indicators like chitinase-3-like protein 1 (YKL-40), providing insights into disease progression and response to ; elevated levels in serum and CSF predict faster decline and reflect ongoing neuroinflammatory damage. This temporal dynamic emphasizes the therapeutic window for modulating glial responses. Recent advancements as of 2025 highlight the as a central hub in neuroinflammation, integrating genetic and environmental triggers to drive IL-1β-mediated toxicity. In patients and models, activation is elevated in and tissues, particularly linked to C9orf72 mutations where dipeptide repeats directly stimulate assembly, leading to and amplified cytokine release. Post-mortem analyses confirm upregulation in brain and , correlating with motor deficits. Concurrently, gene therapies targeting microglial genes, such as antisense against or C9orf72 in microglia-specific models, have shown promise in preclinical studies by reducing activity and extending survival; for instance, TBK1 modulation in mitigates neuroinflammation in /FTD models. These developments, including ongoing clinical trials for inhibitors, position -targeted interventions as emerging strategies to halt progression.

Multiple Sclerosis

Multiple sclerosis (MS) is a primary autoimmune demyelinating disorder of the , where neuroinflammation drives the destruction of sheaths and subsequent neurodegeneration, affecting an estimated 2.9 million people globally as of 2023. The disease often follows a relapsing-remitting course in its early stages, characterized by acute inflammatory flares that disrupt the blood-brain barrier and lead to focal demyelination in , while later progressive phases involve smoldering, persistent glial activation contributing to irreversible tissue damage. Environmental triggers, such as Epstein-Barr virus (EBV) infection, play a critical role in initiating adaptive immune dysregulation; a 2022 of over 10 million U.S. military personnel found that EBV infection precedes MS onset and elevates risk by 32-fold through molecular mimicry and B-cell transformation. Adaptive immunity in MS centers on autoreactive T-cells, particularly Th17 subsets, which cross the blood-brain barrier to target antigens like myelin basic protein, forming perivascular cuffs of lymphocytes and macrophages around venules in lesions. These T-cells secrete pro-inflammatory cytokines such as IL-17 and IFN-γ, amplifying local and recruiting further immune effectors. B-cells contribute by producing autoantibodies against (MOG) and other components, while also differentiating into plasma cells that sustain chronic humoral responses within the CNS. Innate immune responses complement adaptive mechanisms, with microglia forming nodules in early plaques that serve as sites of and initial demyelination in normal-appearing . Chronic active lesions, identifiable by their iron-rimmed appearance on susceptibility-weighted MRI, harbor smoldering driven by activated and macrophages that phagocytose debris and release oxidative stressors, perpetuating axonal injury even in the absence of overt relapses. Gray matter pathology in MS includes widespread cortical demyelination, particularly in subpial regions, which is closely linked to meningeal where tertiary lymphoid structures release soluble factors like TNF-α and lymphotoxin that diffuse into adjacent , promoting apoptosis and neuronal loss. Active across disease phases is commonly assessed via MRI, where enhancement signals blood-brain barrier leakage and acute immune cell infiltration in evolving lesions.

Other Neurodegenerative Diseases and Conditions

Neuroinflammation is also implicated in , where mutant protein aggregates trigger microglial activation and release, contributing to striatal neuronal loss and motor-cognitive deficits. In HD mouse models, NLRP3 inflammasome inhibition reduces inflammation and improves survival, highlighting its therapeutic potential. initiates acute neuroinflammation via microglial and astrocytic responses to mechanical damage, leading to blood-brain barrier disruption and secondary neurodegeneration. Chronic inflammation post-TBI is linked to increased risk of Alzheimer's and Parkinson's diseases, with elevated persisting for years. In , ischemic injury rapidly activates resident and recruits peripheral immune cells, exacerbating infarct expansion through pro-inflammatory mediators like IL-1β and TNF-α. While acute inflammation aids debris clearance, unresolved responses promote long-term .

Psychiatric and Neurodevelopmental Disorders

Neuroinflammation has been implicated in the pathogenesis of (MDD), where elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) correlate with symptom severity, particularly . Studies show that increased plasma IL-6 is associated with reduced gray matter volume in striatal regions, contributing to motivational deficits in affected individuals. In , microglial activation in the , often triggered by prenatal infections, disrupts and neuronal connectivity, leading to cognitive and psychotic symptoms. Postmortem and imaging evidence supports heightened microglial density in prefrontal areas of patients with , linking early-life immune challenges to long-term neuroinflammatory changes. In neurodevelopmental disorders, maternal immune activation (MIA) during pregnancy serves as a key model for , where elevated maternal cytokines like IL-6 and interferon-gamma cross the , altering fetal development and cytokine profiles in (CSF) of offspring. Animal models of MIA replicate ASD-like behaviors, including social deficits and repetitive actions, through persistent neuroinflammation in regions like the and . For attention-deficit/hyperactivity disorder (ADHD), low-grade inflammation is evident, with peripheral cytokine elevations and microglial changes contributing to and . Reviews indicate that ADHD patients exhibit systemic inflammatory markers, such as increased tumor necrosis factor-alpha, which may exacerbate attentional biases via hippocampal and prefrontal involvement. Mechanistically, neuroinflammation in these disorders involves hypothalamic-pituitary-adrenal (HPA) axis dysregulation, where chronic cytokine release amplifies glucocorticoid resistance and stress responses, perpetuating mood and behavioral alterations. Prenatal and perinatal triggers, including maternal infections and stress, initiate MIA, leading to offspring neuroinflammation and heightened vulnerability to psychiatric outcomes. Recent meta-analyses confirm elevated pro-inflammatory cytokines in MDD, with IL-6 levels significantly higher in first-episode patients compared to controls, supporting inflammation as a core feature. Unlike the focal, protein-aggregate-driven neuroinflammation in neurodegenerative diseases, psychiatric and neurodevelopmental conditions feature more subtle, diffuse microglial activation across distributed networks, potentially allowing greater reversibility through targeted interventions. Emerging evidence suggests that modulating this inflammation can ameliorate symptoms, as seen in preclinical models where anti-cytokine therapies restore balance and behavioral phenotypes. Recent studies on highlight its psychiatric sequelae, including and anxiety, driven by persistent neuroinflammation following infection, with elevated cytokines mirroring those in primary psychiatric disorders. Biomarkers like (CRP) aid in stratifying risk, as elevated levels predict neuroinflammatory burden and symptom persistence in MDD, , and . Aging may modulate these effects, as seen in late-life where cumulative inflammatory load exacerbates dysregulation.

Therapeutic Strategies

Pharmacological Interventions

Pharmacological interventions targeting neuroinflammation primarily focus on modulating immune responses in the (CNS), with an emphasis on drugs and biologics that inhibit pro-inflammatory pathways while minimizing disruption to protective mechanisms. These therapies aim to reduce microglial activation, release, and activity, which are central to neuroinflammatory processes in conditions like (AD), (PD), and (MS). Efficacy varies by disease stage and CNS penetration, with ongoing clinical trials evaluating safety and long-term outcomes. Recent advancements emphasize precision targeting to avoid immunosuppression-related risks. Anti-cytokine therapies, particularly monoclonal antibodies, have shown promise in dampening neuroinflammation by neutralizing key pro-inflammatory mediators. For instance, anti-IL-1β antibodies such as have been explored for CNS manifestations resembling cryopyrin-associated periodic syndromes (CAPS), where they reduce IL-1β-driven microglial activation and associated neuronal damage. These biologics selectively block signaling, preserving other immune functions, but require careful monitoring for CNS-specific effects. Microglia modulators represent another key class, aiming to reprogram or deplete activated to curb . , a with properties, inhibits microglial toward pro-inflammatory M1 states and has been tested in clinical trials for neurodegenerative diseases. In a phase III trial for mild AD, at 200 mg daily over 24 months showed no significant cognitive benefits. For and AD preclinical models, CSF1R inhibitors like PLX3397 (pexidartinib) deplete pathogenic , reducing amyloid-beta accumulation and pathology by up to 50% in mouse models, though human trials are pending due to concerns over microglial rebound. These agents highlight the dual role of , necessitating timed administration to avoid exacerbating neurodegeneration. Inflammasome inhibitors target the pathway, a critical amplifier of neuroinflammation involving IL-1β and IL-18 release. MCC950, a potent blocker, and its derivatives have demonstrated efficacy in preclinical models of and by suppressing caspase-1 activation and , with reductions in neuroinflammatory cytokines by 60-80%. As of 2024, phase II trials of inhibitors like DFV890 (a MCC950 analog) are evaluating safety in inflammatory conditions such as and coronary heart disease, with early data showing decreased peripheral inflammation markers that may potentially translate to . Challenges include optimizing CNS delivery to achieve therapeutic levels without . Broad-spectrum agents provide symptomatic relief in acute neuroinflammatory scenarios but face limitations in chronic use. Non-steroidal drugs (NSAIDs) like ibuprofen exhibit poor penetration, restricting their impact on CNS inflammation despite epidemiological evidence of reduced risk with long-term use. Corticosteroids, such as , are standard for acute (TBI), rapidly suppressing and storms, but prolonged administration risks hippocampal . Disease-specific immunomodulators like , approved for , sequester lymphocytes and indirectly attenuate neuroinflammation by reducing T-cell infiltration, with preclinical studies showing decreased microglial activation in models. TNF inhibitors like have been trialed in but failed due to increased risk of demyelination and CNS adverse events, leading to in demyelinating diseases. By 2025, biomarker-guided therapies have advanced pharmacological strategies, using tools like TSPO-PET imaging to quantify microglial activation and tailor interventions. TSPO-PET identifies neuroinflammatory hotspots, enabling personalized dosing of anti-inflammatory agents and predicting response in and trials, with sensitivity surpassing traditional CSF biomarkers; for example, intranasal foralumab reduced microglial activation in moderate patients as measured by TSPO-PET. Gene editing approaches, such as -Cas9 targeting TREM2 variants, are emerging in preclinical stages to enhance microglial of , potentially restoring homeostatic functions without broad . However, challenges persist, including off-target effects in delivery and variable permeability, underscoring the need for nanoparticle-enhanced formulations to improve efficacy. As of 2025, the phase III EMPHASIS has initiated to assess minocycline's efficacy in improving functional outcomes in acute ischemic patients.

