J Neuroinflammation [JOURNAL]
Sun
200 papers
D-serine ameliorates cognitive deficits by preserving neuronal and synaptic function in experimental anti-NMDAR encephalitis.
Yao Y, E ED, Yang JH … +7 more , Liu C, Xu TY, Zhang T, Huang Y, Wei C, Li X, Zhang XQ
J Neuroinflammation · 2026 Mar · PMID 41896867 · Full text
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an antibody-mediated autoimmune disorder characterized by neuroinflammation, synaptic dysfunction, and prominent cognitive impairment. While immunotherapies redu...
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an antibody-mediated autoimmune disorder characterized by neuroinflammation, synaptic dysfunction, and prominent cognitive impairment. While immunotherapies reduce antibody burden, cognitive recovery is often incomplete, suggesting that persistent neuronal dysfunction contributes to disease outcome. Here, we investigated the effects of D-serine, an endogenous NMDAR co-agonist, in a mouse model of anti-NMDAR encephalitis induced by active immunization with the GluN1₃₅₉–₃₇₈ peptide. Immunized mice exhibited sustained learning and memory deficits accompanied by hippocampal neuronal integrity, dendritic disruption, and decreased expression of synaptic proteins. D-serine administration during the established disease phase significantly improved cognitive performance, partially restored NMDAR1 expression, and ameliorated neuronal and synaptic alterations in the hippocampus. Proteomic analysis further revealed that D-serine was associated with the partial normalization of proteins involved in axonal development, synaptic transmission, and receptor-related signaling pathways. In parallel, GluN1₃₅₉–₃₇₈ immunization induced increased microglial density and activation-associated changes, while D-serine had limited effects on microglial abundance and morphology but attenuated TSPO expression within IBA1⁺ microglia. