Linlin Yin

Nearly 16 % of the global population suffers from neurological disorders linked to acute or chronic inflammation, including neurodegenerative and cerebral neuroimmune diseases (1, 2). Neuroimmune dysregulation is widely acknowledged as a pivotal mechanism in the pathogenesis of these disorders, involving intricate immune responses and cellular interactions within the central nervous system (CNS) (3). Recent advances at the intersection of neuroscience and immunology have greatly enhanced our understanding of neuroimmune signaling pathways (4). Studies have shown that resident immune cells in the brain, such as microglia and astrocytes, together with peripheral immune cells, including T cells, B cells, and monocytes, play critical roles in neuroinflammation, vascular injury, and cognitive decline (5–7). For instance, the functional states of microglia, such as the pro-inflammatory M1-type and neuroprotective M2-type polarization, as well as their transformation into disease-associated microglia, coupled with aberrant activation of the complement system, are significantly implicated in the progression of neurodegenerative diseases (8). Furthermore, the infiltration of peripheral immune cells and their communication with the CNS remain major themes in neuroimmune research (9, 10). This research topic brings together cutting-edge advances in neuroimmune signaling, novel microglial polarization states, peripheral immune system-to-CNS immune crosstalk, and multi-omics biomarkers associated with cognitive impairment and dementia, with a special focus on innovative therapeutic strategies targeting neuroimmune inflammation. The collection includes six papers: four original research papers, one systematic review, and one opinion piece. Advanced insights into neuroimmune communication signaling in neurological disorders Advances in sequencing technologies, particularly epitranscriptomic and single-cell sequencing (scRNA-seq), have profoundly improved our understanding of brain cell types, states, and regulatory mechanisms (11, 12). Epigenetic dysfunction leading to altered gene expression in the brain is recognized as a key pathophysiological feature of aging-related neurodegeneration (13). N6-methyladenosine (m6A) RNA methylation and demethylation, the most prevalent internal RNA modifications in eukaryotes, regulate multiple aspects of RNA metabolism and associated signaling pathways (14). Given the strong genetic component of Alzheimer's disease (AD) and related dementias, Liao et al. demonstrated that chronic intermittent ethanol exposure reduced Th2 immune cells in the brains of AD mice. Using Methylated RNA Immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq), they further revealed that increased expression of RNA binding motif protein 15B (Rbm15b) and decreased expression of heterogeneous nuclear ribonucleoprotein A2/B1 (Hnrnpa2b1) contributed to synaptic dysfunction and neuroinflammation underlying memory impairment. This study provides an epigenetic link between chronic alcohol consumption and cognitive deficits in AD mice. Beyond inflammation triggered by chronic external factors, intrinsic immune signaling pathways also play crucial roles in AD. Li et al. identified dysregulated expression of multiple NOD-like receptor (NLR) family members in hippocampal RNA-seq data from AD patients. They further confirmed significant upregulation of NLR family pyrin domain-containing 3 (NLRP3) in microglia surrounding amyloid-β plaques in both AD mice and human postmortem tissue. Functional studies of NLRP3 could reveal novel therapeutic avenues for AD. Apart from microglia-centered mechanisms in AD, high-throughput technologies are also being used to identify regulatory targets in other neuroimmune disorders. Yu et al. utilized scRNA-seq to examine transcriptional states and cellular composition of peripheral blood mononuclear cells in multiple sclerosis (MS) patients. Integrated with multiple Mendelian randomization approaches, they identified Fc receptor-like 3 (FCRL3), a B cell-specific receptor, as a potential protective immune node, offering a fresh perspective on immunoregulatory mechanisms in MS. Therapeutic opportunities targeting neuroimmune pathways in neurological disorders This research topic also highlights therapeutic strategies aimed at immune-inflammatory mechanisms in neurological diseases. Among the myriad of inflammatory mediators, microRNAs (miRNAs), a subset of small non-coding RNAs, are recognized as key regulators of numerous biological processes, owing to their ability to modulate multiple genes simultaneously (15). miRNAs are highly abundant in the CNS, with each cell type exhibiting a distinct expression profile (16). Elucidating the spatiotemporal regulation of miRNAs and their targets under pathological conditions is essential for developing miRNA-based biomarkers and therapeutic interventions. In this collection, Zhao et al. emphasize the role of a novel miRNA, miR-25802, in AD-related neuroinflammation. They demonstrated that miR-25802 upregulation coincides with early microglial activation in AD, suggesting its potential diagnostic potential. Mechanistically, miR-25802 directly binds to and suppresses Krüppel-like transcription factor 4 (KLF4) mRNA, promoting microglial polarization toward a pro-inflammatory M1 phenotype via nuclear factor κB (NF-κB)-mediated inflammation. The authors also proposed that using AAV9-based delivery of regulators targeting the miR-25802/KLF4/NF-κB axis could offer new treatment strategies for AD. Given the central role of NF-κB in inflammation, Bai et al. conducted a comprehensive bibliometric analysis of 1,468 publications (2008–2023) to delineate the research landscape of NF-κB in cognitive impairment. Their findings identified current and emerging research themes, including neuroinflammation, microglial activation, and NF-κB-mediated signaling networks. The study...