Non-Pharmacological Approaches

Non-pharmacological approaches to mitigating neuroinflammation encompass lifestyle modifications, rehabilitative therapies, and environmental interventions that promote and reduce inflammatory processes in the . These strategies leverage the body's endogenous mechanisms to modulate microglial activation, production, and glial responses, offering accessible alternatives or adjuncts to medical treatments. Evidence from human clinical trials and preclinical models highlights their efficacy in diverse neurological contexts, including neurodegenerative and traumatic conditions, by enhancing and systemic pathways. Exercise, particularly aerobic activities, has demonstrated robust anti-inflammatory effects by suppressing microglial activation and reducing pro-inflammatory cytokines in the brain. In Parkinson's disease trials, chronic aerobic exercise lowered peripheral and central inflammatory markers, including a notable 30% reduction in interleukin-6 (IL-6) levels, correlating with improved motor function. Mechanisms involve the upregulation of brain-derived neurotrophic factor (BDNF) and myokines such as irisin, which inhibit inflammasome formation and promote microglial polarization toward an anti-inflammatory phenotype. Regular physical activity also attenuates neuroinflammation in aging models by strengthening the blood-brain barrier and modulating gut-derived inflammation. Dietary interventions, including anti-inflammatory regimens like the , suppress neuroinflammatory pathways through bioactive components. Rich in omega-3 polyunsaturated fatty acids from sources like fish and , this inhibits nuclear factor kappa B () activation in and reduces cytokine-driven responses in neurodegenerative contexts. The , characterized by high fat and low carbohydrate intake, similarly curbs neuroinflammation in by elevating that penetrate the blood-brain barrier, dampening microglial activation and neuronal excitability. Clinical studies in drug-resistant patients show that adherence to the correlates with decreased seizure frequency and lower levels of inflammatory markers, potentially via enhanced synthesis and reduced glutamate toxicity. Cognitive and behavioral strategies, such as mindfulness meditation and sleep optimization, target stress-induced neuroinflammation by altering immune signaling. Mindfulness-based interventions reduce circulating pro-inflammatory cytokines like IL-6 and tumor necrosis factor-alpha (TNF-α) in high-stress individuals, with long-term practitioners exhibiting blunted inflammatory responses to acute stressors. Chronic elevates TNF-α expression in the , exacerbating microglial priming and cognitive deficits; optimizing sleep duration and quality through behavioral protocols mitigates this by restoring noradrenergic modulation of immune cells and lowering systemic inflammation. Rehabilitative approaches, including task-specific training for (TBI) and (SCI), resolve reactive and promote neural repair. Motor rehabilitation post-SCI reduces expression of inflammatory factors like IL-1β and TNF-α while enhancing anti-inflammatory cytokine profiles, facilitating functional recovery. , involving complex sensory and social stimuli, attenuates neuroinflammation in aging and TBI models by decreasing astrocyte reactivity and microglial proliferation, leading to improved cognitive outcomes in preclinical studies. Emerging evidence as of 2025 underscores innovative applications, such as (VR)-assisted for post-stroke recovery, which enhances motor function and indirectly curbs inflammation through increased BDNF expression and reduced . modulation via in (MS) patients promotes regulatory T-cell activity and suppresses neuroinflammatory cascades, with recent trials showing decreased scores and lower levels after lactobacilli supplementation.