Review article
Ukrainian Neurosurgical Journal. 2026;32(2):3-11
https://doi.org/10.25305/unj.350308
1 Department of Minimally and Laser Spinal Neurosurgery, Romodanov Neurosurgery Institute, Kyiv, Ukraine
2 Department of Neurobiochemistry, Romodanov Neurosurgery Institute, Kyiv, Ukraine
3 Neurosurgery Department, Military Medical Clinical Center of the Southern Region, Odesa, Ukraine
Received: 20 January 2026
Accepted: 27 February 2026
Address for correspondence:
Iryna G. Vasilyeva, Department of Neurobiochemistry, Romodanov Neurosurgery Institute, 32 Platona Maiborody st., Kyiv, 04050, Ukraine, e-mail: vigvasileva@gmail.com
Neuroinflammation is increasingly regarded as a key factor in the progression of neurological disorders. At the same time, in clinical practice it is often interpreted in an overly simplified manner and reduced to nonspecific activation of inflammatory responses.
Objective: to integrate contemporary molecular and cellular evidence in order to conceptualize neuroinflammation as a context-dependent and stage-determined biological program, and to delineate mechanistic determinants relevant to biomarker interpretation and therapeutic stratification.
Materials and methods: A narrative analysis of contemporary experimental, translational, and clinical studies focusing on innate protective mechanisms of the central nervous system was performed. The review emphasizes PRR-mediated recognition of pathogen-associated and damage-associated molecular patterns, intracellular inflammatory signaling pathways (NF-κB, MAPK, JAK/STAT, inflammasome complexes), mechanisms of inflammatory termination and resolution, and the regulatory role of the blood–brain barrier (BBB). Particular attention was given to data on glial cell biology, neurovascular unit signaling, biomarker profiles in cerebrospinal fluid and blood, and disease-specific neuroinflammatory phenotypes.
Results: The synthesized data indicate that neuroinflammation is not a uniform pathological state but represents a dynamic, multicomponent program shaped by the balance between initiation, amplification, resolution, and chronic persistence of inflammatory responses. Two closely interrelated components can be distinguished. The first is a resident innate neuroinflammatory program, predominantly mediated by microglia, astrocytes, and endothelial cells through PRR-dependent protective signaling mechanisms. The second is an adaptive immune component characterized by infiltration of peripheral immune cells and the development of antigen-specific responses. Disruption of resolution mechanisms, insufficient clearance of damage-associated signals, and sustained PRR activation promote the development of chronic neuroinflammation and neurodegenerative changes. The functional state of the BBB emerges as a critical modifier of neuroinflammatory dynamics, directly affecting biomarker interpretation, therapeutic access and clinical response.
Conclusions: Neuroinflammation should be conceptualized as a potentially modifiable biological program rather than a fixed pathological entity. Effective diagnostic and therapeutic strategies require context- and stage-specific stratification that takes into account the dominant inflammatory component, disease phase, etiological triggers, and the functional state of the BBB. Approaches aimed at limiting inflammatory amplification, restoring resolution mechanisms, and stabilizing barrier function are likely to offer greater translational potential than nonspecific anti-inflammatory suppression.
Keywords: neuroinflammation; pattern recognition receptors; innate protective mechanisms; microglia; blood–brain barrier; inflammasome; resolution of inflammation; biomarkers; translational neuroscience
Introduction
Inflammation is an evolutionarily conserved, regulated protective–adaptive tissue response to injury or threat to homeostasis, aimed at limiting damage, eliminating injured structures, and initiating repair. Under conditions of effective resolution, the inflammatory process culminates in functional tissue recovery, whereas dysregulation leads to its persistence and transition into a chronic pathological state [1, 2].
Inflammation of the central nervous system (neuroinflammation) has several clinically significant features determined by the structural isolation of the central nervous system (CNS), the presence of the blood–brain barrier (BBB), and the relatively limited involvement of adaptive immune cells. In contrast to peripheral tissues, inflammatory responses within the CNS parenchyma are predominantly mediated by glial cells—microglia, astrocytes, and oligodendrocytes—whereas neutrophil–monocyte mechanisms become dominant mainly under conditions of substantial disruption of barrier integrity [3, 4]. Microglia integrate immune, trophic, and synaptic regulatory functions, which accounts for the close relationship between inflammatory activation and neuronal dysfunction [4].
From a clinical perspective, neuroinflammation is associated with a high functional “cost”: even moderate or prolonged activation of inflammatory mechanisms may be linked to impaired synaptic transmission, excitotoxicity, reduced neuroplasticity, and progression of neurodegenerative changes. These processes underlie cognitive, motor, and neuropsychiatric disturbances across a broad spectrum of acute and chronic CNS disorders.
At the molecular level, neuroinflammation engages universal inflammatory response programs, including activation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs), signaling pathways involving NF-κB, MAPK, and JAK/STAT, as well as production of key pro-inflammatory mediators, including IL-1β (interleukin-1β), TNF-α (tumour necrosis factor-α), IL-6, and HMGB1 (High Mobility Group Box 1) [5]. Of clinical relevance, these signaling cascades and regulatory circuits determine the balance between inflammatory resolution with tissue recovery and chronic persistence, the latter being associated with progressive neurodegeneration and poorer prognosis [2].
Thus, neuroinflammation should be regarded as a context-dependent manifestation of a universal inflammatory program under CNS conditions, characterized by specific cellular mechanisms, substantial influence on disease course, and potential relevance as a target for diagnostic and therapeutic interventions.
Given the clinical heterogeneity of neuroinflammation and its decisive role in determining the course and prognosis of CNS disorders, understanding the molecular and cellular mechanisms underlying inflammatory activation is of major importance. Analysis of the signaling cascades, cellular interactions, and regulatory circuits governing the initiation, maintenance, and resolution of neuroinflammation is a necessary prerequisite for the identification of diagnostic biomarkers and the development of targeted therapeutic strategies [6].
The aim of this review was to examine the key mechanisms of neuroinflammation with emphasis on their clinical and translational significance.
Mechanisms of neuroinflammation
Initiation of neuroinflammation: PAMP/DAMP → PRR
Neuroinflammation is initiated in response to a broad spectrum of injurious stimuli, including infectious agents, ischemia/reperfusion, oxidative stress, mechanical trauma, and accumulation of pathological protein aggregates during neurodegeneration [7, 8]. Under these conditions, disruption of tissue homeostasis is accompanied by the release of two major classes of inflammatory inducers: pathogen-associated molecular patterns (PAMPs) during infection and damage-associated molecular patterns (DAMPs) during sterile injury [7]. These signals are detected by PRRs.
Of clinical importance, PRR activation may occur before the appearance of overt structural abnormalities on neuroimaging, making these early molecular triggers promising targets for biomarker-based risk stratification and early therapeutic intervention [8,9].
Pattern recognition receptors in the CNS (PRR-mediated sensing)
A central event in the initiation of neuroinflammation is the activation of PRRs, which provide early sensing of both infectious agents and sterile tissue injury within the central nervous system (CNS). The principal classes of PRRs include: (1) TLRs, transmembrane receptors that recognize PAMPs and DAMPs in the extracellular space and within endosomes; (2) NLRs, cytoplasmic sensors whose activation leads to inflammasome assembly and subsequent release of pro-inflammatory cytokines; (3) RIG-I-like receptors (RLRs), intracellular sensors responsible for recognition of viral RNA; and (4) scavenger receptors (SRs), involved in the clearance of modified lipoproteins, amyloid peptides, and cellular debris [10–13].
Within brain tissue, microglia are the principal cellular carriers of PRRs. Astrocytes and oligodendrocytes also express a broad spectrum of PRRs and participate not only in the initiation of inflammatory responses but also in barrier regulation and reparative processes [3, 4]. Data obtained in recent years indicate the expression of specific PRRs on neurons, enabling them to respond to danger signals, modulate intracellular stress responses, and influence cell survival and synaptic function [8].
From a functional perspective, PRR-mediated sensing in the CNS serves as a mechanism of continuous surveillance of cerebral homeostasis. Activation of TLRs and RLRs predominantly mediates the initiation and amplification of inflammatory signaling, whereas NLR-dependent inflammasome pathways convert these signals into an effector response. In a clinical and translational context, PRR signaling is regarded as one of the earliest and potentially modifiable levels of the neuroinflammatory response, thereby creating opportunities for selective therapeutic strategies aimed at modifying disease course rather than merely suppressing inflammatory symptoms.
Chronic or dysregulated PRR activation is associated with the establishment of persistent inflammatory circuits and plays an important role in the pathogenesis of multiple sclerosis and other chronic neuroinflammatory and neurodegenerative conditions [6, 7]. In this context, PRRs and their downstream signaling cascades are considered key pathogenetic mechanisms, as well as promising therapeutic targets and biomarkers of neuroinflammatory activity [6, 7].
Molecular transduction of inflammatory signals in the nervous system
The inflammatory response in the nervous system is formed through coordinated activation of families of innate (sensory) immune receptors, including TLRs, NLRs, RLRs, and SRs. These sensors exhibit cell-specific expression patterns: the highest levels are characteristic of microglia, whereas astrocytes, oligodendrocytes, and neurons demonstrate a more limited and context-dependent profile, reflecting their involvement in homeostatic and stress-associated responses.
Toll-like receptors
TLRs are localized on the plasma membrane and within endosomes, where they mediate the primary recognition of PAMPs and DAMPs. Their activation is accompanied by recruitment of the adaptor proteins MyD88 or TRIF, which, through the TAK1 signaling node, activate the IKK/NF-κB and MAPK/AP-1 signaling axes. As a result, transcription of pro-inflammatory mediators (IL-1β, IL-6, TNF-α), inflammatory enzymes (cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS)), chemokines, and adhesion molecules is induced. Importantly, TLR signaling provides the “priming” phase of the inflammatory response by promoting synthesis of inactive precursor forms of IL-1β and IL-18, as well as upregulation of inflammasome components. A distinct role is played by the TRIF-dependent axis (predominantly associated with TLR3 and TLR4), which leads to induction of type I interferons and secondary activation of JAK/STAT signaling. The combination of primary NF-κB/MAPK activation and secondary JAK/STAT amplification forms stable autocrine and paracrine feedback loops that determine response duration and the potential for chronic neuroinflammation [14–16].
NOD-like receptors
NLRs are cytoplasmic sensors that respond to intracellular PAMPs and DAMPs and play a key role at the post-transcriptional stage of the inflammatory response. Activation of inflammasome complexes, particularly NLRP3, leads to recruitment and activation of caspase-1, which mediates proteolytic maturation of pro-IL-1β and pro-IL-18 into their biologically active forms. Thus, NLRs integrate danger signals with the mechanisms of secretion of key cytokines and determine the intensity of the effector phase of inflammation [17, 18].
RIG-I-like receptors
RLRs are intracellular sensors of viral RNA that function in the cytosol and mediate the antiviral component of innate immunity. Following binding to viral RNA, these receptors interact with the adaptor MAVS (mitochondrial antiviral signaling protein), localized on the outer mitochondrial membrane, thereby initiating activation of the transcription factors IRF3/IRF7 and NF-κB. This leads to synthesis of type I interferons and pro-inflammatory cytokines. Functionally, RLR signaling converges with TLR pathways at the level of NF-κB and may modulate inflammasome responses through mitochondrial mechanisms, thereby linking antiviral defense with the broader inflammatory program [19].
Scavenger receptors (SRs)
SRs mediate the clearance of modified lipids, amyloid peptides, and cellular debris, thereby playing a crucial role in maintaining tissue homeostasis. In the nervous system, they are most prominently expressed in microglia, where they execute phagocytic functions, whereas in other CNS cell types they are primarily involved in regulating metabolism and the local microenvironment. Functionally, SRs act as co-receptors, enhancing the efficiency of TLR and RLR activation through ligand delivery, and they also activate the NLR inflammasome via the induction of lysosomal and mitochondrial stress [20].
Signal integration
Thus, TLRs and RLRs are responsible for the initiation and transcriptional priming of the inflammatory response; NLRs mediate the maturation and secretion of key cytokines; whereas SRs modulate the intensity and spatial organization of these processes. The coordinated interplay among these receptor systems forms a multilayered signaling network that determines the nature of neuroinflammation—ranging from an acute protective response to chronic degenerative changes [2, 4, 6, 7].
Clearance of PAMPs and DAMPs as a critical stage in the resolution of neuroinflammation
Although PRR activation and the production of proinflammatory mediators define the initiation and amplification of the neuroinflammatory response, its resolution critically depends on the efficient cellular clearance of PAMPs and DAMPs. In the CNS, this process is primarily carried out by microglia through phagocytosis, efferocytosis, and receptor-mediated clearance, including mechanisms involving SRs, complement-dependent pathways, and lysosomal degradation [21]. Astrocytes also contribute by facilitating metabolic detoxification, spatial containment of damaged areas, and maintenance of barrier integrity, whereas neurons predominantly serve as passive targets rather than active effectors of clearance [22]. With effective elimination of molecular danger patterns, PRR signaling gradually subsides, promoting a shift of glial cells toward homeostatic and reparative programs. Conversely, impaired clearance of PAMPs/DAMPs leads to their persistence within tissues, sustains chronic PRR activation, and establishes self-perpetuating inflammatory circuits that drive the transition of neuroinflammation into a chronic maladaptive state [23].
Table 1 summarizes the principal PRR platforms involved in neuroinflammation, the relationships between their dominant signaling pathways and functional consequences, and the molecular biomarkers of activation, resolution, and chronicization. The presented scheme illustrates the organization of innate neuroinflammatory signaling (from transcriptional priming to the effector cytokine response) and demonstrates how dysregulated PRR activation contributes to the establishment of persistent inflammatory circuits and neurodegenerative progression.
Table 1. Integration of prr signaling with resolution, chronicity, and biomarker profiles of neuroinflammation
|
PRR / Platform |
Key signaling pathway |
Functional outcome |
Activation markers |
Resolution markers |
Chronicity markers |
|
TLR (TLR2/4/3/7/9) |
MyD88 / TRIF → NF-κB, MAPK, IRF |
Transcriptional initiation of inflammation (Signal 1) |
TNF-α, IL-6, pro-IL-1β, CXCL8, IFN-β |
IL-10, TGF-β, SOCS1/3 |
PersistentTNF-α, IL-6, STAT3- signature |
|
RLR (RIG-I, MDA5) |
MAVS → IRF3/7, NF-κB |
Antiviral state + priming |
IFN-α/β, ISG (MX1, OAS1) |
↓IFN-I, normalization of ISGs |
Chronic IFN signature, ISG persistence |
|
NLR (NLRP3) |
Inflammasome → caspase-1 |
Maturation of IL-1β/IL-18 (Signal 2) |
IL-1β, IL-18, ASC-specks |
Caspase-1 inhibition, ↓IL-1β |
Recurrent activation of IL-1β/IL-18 |
|
Scavenger receptors (CD36, SR-A1) |
Phagocytosis → lysosomal / mitochondrial stress |
Clearance or maintenance of the DAMP loop |
oxLDL, β- amyloid, HMGB1 |
Efferocytosis, ↓DAMPs |
Cellular debris, oxLDL, sCD36 |
|
Microglia |
PRR- integration |
Cellular hub of neuroinflammation |
sTREM2, YKL-40 |
Normalization of sTREM2 |
Chronically ↑YKL-40 |
|
Astrocytes |
TLR/NF-κB, JAK/STAT |
Modulation of the microenvironment |
GFAP (CSF), CCL2 |
↓GFAP, IL-10 |
Sustained ↑GFAP, CCL2 |
|
Impaired clearance |
Persistence of PAMPs/DAMPs → PRR reactivation |
Maintenance of self-amplifying inflammatory circuits |
HMGB1, mtDNA, oxLDL |
Absent or reduced |
IL-6, IL-1β, YKL-40, GFAP, sCD36 |
Note: Signal 1 refers to transcriptional priming; Signal 2 denotes inflammasome activation. ASC specks are aggregates of ASC (apoptosis-associated speck-like protein containing a CARD), indicating inflammasome assembly.
Termination of inflammation and mechanisms of neuroinflammatory response chronicity
The inflammatory response is neither a linear nor a self-sustaining process. Under physiological conditions, it is accompanied by the activation of termination and resolution mechanisms aimed at restoring tissue homeostasis. Crucially, the same signaling platforms that initiate inflammation (TLRs, RLRs, and NLRs) may, under specific conditions, trigger negative regulatory circuits that limit the duration and intensity of the response.
Mechanisms of inflammatory termination and resolution
Termination of inflammation involves the coordinated attenuation of PRR signaling, switching of transcriptional programs, and activation of specialized anti-inflammatory pathways. Key events include the induction of negative regulators of TLR signaling (A20, SOCS, IRAK-M), which suppress NF-κB and MAPK activation [24]; increased production of anti-inflammatory cytokines (primarily IL-10 and TGF-β), which shift the phenotype of microglia and astrocytes toward reparative programs [25, 26]; activation of specialized pro-resolving mediators (resolvins, protectins, and maresins), which reduce chemotaxis and support debris clearance [27]; inhibition of inflammasome activity and reduced secretion of IL-1β and IL-18 [28]; and efficient phagocytosis of apoptotic cells and damage-associated products (efferocytosis), which itself generates anti-inflammatory signals [29].
Within the nervous system, these processes are accompanied by the transition of microglia from a pro-inflammatory to a homeostatic or reparative state, normalization of astrocytic reactivity, and stabilization of neuron–glia interactions [30].
Features and molecular determinants of chronicity. Inflammatory chronicity develops when resolution mechanisms are insufficient or impaired. The principal processes indicating transition to the chronic phase include persistent PRR activation in response to endogenous DAMPs (mitochondrial DNA, oxidized lipids, aggregated proteins) [31]; sustained NF-κB and JAK/STAT activation, maintaining autocrine and paracrine inflammatory loops [14]; stable or recurrent activation of the NLRP3 inflammasome with chronic production of IL-1β and IL-18 [32]; impaired SR-mediated clearance of cellular and myelin debris, which sustains low-grade inflammation [30]; and phenotypic fixation of microglia and astrocytes in a reactive state accompanied by loss of homeostatic functions [33, 34].
Triggers of the neuroinflammatory process: etiological and infectious context
Despite the universality of PRR-dependent signaling mechanisms, the clinical interpretation of neuroinflammation is impossible without consideration of the etiological triggers that initiate or sustain inflammatory processes within the central nervous system. Such triggers include both infectious agents and sterile injurious factors capable of activating common PRR-mediated inflammatory programs (Table 2).
Table 2. Contextual relationship between etiological triggers and neuroinflammatory profiles
|
Context |
What is determined? |
Purpose |
|
Suspected virus-induced inflammation |
Viral DNA/RNA in the CSF |
Confirmation of active or persistent infection |
|
Latent or previous infection |
IgG, CSF/serum antibody index |
Identification of a potential trigger of chronicization |
|
IFN signature without a clearly defined etiology |
Antibodies + ISGs |
Differentiation of sterile inflammation from infection-associated inflammation |
|
Impaired BBB integrity |
Antibodies + Q-albumin |
Accurate interpretation of antibody penetration |
Of particular clinical importance are persistent or latent neurotropic infections, especially herpesviruses, which may remain within nervous tissue for prolonged periods and undergo periodic reactivation without overt manifestations of acute infection. Under such conditions, chronic or intermittent activation of RLR-dependent and TLR-dependent pathways occurs, sustaining low-grade neuroinflammation even in the absence of clinically manifest infectious disease [35].
In this context, the neuroinflammatory response may be characterized by a persistent interferon signature, inflammasome activation, and progressive BBB dysfunction, thereby shaping a phenotype of chronic neuroinflammation. Detection of viral DNA/RNA or specific antibodies in cerebrospinal fluid (CSF) and blood enables differentiation between infection-mediated neuroinflammatory processes and sterile inflammation, which is of fundamental importance for the selection of an appropriate therapeutic strategy [35].
Interpretation of PRR-mediated inflammatory signatures without etiological verification of infectious triggers may result in the misclassification of neuroinflammatory conditions and, consequently, in suboptimal therapeutic decisions [35]. Therefore, etiological verification of the pathogen or its immunological markers should be considered a contextual modifier in the interpretation of PRR activation, biomarker profiles, and treatment response.
An important, yet often underestimated, component in the initiation and maintenance of the neuroinflammatory process is inflammatory activation of the CNS vascular endothelium. Endothelial cells express PRRs and are capable of directly responding to systemic and local danger signals, including PAMPs and DAMPs. Their activation is accompanied by the induction of NF-κB-dependent and MAPK-dependent programs, expression of adhesion molecules (ICAM-1, VCAM-1), and secretion of cytokines and chemokines [36, 37].
Endothelial inflammation leads to BBB dysfunction, disruption of tight junctions, and increased permeability. Even in the absence of overt structural barrier damage, the endothelium may translate systemic inflammation into a central immune response by activating microglia and modulating neuronal function through paracrine mechanisms [36, 37].
The blood–brain barrier as a modifier of the neuroinflammatory process
The blood–brain barrier is not merely a physical boundary between the systemic circulation and the CNS, but also an active modifier of the neuroinflammatory process (Table 3), determining the intensity, spatial organization, and dynamics of the inflammatory response within the CNS. Its functional state changes in response to PRR-dependent signaling, as well as to the effects of cytokines, interferons, and products of tissue injury [38].
Table 3. Therapeutic strategies in the context of the functional state of the blood–brain barrier and expected biomarkers
|
Therapeutic approach |
Functional state of the BBB |
Expected therapeutic effect |
Expected biomarkers (CSF/Blood) |
|
Corticosteroids |
Acutely disrupted, “open” |
Reduction of edema and suppression of cytokine release |
↓IL-6, ↓TNF-α, ↓MMP-9, ↓ Q-albumin |
|
Anti-IL-1β/anti-TNF therapy |
Partially disrupted |
Reduction of inflammasome and NF-κB activation |
↓IL-1β, ↓IL-18, ↓CRP |
|
JAK/STAT inhibitors |
Dysfunctional, with chronic activation |
Limitation of autocrine/paracrine inflammatory loops |
↓STAT3-сигнатура, ↓IL-6 |
|
Antiviral therapy/IFN modulation |
Acute inflammation with RLR activation |
Reduction of viral load and normalization of IFN |
↓IFN-α/β, ↓ISG (MX1, OAS1) |
|
Nanoparticles, exosomes |
Relatively intact |
Improved drug delivery to the CNS |
Targeted therapeutic markers, stable Q-albumin |
|
Intranasal delivery |
Intact |
BBB bypass with localized therapeutic action |
Local changes in biomarkers without systemic activation |
During the acute phase of inflammation or CNS injury, the BBB is frequently characterized by increased permeability, creating a therapeutic “window” while simultaneously contributing to secondary injury. In subacute and chronic conditions, the BBB may appear structurally restored while remaining functionally dysregulated, with impaired transport and persistent endothelial activation. This reduces the effectiveness of systemic therapy and increases the risk of inflammatory chronicization [39, 40].
Context-dependent manifestation of neuroinflammation across different nosologies. Although the fundamental mechanisms of neuroinflammation are universal, their manifestation differs substantially depending on the specific nosology (Table 4). In neurotrauma and ischemia, acute DAMP-mediated responses predominate, whereas neurodegenerative diseases are characterized by prolonged low-symptom glial activation [41]. In CNS tumors, neuroinflammation is integrated with an immunosuppressive microenvironment [42], while in chronic pain and neuropsychiatric disorders it is associated with disrupted neuron–glia communication [43, 44].
