Aug 2026· Nature reviews. Immunology· 0 citations· 152 references
Medicine
TL;DR
The concept of excitotoxicity is extended beyond glutamate receptor overactivation to include innate and adaptive immune pathways, introducing the framework of immune-mediated excitotoxicity and defining three hallmarks - feedback, stressor and chronicity - as organizing principles of this paradigm.
The mechanisms linking systemic inflammation to brain dysfunction are evaluated and emerging translational opportunities are highlighted, including the therapeutic repurposing of cytokine-targeting and immunomodulatory agents for neuropsychiatric interventions.
Yelin Lee, Jaewon Ko, J. Um· Experimental and Molecular M...· 0 citations
Neurodegenerative diseases represent a major global public health challenge, imposing substantial societal and economic burdens. Their complex pathogenesis and limited therapeutic options underscore an urgent need for new paradigms. Emerging evidence indicates that dysregulation of the brain's immune microenvironment is a critical driver of disease progression. Conventional wisdom posits that peripheral immune cells and central glial cells serve as the primary initiators of neuroimmune responses, whereas neurons are regarded merely as passive recipients of inflammatory damage. Emerging evidence suggests that upon receiving pathological signals in the central nervous system, neurons may become more vulnerable and participate in the onset of neuroimmune processes, positioning them as potential targets for early intervention in neurodegenerative diseases. This article systematically reviews the contribution of neuron-derived immune-inflammatory responses in neurodegenerative diseases and potential intervention strategies. We first outline the capacity of neurons to regulate neuroimmune responses and detail the underlying molecular mechanisms. Then we compare the specific mechanisms by which neurons with different susceptibility drive and amplify neuroinflammation in various neurodegenerative diseases such as alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, vascular cognitive impairment, and transformed these mechanisms into intervention strategies targeting neurons,. This article aims to break through the traditional concept of passive neuronal damage, systematically integrate intervention strategies that shift from targeting peripheral immune and glial cells to regulating neuron-derived immunity, thereby providing a new theoretical framework for overcoming current clinical limitations and identifying effective therapeutic targets for the prevention and treatment of neurodegenerative diseases.
Jie Bu, Xuan Nie, Haiting Luo et al.· Pharmacological Research· 0 citations
Neurodegeneration is increasingly recognized not only as a disorder of neurons but also as a breakdown of dialogue between the nervous and immune systems. Recent discoveries reveal that immune cells and inflammatory signals are deeply interwoven with brain function across the lifespan. Far from passive responders, immune cells act as sentinels and shapers of neuronal resilience, vulnerability, and repair. Together, robust data support a model in which neurodegeneration emerges from complex interactions between neural and immune networks, positioning the immune system as both a sensor and driver of brain health. This perspective synthesizes a growing body of work arguing that neurodegenerative diseases are a failure of neuroimmune crosstalk-where protective signals are lost, and maladaptive responses take hold. By restoring immune homeostasis, fine-tuning inflammatory responses, or targeting epigenetic regulators of the immune state, it may be possible not only to slow degeneration but also to promote recovery. We outline the key challenges and opportunities for this paradigm shift and highlight how a deeper integration of neuroscience and immunology could transform the future of treating neurodegenerative diseases. Lastly, we describe critical focus areas to improve our understanding of neurodegeneration and highlight the development of immune-based therapeutics for neurodegeneration.
F. C. Bennett, Soyon Hong, Ning Jiang et al.· Cell· 0 citations
Neurotoxicity is generally thought to result from exogenous agents like environmental chemicals, drugs and biological toxins. However, increasing evidence suggests that many endogenous molecules that play a critical role in normal brain function can become neurotoxic when the regulatory mechanism involved in their production, metabolism, compartmentalization and clearance are disrupted. This shift underlies the basis of endogenous neurotoxicity. This review discusses the major endogenous sources of neurotoxicity: metabolic neurotoxins, dysfunctional neurotransmitters, protein aggregates and inflammatory mediators. These endogenous factors arise from different physiological pathways, but share common pathogenic mechanisms, all of which involve an underlying state of oxidative stress, mitochondrial dysfunction, impaired proteostasis, excitotoxic signalling, neurovascular dysfunction and maladaptive neuroglial responses. This is not a singular process but a network of interconnected processes, which work together to progressively diminish neuronal resilience and promote synaptic dysfunction and neurodegeneration. The review also underscores the critical role of astrocytes, microglia and other glial cells in the maintenance of neuronal homeostasis. By integrating diverse endogenous neurotoxic pathways within a unified homeostasis-centred framework, this review provides a broader perspective on the mechanisms linking metabolic disorders, aging and neurodegenerative diseases. This framework suggests that effective therapeutic strategies may require restoration of physiological regulatory networks rather than targeting individual neurotoxic molecules in isolation. A systems-level understanding of endogenous neurotoxicity may therefore facilitate the development of earlier biomarkers and more effective interventions aimed at preserving neuronal homeostasis and preventing progressive neurological dysfunction.
Sangeeta Yanglem, Borish Loushambam, Sorokhaibam Mexico Singh et al.· Neuroglia· 0 citations
Glutamate (Glu), although the main excitatory neurotransmitter (NT) of the central nervous system (CNS), evidence recognizes its role in influencing immune cell function and activation, including cytokine production, cell proliferation, migration, and survival. Importantly, dysregulation of Glu homeostasis has been implicated in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive cognitive decline, neuronal loss and neuroinflammation. This review synthesizes current evidence on the biochemistry of the glutamatergic synapse, as well as the expression and signaling of Glu receptors (GluRs) in human immune cells. Furthermore, it examines two major hypotheses of AD pathogenesis —the glutamatergic and the neuroimmune hypothesis— and proposes a unified glutamatergic–neuroimmune framework. In this model, disrupted glutamatergic signaling at the neuron–glia–immune interface may represent a central contributor to AD pathology. Understanding the glutamatergic–neuroimmune axis may provide novel insights into therapeutic strategies targeting neuroimmune modulation in AD.
Nikolaos A. Chinas, Harry Alexopoulos· Cellular and molecular neuro...· 0 citations
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.
Yujie Bo, Chongyang Tang, Xiongfei Wang et al.· Autoimmunity Reviews· 0 citations