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy of the central nervous system, mediated by antibodies against aquaporin-4 water channel protein (AQP4-Abs), resulting in damage of astrocytes with subsequent demyelination and axonal damage. Extracellular communication through astrocyte-derived extracellular vesicles (ADEVs) has received growing interest in association with astrocytopathies. However, to what extent ADEVs contribute to NMOSD pathogenesis remains unclear. Here, through proteomic screening of patient-derived ADEVs, we observed an increase in apolipoprotein E (APOE)–rich ADEVs in patients with AQP4-Abs–positive NMOSD. Intracerebral injection of the APOE-mimetic peptide APOE _130–149 attenuated microglial reactivity, neuroinflammation, and brain lesions in a mouse model of NMOSD. The protective effect of APOE in NMOSD pathogenesis was further established by the exacerbated lesion volume in APOE-deficient mice, which could be rescued by exogenous APOE administration. Genetic knockdown of the APOE receptor lipoprotein receptor–related protein 1 (LRP1) could block the restorative effects of APOE _130–149 administration. The transfusion ADEVs derived from patients with NMOSD and healthy controls also alleviated astrocyte loss, reactive microgliosis, and demyelination in NMOSD mice. The slightly larger beneficial effect of patient-derived ADEVs as compared to ADEVs from healthy controls was further augmented in APOE ^−/− mice. These results indicate that APOE from astrocyte-derived extracellular vesicles could mediate disease-modifying astrocyte-microglia cross-talk in NMOSD.

Objectives: Data on peripheral blood mononuclear cells (PBMCs) characteristics of aquaporin‐4 (AQP4)‐IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) are lacking. In this study, we describe the whole PBMCs landscape of the above diseases using cytometry by time‐of‐flight mass spectrometry (CyTOF). Methods: The immune cell populations were phenotyped and clustered using CyTOF isolated from 27 AQP4‐IgG seropositive NMOSD, 11 MOGAD patients, and 15 healthy individuals. RNA sequencing was employed to identify critical genes. Fluorescence cytometry and qPCR analysis were applied to further validate the algorithm‐based results that were obtained. Results: We identified an increased population of CD11b+ mononuclear phagocytes (MNPs) in patients with high expression of CCR2, whose abundance may correlate with brain inflammatory infiltration. Using fluorescence cytometry, we confirmed the CCR2+ monocyte subsets in a second cohort of patients. Moreover, there was a wavering of B, CD4+ T, and NKT cells between AQP4‐IgG seropositive NMOSD and MOGAD. Conclusions: Our findings describe the whole landscape of PBMCs in two similar demyelinated diseases and suggest that, besides MNPs, T, NK and B, cells were all involved in the pathogenesis. The identified cell population may be used as a predictor for monitoring disease development or treatment responses.

Background Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein-antibody associated disease (MOGAD) are rare demyelinating diseases of the central nervous system but can cause severe disability. Although these two diseases share inherent similarities, they show different pathogenesis, clinical features, and treatment response. Investigation performed by a more powerful approach is needed. Methods Cytometry by time-of-flight mass spectrometry (CyTOF) was used to cluster and phenotype the immune cell subsets in peripheral blood mononuclear cells (PBMCs) isolated from patients with NMOSD or MOGAD and healthy controls (HC). RNA sequencing was used to screen pivotal genes. The obtained algorithm-based data were further verified through traditional flow cytometry and qPCR analysis. Results We identified 29 cell clusters and found several immune cluster changes between NMOSD and MOGAD. Interestingly, no significant differences were found in the B cells fraction between patients and HC group. Immunity dysfunction was mainly attributed to changes of diverse subsets in T cells and mononuclear phagocytes (MNPs). Similar properties of two distinct CD56 + natural killer (NK) cell phenotypes and transcription factor T-bet + or chemokine receptor CCR2 + subsets were shown between patients and health. Conclusions Our results show an overview of the circulating PBMCs landscape of NMOSD and MOGAD patients compared to that of HC. Our data reveal that different immune phenotypes may involve in the distinct pathogenesis of NMOSD and MOGAD and highlight T cells or MNPs as a potential target for precision treatment.