Table 4. Nosology-specific patterns of blood–brain barrier dysfunction and mechanisms of neuroinflammation
|
Nosology |
Typical BBB State |
Dominant Mechanisms of Inflammation |
Therapeutic Implications |
Clinically Relevant Biomarkers (CSF/Blood) |
|
Acute traumatic brain injury |
Severely disrupted, transiently “open” |
TLR/NLR activation, inflammasome activation, matrix metalloproteinases |
Utilization of the therapeutic window; control of secondary injury |
↑Q-albumin, ↑IL-1β, ↑TNF-α, ↑MMP-9, ↑GFAP |
|
Ischemic stroke |
Phase-dependent disruption (acute → partially restored) |
TLR4, NLRP3, oxidative stress |
Phase-oriented therapy; limitation of reperfusion injury |
↑IL-6, ↑IL-1β, ↑S100B, ↑CRP |
|
Neuroinfections (viral) |
Disrupted |
RLR → IFN-I, TLR3/7 |
Antiviral therapy adjusted for BBB permeability |
↑IFN-α/β, ↑ISG (MX1), ↑CXCL10 |
|
Multiple sclerosis |
Chronically dysfunctional |
TLR/NLR signaling, adaptive immunity |
Immunomodulation combined with control of barrier function |
↑OCB, ↑CXCL13, ↑GFAP |
|
Alzheimer’s disease |
Functionally impaired (low-grade leakage) |
SR (CD36), NLRP3, DAMPs |
Targeting resolution pathways and clearance mechanisms |
↑Aβ, ↑p-tau, ↑YKL-40, ↑sTREM2 |
|
Parkinsonism |
Partially disrupted |
Microglial activation, NLRP3 |
Modulation of neuroinflammation |
↑IL-6, ↑α-synuclein, ↑GFAP |
|
Chronic posttraumatic encephalopathy |
Dysregulated, incompletely restored |
Persistent NF-κB activation, DAMPs |
Combined therapy (anti-inflammatory + pro-resolution) |
↑IL-6, ↑GFAP, ↑NfL |
|
Neuro-Oncology (perifocal inflammation) |
Locally disrupted |
TLR/SR signaling, cytokine microenvironment |
Local drug delivery and edema control |
↑VEGF, ↑IL-8, ↑GFAP |
Discussion
This review summarizes current concepts of neuroinflammation as a multilevel biological process arising from the interaction between sensing mechanisms, intracellular signal transduction, regulation of barrier structures, and the tissue-specific vulnerability of the CNS. Neuroinflammation is not a homogeneous pathological condition. Rather, it should be regarded as a dynamic, phase-specific program whose clinical consequences are determined by the balance among initiation, amplification, resolution, and BBB-mediated modulation [1–3].
Conceptually, it is important to distinguish at least two interconnected, yet non-identical, levels of immune activity within the CNS. The first level is the innate neuroinflammatory program, implemented predominantly by resident cells (microglia, astrocytes, and endothelial cells of the neurovascular unit) and initiated through PRR signaling in response to infectious and sterile danger signals. The second level is the adaptive immune component, characterized by the involvement of peripheral T cells and B cells, the development of clonally specific responses, and tissue-mediated injury, which may coexist with the neuroinflammatory program or predominate in certain nosologies and phases of the process [1,4]. Such stratified differentiation is required not to “divide” a single process, but to ensure accurate interpretation of biomarkers, prognosis, and therapeutic strategy selection.
The principal conclusion is that activation of the innate neuroinflammatory program is not inherently pathological. PRR-dependent signaling provides a surveillance mechanism enabling rapid detection of infectious and sterile threats. Short-term activation of Toll-like and NOD-like receptors supports anti-infectious defense, clearance of damaged structures, and tissue adaptation. Pathological consequences arise predominantly not from activation itself, but from impaired termination and resolution, resulting in prolonged signaling, fixation of the reactive glial phenotype, and progressive tissue dysfunction [2,4]. At the same time, under conditions of a substantial contribution from the adaptive immune component (with clonal specificity and cellular infiltration), mechanisms of injury and therapeutic targets may shift from regulation of resident glia and PRR-associated pathways toward control of cellular migration, antigen-mediated responses, and effector functions of T cells and B cells [1].
The analyzed data emphasize the importance of distinguishing between the initiation phase and the persistence (chronicization) phase of neuroinflammation. At early stages, PRR-mediated activation reflects an adaptive response to acute injury, whereas prolonged activation maintained by autocrine and paracrine cytokine loops drives the transition toward a chronic, maladaptive process. This has direct translational implications: nonspecific suppression of early stages of the innate program may weaken protective mechanisms, whereas interventions aimed at controlling amplification, persistence, and/or enhancing resolution possess greater disease-modifying potential [2,4]. If the adaptive immune component predominates in a clinical context, the critical factors become the recruitment and retention phases of effector cells within the CNS, as well as the barrier mechanisms determining the intensity of infiltration. In such circumstances, the same “cytokine” signature may have different implications depending on whether it results from resident glial activation or accompanies a clonally mediated immune response [1, 3].
The BBB plays a distinct integrative role in shaping the neuroinflammatory process. It should be regarded not merely as an obstacle to drug penetration, but also as an active regulator of neuroinflammatory dynamics and therapeutic responsiveness. Inflammation-induced alterations in endothelial tight junctions, transporter expression, and neurovascular interactions transform the CNS microenvironment, influencing both immune communication and the availability of pharmacological agents. Accordingly, variability in the functional state of the BBB may explain differences in clinical responses to identical interventions depending on disease stage or individual patient characteristics [3,5–7]. Within the proposed stratification framework, the BBB has a dual role: it modulates the intensity of the innate neuroinflammatory program through endothelial activation and neurovascular signaling, while simultaneously determining the magnitude of the adaptive immune component by controlling the migration and penetration of peripheral immune cells into the CNS [3, 6].
This approach challenges the simplified use of inflammatory biomarkers. Elevated cytokine levels in blood or CSF do not invariably reflect active neuroinflammation and cannot automatically be interpreted as therapeutic targets. Interpretation should be integrative, taking into account disease phase, etiological context, and BBB status. It should also include assessment of which component predominates — the resident (innate) neuroinflammatory program or the infiltrative (adaptive immune) component. Without such differentiation, the risk of erroneous clinical decisions and overestimation of “inflammatory activity” as the sole basis for therapy substantially increases [1, 7, 8].
