Neurodegeneration as a dysregulation of neuroimmune crosstalk.

Neuron-Derived Neuroinflammation in Neurodegenerative Diseases: Mechanisms and Intervention Prospects.

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.

A vicious cycle of microglial dysfunction: bridging synaptic pruning and neuroinflammation across the neurodevelopmental continuum

Rather than viewing classical neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and severe psychiatric illnesses like schizophrenia (SCZ) as isolated diagnostic silos, modern biological psychiatry increasingly conceptualizes them along a shared neurodevelopmental continuum. Although altered synaptic connectivity and sustained immune dysregulation are both well-documented pathological features, the mechanistic crosstalk between them remains incompletely understood. In this review, we propose that microglia occupy a central position at the interface of these processes because of their dual roles in circuit remodeling and immune surveillance. While individual components, including complement-mediated pruning and inflammasome activation, have been extensively studied, the novelty of our framework lies in integrating these fragmented findings into a cohesive, bidirectional Dysregulated Pruning-Neuroinflammation Cycle to describe how the disruption of microglial homeostasis can sustain a self-perpetuating pathological loop. In this model, the vicious cycle may be initiated through an Outside-In route in which environmental inflammatory insults disrupt synaptic pruning, or through an Inside-Out route in which aberrant synaptic elimination releases danger signals that promote neuroinflammation. By considering early-onset ASD and adolescent/early-adult-onset SCZ, we propose that the interplay among timing, patterning, and background biases neurodevelopmental trajectories toward distinct clinical outcomes. Accordingly, this model highlights disease-modifying therapeutic strategies aimed at restoring microglial homeostasis to potentially mitigate the self-sustaining pathology in these clinically significant neurodevelopmental and psychiatric disorders.

Cellular state transitions in neuroimmune disorders

Neuroimmune disorders are increasingly understood not as the consequence of dysfunction in isolated cell types, but as dynamic diseases shaped by coordinated transitions across interacting neural and immune cell states. This narrative review synthesizes current evidence showing how microglia, astrocytes, neural stem cells, vascular elements, and infiltrating peripheral immune cells shift between homeostatic, inflammatory, reparative, and disease-associated states in response to injury, infection, degeneration, and metabolic stress. We highlight how cytokine signaling, damage-associated molecular patterns, oxidative and metabolic stress, and transcriptional and epigenetic reprogramming reshape neuroimmune behavior across these cellular populations, thereby influencing inflammation, synaptic remodeling, tissue repair, and disease progression. By framing neurological disorders as state transition networks rather than static cellular abnormalities, this review integrates emerging insights from single-cell and spatial profiling with systems-level neuroimmunology and identifies cellular plasticity as both a mechanistic principle and a therapeutic opportunity. This perspective provides a unifying conceptual framework for understanding neuroimmune pathology in disorders such as Alzheimer’s disease, multiple sclerosis, stroke, and traumatic brain injury, while also pointing toward next-generation strategies that selectively modulate maladaptive cellular programs and promote regenerative neuroimmune states.

The Neuroimmune Axis in Sepsis: From Pathophysiological Circuits to Precision Neuromodulation

Abstract Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response, is characterized by a dynamic progression from hyperinflammation to immunosuppression. Its persistently high mortality underscores the limitations of therapies focused solely on immune homeostasis. This review advocates a paradigm shift that positions the nervous system as a central orchestrator of host defense through a hierarchical neuroimmune axis. This axis comprises three interconnected tiers: (1) peripheral effector pathways—the cholinergic anti-inflammatory pathway and the sympathetic-adrenal-medullary axis; (2) central integrative hubs in the brainstem (eg, nucleus tractus solitarius) and limbic system; and (3) molecular translators that convert neural signals into cellular immune responses. In sepsis, maladaptive plasticity within these circuits leads to a pathological “uncoupling” of immune sensing from neural control, driving organ dysfunction and perpetuating both runaway inflammation and subsequent immunosuppression. We critically evaluate emerging neuromodulation strategies—including bioelectronic vagus nerve stimulation, splenic focused ultrasound, precise electroacupuncture, and receptor-specific pharmacology—with careful distinction between established mechanistic evidence, preclinical findings, and early-stage clinical data. The future direction lies in precision neuromodulation, an evolving concept encompassing closed-loop systems responsive to dynamic biomarkers, chronotherapy, and targeted nanomedicine, though these approaches require substantial technical and clinical validation. This framework charts a roadmap for evolving sepsis management from supportive care toward proactive modulation of endogenous regulatory networks, while emphasizing that further mechanistic studies, biomarker validation, and well-designed clinical trials are essential prerequisites for clinical translation.

Microglia-centered cellular crosstalk in neurodegeneration.

Cytokine-mediated immune-to-brain signaling in neural circuit disorders

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.