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Editorial: Neuro-immune interaction in disease
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DOI：10.3389/fncel.2026.1931155.png)
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Abstract
En 中文
The recognition that the central nervous system (CNS) and the immune system are not isolated compartments but partners in a continuous dialogue has reshaped how we understand neurological disease. What was once framed as the brain's "immune privilege" is now understood as a tightly regulated; bidirectional exchange that sustains homeostasis under healthy conditions and; when dysregulated; becomes a driver of pathology. Microglia; once thought quiescent; continuously survey the parenchyma and react within minutes to perturbation (Nimmerjahn et al.; 2005); and the discovery of functional lymphatic vessels in the dural sinuses revised long-held assumptions about how immune cells enter and leave the CNS (Louveau et al.; 2015). The Research Topic; "Neuro-immune interaction in disease; " brings together five contributions; including two original studies and three reviews; that map this territory across human postmortem tissue; animal models; and emerging molecular mechanisms. Spanning Alzheimer's disease; Parkinson's disease; and post-ischemic neurodegeneration; the collection illustrates both how much the neuroimmune framework now explains and how much remains contested.Several threads run through these papers. The first is the centrality of communication between neurons; glia; and peripheral immune cells; a principle now well established across neurodegenerative disorders; where misfolded proteins engage glial pattern-recognition receptors and trigger an innate immune response that shapes disease progression (Heneka et al.; 2015). Chu et al. provide a striking example in human Parkinson's disease and related disorders (Chu et al.; 2025). Examining postmortem substantia nigra across control; prodromal; Parkinson's disease; and progressive supranuclear palsy cases; they show that CX3CL1; a chemokine that mediates neuron-to-microglia signaling; is reduced in surviving neurons but elevated in vascular endothelial cells. The decline in neuronal fractalkine tracked with microglial density; while its rise in endothelium correlated with infiltrating CD4+ T cells. Notably; synucleinopathy and tauopathy displayed a shared pattern; suggesting that this dual shift is a convergent feature of neuroinflammation rather than a disease-specific one. This places a single signaling axis at the intersection of resident glial activation and peripheral immune recruitment; consistent with the broader recognition that both central and peripheral immune compartments are altered in Parkinson's disease (Roodveldt et al.; 2024).A second theme is that neuroimmune signaling extends well beyond the brain's borders. Müller and Di Benedetto surveyed the cellular and molecular foundations of neuroimmune crosstalk; with particular to Alzheimer's disease (Müller and Di Benedetto; 2025). Their mini-review situates microglial 44 activation and cytokine signaling within a wider physiology that the blood-brain barrier; the 45 glymphatic system; circadian regulation; and the gut-brain axis. the other shows that one of the most-cited markers of immune involvement/parenchymal T cell infiltration 83 may be more limited and more methodologically contingent than assumed. These positions are 84 complementary rather than contradictory: they jointly demand that claims about neuroimmune 85 involvement be specified by region; cell type; disease stage; and model system. This insistence on specificity is the collective contribution of Topic. Neuroimmune interaction is real and consequential; 87 but its details including which signal; which cell; which compartment; which moment in the disease 88 course; determine whether it is protective destructive. 89 Several open questions follow. How can findings from human postmortem tissue; which captures end-90 stage pathology; reconciled with model systems that access earlier; more dynamic phases? Which 91 neuroimmune signals are causal drivers versus downstream consequences? And how should the field 92 standardize regional sampling and analytical pipelines so that immune cell findings become reproducible 93 across cohorts? Therapeutically; the work here suggests that timing and selectivity will matter as much 94 as target identity; given inflammation's dual role. 95We thank the authors and reviewers whose work made this Research Topic possible. Together these 96 contributions advance a more precise and more cautious account of neuroimmune interaction in 97 disease-one that we hope will guide the next generation of mechanistic and translational studies. 98
Keywords:
T cells
microglia
Alzheimer's disease
neuroinflammation
Parkinson's disease
neuroimmune interaction
post-ischemic neurodegeneration
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