The situation is further complicated by the interaction between infectious and sterile triggers. Infectious insults may leave a prolonged immunological “imprint,” lowering the activation threshold of the innate neuroinflammatory program during subsequent noninfectious injury. Conversely, sterile processes may mimic infectious responses through shared PRR-mediated pathways. This highlights the limitations of a purely etiological approach and substantiates the need for mechanistically grounded stratification in diagnosis and treatment [2, 3].
From a therapeutic perspective, the findings of this review support a paradigm shift from generalized anti-inflammatory suppression toward context-dependent and resolution-oriented strategies. Targeting key signaling nodes, stabilizing barrier functions, and stimulating active resolution mechanisms may provide superior outcomes compared with nonspecific cytokine blockade. At the same time, the timing of intervention is critically important: therapies effective during early stages may lose efficacy or even exert adverse effects once persistence of the neuroinflammatory program has been established or when the infiltrative adaptive immune component predominates, under which therapeutic priorities and biomarker targets may differ [1, 2, 4, 7].
Overall, neuroinflammation should be considered a modifiable biological program rather than a fixed pathological entity. Its clinical significance arises from the interaction of molecular signals, cellular responses, and barrier mechanisms that evolve over time. Recognition of this dynamic nature and of the stratification between the resident (innate) neuroinflammatory program and the infiltrative (adaptive immune) component constitutes a necessary prerequisite for translating fundamental knowledge into effective clinical strategies [1, 3].
Conclusions
Neuroinflammation is a complex, dynamic, and context-dependent biological process that extends beyond the simplified concept of local or systemic overproduction of pro-inflammatory mediators. The data summarized in this review indicate that the clinical significance of neuroinflammation is determined not by immune activation itself, but by the balance among initiation, amplification, resolution, and barrier regulation of the inflammatory response within the CNS.
A fundamental aspect is the distinction between two interconnected components of the neuroinflammatory process. The first is the innate neuroinflammatory program, implemented predominantly by resident CNS cells (microglia, astrocytes, and endothelial cells of the neurovascular unit) and initiated through PRR-dependent sensing of infectious and sterile danger signals. Its short-term activation constitutes an essential component of immune surveillance, adaptation to injury, and tissue repair. The second is the adaptive immune component, characterized by the involvement of peripheral T cells and B cells, clonally specific responses, and tissue-mediated effects that may coexist with the innate program or predominate in certain nosologies and phases of the process.
The pathological consequences of neuroinflammation arise primarily from impaired mechanisms of termination and resolution of the innate program and/or from its sustained integration with the adaptive immune component. Persistent signaling, fixation of the reactive glial phenotype, formation of self-sustaining cytokine loops, and barrier dysfunction transform an initially protective response into a chronic pathological process underlying neurodegeneration, cognitive impairment, and reduced functional recovery.
The blood–brain barrier is a key modifier of both components of neuroinflammation. On the one hand, it regulates the intensity and spatial organization of the innate neuroinflammatory program through endothelial activation and neurovascular communication; on the other hand, it determines the magnitude and nature of the adaptive immune component by controlling the penetration and retention of peripheral immune cells within the CNS. The functional state of the BBB directly influences both biomarker interpretation and the variability of clinical responses to therapy.
The presented findings highlight the limitations of universal anti-inflammatory strategies. Effective treatment requires a context-dependent and stage-specific approach that takes into account: (1) the predominance of the innate neuroinflammatory program or the adaptive immune component, (2) the phase of the process (initiation or persistence), (3) the functional state of the BBB, and (4) the biomarker profile in blood and CSF. Under such conditions, priority should be given to strategies aimed not only at suppressing inflammation, but also at controlling amplification, stabilizing barrier functions, and stimulating active resolution mechanisms.
Overall, neuroinflammation should be regarded as a modifiable and potentially manageable biological program rather than a fixed pathological entity. A clear distinction between the resident (innate) neuroinflammatory program and the infiltrative (adaptive immune) component provides the methodological basis for accurate biomarker interpretation, personalization of therapeutic interventions, and effective translation of fundamental mechanisms into clinically meaningful solutions.
Disclosure
Acknowledgments
Certain fragments of the text were generated or edited with the assistance of ChatGPT (OpenAI, San Francisco, USA). All statements were verified by the authors.
Conflict of Interest
The authors declare no conflict of interest.
Funding
This research received no external funding.
References