Background: Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disease characterized by complex neuropsychiatric syndrome and cerebrospinal fluid (CSF) NMDAR antibodies. Triggering receptor expressed on myeloid cells 2 (TREM2) has been reported to be associated with inflammation of the central nervous system (CNS). Matrix metalloproteinase-9 (MMP9) and cluster of differentiation (CD44) were measured to evaluate blood‒brain barrier (BBB) permeability in anti-NMDAR encephalitis. The roles of microglial activation and BBB disruption in anti-NMDAR encephalitis are not well known. Findings: In this work, we detected increased expression levels of CSF sTREM2, CSF and serum CD44, and serum MMP9 in anti-NMDAR encephalitis patients compared with controls. CSF sTREM2 levels were positively related to both CSF CD44 levels (r = 0.702, p < 0.0001) and serum MMP9 levels (r = 0.428, p = 0.021). In addition, CSF sTREM2 levels were related to clinical parameters (modified Rankin Scale scores, r = 0.422, p = 0.023, and Glasgow Coma Scale scores, r = − 0.401, p = 0.031). Conclusion: Increased sTREM2 levels in CSF as well as increased CD44 and MMP9 in serum and CSF reflected activation of microglia and disruption of the BBB in anti-NMDAR encephalitis, expanding the understanding of neuroinflammation in this disease. The factors mentioned above may have potential as novel targets for intervention or novel diagnostic biomarkers.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory and demyelinating disorder that can lead to serious disability and mortality. Humoral fluid biomarkers with specific, convenient, and efficient profiles that could characterize and monitor disease activity or severity are very useful. We aimed to develop a sensitive and high-throughput liquid chromatography–tandem mass spectrometry (LC-MS)/MS-based analytical method for novel biomarkers finding in NMOSD patients and verified its function tentatively.Methods: Serum samples were collected from 47 NMOSD patients, 18 patients with other neurological disorders (ONDs), and 35 healthy controls (HC). Cerebrospinal fluid (CSF) samples were collected from 18 NMOSD and 17 OND patients. Three aromatic amino acids (phenylalanine, tyrosine, and tryptophan) and nine important metabolites that included phenylacetylglutamine (PAGln), indoleacrylic acid (IA), 3-indole acetic acid (IAA), 5-hydroxyindoleacetic acid (HIAA), hippuric acid (HA), I-3-carboxylic acid (I-3-CA), kynurenine (KYN), kynurenic acid (KYNA), and quinine (QUIN) were analyzed by using the liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based method. The profile of IA was further analyzed, and its function was verified in an astrocyte injury model stimulated by NMO-IgG, which represents important events in NMOSD pathogenesis.Results: In the serum, tyrosine and some of the tryptophan metabolites IA and I-3-CA decreased, and HIAA increased significantly in NMOSD patients. The CSF levels of phenylalanine and tyrosine showed a significant increase exactly during the relapse stage, and IA in the CSF was also increased markedly during the relapse and remission phases. All conversion ratios had similar profiles with their level fluctuations. In addition, the serum IA levels negatively correlated with glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels in the serum of NMOSD patients were measured by using ultra-sensitive single-molecule arrays (Simoa). IA showed an anti-inflammatory effect in an in vitro astrocyte injury model.Conclusion: Our data suggest that essential aromatic amino acid tryptophan metabolites IA in the serum or CSF may serve as a novel promising biomarker to monitor and predict the activity and severity of NMOSD disease. Supplying or enhancing IA function can promote anti-inflammatory responses and may have therapeutic benefits.

Introduction: Aquaporin-4 immunoglobulin G (AQP4-IgG)-induced astrocytes injury is a key mechanism in the pathogenesis of neuromyelitis spectrum disorder (NMOSD), and although CCL2 is involved, its specific role has not been reported. We aimed to further investigate the role and potential mechanisms of CCL2 in AQP4-IgG-induced astrocyte injury.Methods: First, we evaluated CCL2 levels in paired samples of subject patients by automated microfluidic platform, Ella®. Second, we knock down astrocyte's CCL2 gene in vitro and in vivo to define the function of CCL2 in AQP4-IgG-induced astrocyte injury. Third, astrocyte injury and brain injury in live mice were assessed by immunofluorescence staining and 7.0T MRI, respectively. Western blotting and high-content screening were conducted to clarify the activation of inflammatory signaling pathways, and changes in CCL2 mRNA and cytokine/chemokines were measured by qPCR technique and flow cytometry, respectively.Results: There were greatly higher CSF-CCL2 levels in NMOSD patients than that in other non-inflammatory neurological diseases (OND) groups. Blocking astrocyte CCL2 gene expression can efficiently mitigate AQP4-IgG-induced damage in vitro and in vivo. Interestingly, prevention of CCL2 expression could decrease other inflammatory cytokines released, including IL-6 and IL-1β. Our data suggest that CCL2 involves in the initiation and plays a pivotal role in AQP4-IgG-damaged astrocytes.Discussion: Our results indicate that CCL2 may serve as a promising candidate target for inflammatory disorder therapy, including NMOSD.