Aug 2026· Autoimmunity Reviews· Vol 25, pp.
104165
· 0 citations· 127 references
Medicine
TL;DR
This framework integrates immune mechanisms, glial-synaptic interactions, and network-level dysfunction into a unified pathogenic continuum and explains why interventions targeting only a single aspect, such as immunotherapy or surgical seizure control alone, consistently fail to halt disease progression.
Abstract
Rasmussen's encephalitis (RE) is a rare and devastating immune-mediated epileptic encephalopathy characterized by drug-resistant seizures, progressive hemispheric atrophy, and irreversible neurological decline. Although T-cell-driven neuroinflammation and microglial activation are recognized pathological hallmarks, current models remain insufficient to explain the relentless chronic progression and the limited long-term efficacy of immunotherapies. Here, we propose an integrative neuroinflammation-network remodeling feedback framework to conceptualize RE as a self-sustaining immune-network disorder rather than a purely inflammatory disease. In this model, immune-mediated cytotoxicity, persistent activation of tissue-resident memory T cells, and glial dysregulation converge to disrupt synaptic homeostasis and large-scale network organization. Recurrent epileptic discharges and focal neuroinflammation synergistically compromise blood-brain barrier integrity, facilitating sustained immune infiltration and amplifying glial-driven inflammatory cascades. These processes, in turn, promote excitatory-inhibitory imbalance, pathological network synchronization, and progressive neuronal loss, reinforcing a vicious cycle of network instability and immune activation. This framework integrates immune mechanisms, glial-synaptic interactions, and network-level dysfunction into a unified pathogenic continuum. It thereby explains why interventions targeting only a single aspect, such as immunotherapy or surgical seizure control alone, consistently fail to halt disease progression. Importantly, it highlights the rationale for stage-specific, multi-target therapeutic strategies aimed at simultaneously modulating immune responses and restoring network stability. Beyond RE, this conceptual model provides a broader paradigm for understanding chronic epileptic and neuroimmune disorders driven by maladaptive immune-network coupling.
Post-COVID-19 syndrome (PCS) is an escalating global health concern, marked by persistent cognitive, neurological, and psychiatric symptoms following acute SARS-CoV-2 infection. Although its underlying mechanisms remain incompletely understood, mounting evidence implicates chronic neuroinflammation as a key driver. Sustained microglial and astrocyte activation, blood-brain barrier disruption, and aberrant cytokine signaling contribute to prolonged immune dysregulation within the central nervous system, promoting long-term brain dysfunction. In this expert review, we synthesize emerging insights into how neuroimmune processes impair brain function in PCS. We explore novel mechanistic pathways - including local sleep intrusions, impaired memory reconsolidation, and astrocyte-mediated destabilization of functional networks - that may underlie the syndrome's fluctuating and heterogeneous presentation. We evaluate fluid biomarkers of neuroinflammation, including glial fibrillary acidic protein (GFAP), soluble TREM2, S100β, and pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α. In parallel, we highlight converging neuroimaging biomarkers derived from PET and MRI studies. These include increased TSPO-PET binding in limbic and frontal regions, alterations in cerebral blood flow and oxygen metabolism, neurometabolic changes detected via MR spectroscopy (e.g., elevated myo-inositol and choline), and increased free water content on diffusion imaging - each suggestive of glial activation and network-level dysfunction. We propose a multiscale, longitudinal framework that integrates molecular, neuroimaging, and behavioral data to link immune dysregulation with brain network instability and symptom emergence. Such integrative approaches are critical for advancing precision diagnostics and informing the development of targeted, mechanism-based treatments for individuals affected by PCS.
Daniel Martins, Danielle Beckman, M. Loggia et al.· Translational Psychiatry· 2 citations
Alzheimer’s disease (AD) has long been framed around amyloid-beta (Aβ) and tau pathology, yet mounting evidence indicates that dysfunctional microglia–astrocyte crosstalk is an important, and often underappreciated, contributor to disease progression that operates alongside—rather than in place of—neuronal, vascular, and proteinopathic mechanisms. Here we propose a three-stage framework in which glial communication transitions from silent vulnerability through organized defense to maladaptive collapse. During preclinical aging, gut dysbiosis, diminished tryptophan-derived aryl hydrocarbon receptor (AHR) ligands, and blood–brain barrier weakening prime glia toward inflammatory states with elevated complement tone. Upon Aβ accumulation, microglia and astrocytes initially mount a compensatory response—forming reactive glial nets, containing plaques, clearing tau, and executing complement-guided synaptic pruning. However, sustained pathological burden triggers self-reinforcing loops involving the C3–C3aR axis and IL-1α/TNF-α/C1q signaling, converting the glial network into a propagation engine for tau spreading and synapse loss—the strongest correlate of cognitive decline. We discuss the tryptophan–microbiota–AHR axis as one candidate upstream modulator, while emphasizing that direct human evidence remains limited, and highlight APOE4 in exacerbating microglia-dependent synaptic phagocytosis. To support testability, we operationally define maladaptive loops and communication collapse, and specify measurable variables, fluid/imaging biomarker proxies (e.g., the sTREM2/GFAP ratio), and falsifiable predictions. This framework, presented as an integrative hypothesis rather than an established principle, argues that future therapies must combine protein-targeted approaches with restoration of glial communication homeostasis.
Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a complex and heterogeneous pathogenesis. Accumulating preclinical and clinical evidence indicates that neuroinflammation is an important modulator of ALS pathophysiology, involving activation of resident central nervous system immune cells, dysfunction of glial support systems, disruption of neurovascular barriers, and altered recruitment of peripheral immune cells. ALS-associated neuroinflammation is temporally dynamic and varies across anatomical compartments and cellular contexts. Multiple animal models, human neuroimaging, and post-mortem tissue suggest that relatively regulated or compensatory immune responses during early stage may progressively shift to persistent, maladaptive, and potentially neurotoxic inflammatory circuits in later stage. Although previous studies have described stage-dependent changes in individual immune cell populations, an integrated stage-dependent systematic framework that unifies dynamic alterations in both central and peripheral immune compartments remains insufficiently established. In this review, we propose a four-phase conceptual framework for ALS neuroinflammation across the progressive ALS pathogenesis, aiming to provide theoretical guidance for staging inflammatory therapeutic interventions.
Perioperative neurocognitive disorders (PND) are common and highly heterogeneous neurological complications in older and otherwise vulnerable surgical patients, with clinical manifestations ranging from delayed cognitive recovery to persistent postoperative cognitive decline. Although neuroinflammation is closely associated with the development of PND, an integrative framework is still lacking to explain how perioperative systemic immune activation leads to sustained central immune imbalance and cognitive dysfunction. Here, we propose that the brain immune landscape is a key determinant of susceptibility to PND. This landscape represents a baseline phenotype defined by central immune cell states, inflammatory activation thresholds, and resolution capacity. Within this microglia-centered framework, multiple perioperative factors may jointly drive maladaptive transitions in microglial states. We further discuss mitochondrial stress, glycolytic bias, epigenetic remodeling, non-coding RNA regulation, and trained immunity-like mechanisms, suggesting that these processes may serve as important drivers of sustained neuroimmune imbalance. This perspective supports time- and state-dependent, biomarker-guided intervention strategies aimed at preserving inflammatory resolution and enhancing perioperative cognitive resilience.
Mengjie Chen, Jia-Qi Ning, Jia-Xi Liu et al.· Frontiers in Immunology· 0 citations
Introduction Chronic neuroinflammation is a hallmark of neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease) and neuropsychiatric disorders (major depression, schizophrenia). However, current models fail to explain why some individuals develop persistent neuroinflammation while others maintain homeostasis, nor why similar inflammatory pathology produces such diverse clinical phenotypes. Hypothesis We propose that pathological neuroinflammation emerges from a failure of allostatic integrity—the capacity of the organism to maintain adaptive circular information flow across five interconnected levels: (1) genetic architecture and morphogenetic programming, (2) epigenetic molecular memory, (3) allostatic load and systemic physiological adaptation, (4) the psychoneuroimmuneendocrine (PINE) network, and (5) interoceptive-neuronal integration. When this circular flow is disrupted, maladaptive stable states become entrenched, perpetuating chronic inflammation. Development of the hypothesis Synthesizing evidence from longitudinal and mechanistic studies (with foundational older works cited where necessary), we discuss how: (a) early-life stress epigenetically programs inflammatory reactivity; (b) elevated allostatic load predicts chronic neuroinflammation; (c) PINE network dysregulation perpetuates pro-inflammatory signaling; and (d) interoceptive dysfunction may prevent the downregulation of inflammation. Allostatic integrity is introduced as a dynamic systems-level property hypothesized to moderate the relationship between inflammatory pathology and clinical expression. Testable predictions The framework generates falsifiable predictions: (1) composite indices of allostatic integrity will outperform single biomarkers in predicting transition to chronic neuroinflammation; (2) multidomain interventions targeting multiple levels will produce multiplicative (synergistic) effects; (3) patients with similar inflammatory profiles but contrasting allostatic integrity will show markedly different clinical trajectories; and (4) improvements in allostatic integrity will correlate with reduced neuroinflammation independent of direct anti-inflammatory therapies. Conclusion The Hierarchical-Circular Model reframes chronic neuroinflammation not as a linear cascade but as a potential systemic failure of biological memory and allostatic integrity. Pending empirical validation, this framework may offer a conceptual basis for biomarker development, multidomain prevention, and personalized treatment strategies.
Samuel Ruesga Mundo· Frontiers in Systems Neurosc...· 0 citations
A “cellular state–pathological network–therapeutic window” framework is proposed and the roles of microglia in amyloid-β plaque seeding and compaction, NLRP3 inflammasome activation, mitochondrial DNA–cGAS–STING signaling, complement-mediated synaptic engulfment, and bidirectional microglia–tau feedback are systematically discussed.
Lian-Jing Xu, Ying Zhang, Li Jiang et al.· Frontiers in Cellular Neuros...· 0 citations
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