1. Gong T, Liu L, Jiang W, Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20(2):95–112. https://doi.org/10.1038/s41577-019-0215-7
2. Nathan C. Nonresolving inflammation redux. Immunity. 2022;55(4):592–605. https://doi.org/10.1016/j.immuni.2022.03.016
3. Escartin C, Galea E, Lakatos A, O'Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhäuser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, Cunningham C, Deneen B, De Strooper B, Díaz-Castro B, Farina C, Freeman M, Gallo V, Goldman JE, Goldman SA, Götz M, Gutiérrez A, Haydon PG, Heiland DH, Hol EM, Holt MG, Iino M, Kastanenka KV, Kettenmann H, Khakh BS, Koizumi S, Lee CJ, Liddelow SA, MacVicar BA, Magistretti P, Messing A, Mishra A, Molofsky AV, Murai KK, Norris CM, Okada S, Oliet SHR, Oliveira JF, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Pérez-Nievas BG, Pfrieger FW, Poskanzer KE, Quintana FJ, Ransohoff RM, Riquelme-Perez M, Robel S, Rose CR, Rothstein JD, Rouach N, Rowitch DH, Semyanov A, Sirko S, Sontheimer H, Swanson RA, Vitorica J, Wanner IB, Wood LB, Wu J, Zheng B, Zimmer ER, Zorec R, Sofroniew MV, Verkhratsky A. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021 Mar;24(3):312-325. https://doi.org/10.1038/s41593-020-00783-4
4. Prinz M, Masuda T, Wheeler MA, Quintana FJ. Microglia and Central Nervous System-Associated Macrophages-From Origin to Disease Modulation. Annu Rev Immunol. 2021 Apr 26;39:251-277. https://doi.org/10.1146/annurev-immunol-093019-110159
5. Kawai T, Akira S. Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins. EMBO Mol Med. 2011 Sep;3(9):513-27. https://doi.org/10.1002/emmm.201100160
6. Hampel H, Caraci F, Cuello AC, Caruso G, Nisticò R, Corbo M, Baldacci F, Toschi N, Garaci F, Chiesa PA, Verdooner SR, Akman-Anderson L, Hernández F, Ávila J, Emanuele E, Valenzuela PL, Lucía A, Watling M, Imbimbo BP, Vergallo A, Lista S. A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease. Front Immunol. 2020 Mar 31;11:456. https://doi.org/10.3389/fimmu.2020.00456
7. Zhang W, Xiao D, Mao Q, Xia H. Role of neuroinflammation in neurodegeneration development. Signal Transduct Target Ther. 2023 Jul 12;8(1):267. https://doi.org/10.1038/s41392-023-01486-5
8. Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, Amit I, Audinat E, Bechmann I, Bennett M, Bennett F, Bessis A, Biber K, Bilbo S, Blurton-Jones M, Boddeke E, Brites D, Brône B, Brown GC, Butovsky O, Carson MJ, Castellano B, Colonna M, Cowley SA, Cunningham C, Davalos D, De Jager PL, de Strooper B, Denes A, Eggen BJL, Eyo U, Galea E, Garel S, Ginhoux F, Glass CK, Gokce O, Gomez-Nicola D, González B, Gordon S, Graeber MB, Greenhalgh AD, Gressens P, Greter M, Gutmann DH, Haass C, Heneka MT, Heppner FL, Hong S, Hume DA, Jung S, Kettenmann H, Kipnis J, Koyama R, Lemke G, Lynch M, Majewska A, Malcangio M, Malm T, Mancuso R, Masuda T, Matteoli M, McColl BW, Miron VE, Molofsky AV, Monje M, Mracsko E, Nadjar A, Neher JJ, Neniskyte U, Neumann H, Noda M, Peng B, Peri F, Perry VH, Popovich PG, Pridans C, Priller J, Prinz M, Ragozzino D, Ransohoff RM, Salter MW, Schaefer A, Schafer DP, Schwartz M, Simons M, Smith CJ, Streit WJ, Tay TL, Tsai LH, Verkhratsky A, von Bernhardi R, Wake H, Wittamer V, Wolf SA, Wu LJ, Wyss-Coray T. Microglia states and nomenclature: A field at its crossroads. Neuron. 2022 Nov 2;110(21):3458-3483. https://doi.org/10.1016/j.neuron.2022.10.020
9. Deczkowska A, Weiner A, Amit I. The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway. Cell. 2020 Jun 11;181(6):1207-1217. https://doi.org/10.1016/j.cell.2020.05.003
10. Pascual M, Calvo-Rodriguez M, Núñez L, Villalobos C, Ureña J, Guerri C. Toll-like receptors in neuroinflammation, neurodegeneration, and alcohol-induced brain damage. IUBMB Life. 2021 Jul;73(7):900-915. https://doi.org/10.1002/iub.2510
11. Kodi T, Sankhe R, Gopinathan A, Nandakumar K, Kishore A. New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation. J Neuroimmune Pharmacol. 2024 Feb 29;19(1):7. https://doi.org/10.1007/s11481-024-10101-5
12. Stok JE, Vega Quiroz ME, van der Veen AG. Self RNA Sensing by RIG-I-like Receptors in Viral Infection and Sterile Inflammation. J Immunol. 2020 Aug 15;205(4):883-891. https://doi.org/10.4049/jimmunol.2000488
13. Garcia-Bonilla L, Sciortino R, Shahanoor Z, Racchumi G, Janakiraman M, Montaner J, Zhou P, Anrather J, Iadecola C. Role of microglial and endothelial CD36 in post-ischemic inflammasome activation and interleukin-1β-induced endothelial activation. Brain Behav Immun. 2021 Jul;95:489-501. https://doi.org/10.1016/j.bbi.2021.04.010
14. Ageeva T, Rizvanov A, Mukhamedshina Y. NF-κB and JAK/STAT Signaling Pathways as Crucial Regulators of Neuroinflammation and Astrocyte Modulation in Spinal Cord Injury. Cells. 2024 Mar 26;13(7):581. https://doi.org/10.3390/cells13070581
15. Andronie-Cioara FL, Ardelean AI, Nistor-Cseppento CD, Jurcau A, Jurcau MC, Pascalau N, Marcu F. Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression. Int J Mol Sci. 2023 Jan 18;24(3):1869. https://doi.org/10.3390/ijms24031869
16. Müller L, Di Benedetto S, Müller V. The dual nature of neuroinflammation in networked brain. Front Immunol. 2025 Aug 20;16:1659947. https://doi.org/10.3389/fimmu.2025.1659947
17. He KL, Yu X, Xia L, Xie YD, Qi EB, Wan L, Hua XM, Jing CH. A new perspective on the regulation of neuroinflammation in intracerebral hemorrhage: mechanisms of NLRP3 inflammasome activation and therapeutic strategies. Front Immunol. 2025 Feb 27;16:1526786. https://doi.org/10.3389/fimmu.2025.1526786
18. Darabniya A. The neuroinflammatory triumvirate: NF-κB, NLRP3, and mTOR in spinal cord injury. Inflammopharmacology. 2025 Oct;33(10):5769-5775. https://doi.org/10.1007/s10787-025-01952-2
19. Dorrity TJ, Shin H, Gertie JA, Chung H. The Sixth Sense: Self-nucleic acid sensing in the brain. Adv Immunol. 2024;161:53-83. https://doi.org/10.1016/bs.ai.2024.03.001
20. Ding S, Choi SH, Miller YI. Amyloid β-Induced Inflammarafts in Alzheimer's Disease. Int J Mol Sci. 2025 May 10;26(10):4592. https://doi.org/10.3390/ijms26104592
21. Hassan H, Rawlinson C, Lan YL, Jenkins S, Chen R. Microglia-Mediated Phagocytosis in Alzheimer's Disease: Mechanisms, Heterogeneity, and Therapeutic Insights. Biomolecules. 2025 Nov 20;15(11):1629. https://doi.org/10.3390/biom15111629
22. He L, Zhang R, Yang M, Lu M. The role of astrocyte in neuroinflammation in traumatic brain injury. Biochim Biophys Acta Mol Basis Dis. 2024 Mar;1870(3):166992. https://doi.org/10.1016/j.bbadis.2023.166992
23. Roh JS, Sohn DH. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Netw. 2018 Aug 13;18(4):e27. https://doi.org/10.4110/in.2018.18.e27
24. Wang AG, Son M, Kenna E, Thom N, Tay S. NF-κB memory coordinates transcriptional responses to dynamic inflammatory stimuli. Cell Rep. 2022 Aug 16;40(7):111159. https://doi.org/10.1016/j.celrep.2022.111159
25. Cavalcanti RR, Almeida FM, Martinez AMB, Freria CM. Neuroinflammation: targeting microglia for neuroprotection and repair after spinal cord injury. Front Immunol. 2025 Oct 6;16:1670650. https://doi.org/10.3389/fimmu.2025.1670650
26. Lößlein L, Linnerbauer M, Zuber F, Tsaktanis T, Vandrey O, Peter A, Panier F, Zissler J, Riekher V, Bäuerle T, Hanspach J, Laun FB, Nagel L, Mészáros L, Zunke F, Winkler J, Naumann UJ, Schwingen N, Neumaier E, Liesz A, Quintana F, Rothhammer V. TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation. Nat Commun. 2025 Jun 19;16(1):5344. https://doi.org/10.1038/s41467-025-60363-7
27. Serhan CN, Chiang N. Resolvins and cysteinyl-containing pro-resolving mediators activate resolution of infectious inflammation and tissue regeneration. Prostaglandins Other Lipid Mediat. 2023 Jun;166:106718. https://doi.org/10.1016/j.prostaglandins.2023.106718
28. Xu W, Huang Y, Zhou R. NLRP3 inflammasome in neuroinflammation and central nervous system diseases. Cell Mol Immunol. 2025 Apr;22(4):341-355. https://doi.org/10.1038/s41423-025-01275-w
29. Andoh M, Koyama R. Comparative Review of Microglia and Monocytes in CNS Phagocytosis. Cells. 2021 Sep 27;10(10):2555. https://doi.org/10.3390/cells10102555
30. Ahremenko E, Andreev A, Apushkin D, Korkotian E. Glial Cells in the Early Stages of Neurodegeneration: Pathogenesis and Therapeutic Targets. Int J Mol Sci. 2025 Dec 12;26(24):11995. https://doi.org/10.3390/ijms262411995
31. Lin H, Xiong W, Fu L, Yi J, Yang J. Damage-associated molecular patterns (DAMPs) in diseases: implications for therapy. Mol Biomed. 2025 Aug 29;6(1):60. https://doi.org/10.1186/s43556-025-00305-3
32. Chiarini A, Gui L, Viviani C, Armato U, Dal Prà I. NLRP3 Inflammasome's Activation in Acute and Chronic Brain Diseases-An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes. Biomedicines. 2023 Mar 23;11(4):999. https://doi.org/10.3390/biomedicines11040999
33. Taban Q, Mumtaz PT, Masoodi KZ, Haq E, Ahmad SM. Scavenger receptors in host defense: from functional aspects to mode of action. Cell Commun Signal. 2022 Jan 3;20(1):2. https://doi.org/10.1186/s12964-021-00812-0
34. Walz W. Reactive microglia and astrocyte phenotype transitions: a framework. In: The Gliocentric Brain. Cham: Springer; 2023. https://doi.org/10.1007/978-3-031-48105-5_4
35. Graninger M, Puchhammer-Stöckl E, Vietzen H. Herpesvirus-host interactions in neurological diseases: the immunogenetic role of HLA-E. J Virol. 2025 Dec 23;99(12):e0086925. https://doi.org/10.1128/jvi.00869-25
36. Acioglu C, Elkabes S. Innate immune sensors and regulators at the blood brain barrier: focus on toll-like receptors and inflammasomes as mediators of neuro-immune crosstalk and inflammation. J Neuroinflammation. 2025 Feb 15;22(1):39. https://doi.org/10.1186/s12974-025-03360-3
37. Gullotta GS, Costantino G, Sortino MA, Spampinato SF. Microglia and the Blood-Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions. Int J Mol Sci. 2023 May 23;24(11):9144. https://doi.org/10.3390/ijms24119144
38. Gryka-Marton M, Grabowska AD, Szukiewicz D. Breaking the Barrier: The Role of Proinflammatory Cytokines in BBB Dysfunction. Int J Mol Sci. 2025 Apr 9;26(8):3532. https://doi.org/10.3390/ijms26083532
39. Wu D, Chen Q, Chen X, Han F, Chen Z, Wang Y. The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Target Ther. 2023 May 25;8(1):217. https://doi.org/10.1038/s41392-023-01481-w
40. Archie SR, Al Shoyaib A, Cucullo L. Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview. Pharmaceutics. 2021 Oct 26;13(11):1779. https://doi.org/10.3390/pharmaceutics13111779
41. French SR, Meyer BP, Arias JC, Levendovzsky SR, Weinkauf CC. Biomarkers of blood-brain barrier and neurovascular unit integrity in human cognitive impairment and dementia. Alzheimers Dement. 2025 Mar;21(3):e70104. https://doi.org/10.1002/alz.70104
42. Stanzione R, Forte M, Cotugno M, Bianchi F, Marchitti S, Rubattu S. Role of DAMPs and leukocyte infiltration in ischemic stroke: insights from animal models and translation to the human disease. Cell Mol Neurobiol. 2022;42(3):545-56. https://doi.org/10.1007/s10571-020-00966-4
43. Bao Y, Chen Z, Su Y, Guo T, Du H, Jia X. From neuroinflammation to gliomagenesis: immune drivers of malignant transformation in the CNS. Front Immunol. 2025 Dec 1;16:1682030. https://doi.org/10.3389/fimmu.2025.1682030
44. McKenzie A, Dombrower R, Theeraphapphong N, McKenzie S, Hijazin MA. Glial Activation, Neuroinflammation, and Loss of Neuroprotection in Chronic Pain: Cellular Mechanisms and Emerging Therapeutic Strategies. Biomedicines. 2025 Dec 26;14(1):58. https://doi.org/10.3390/biomedicines14010058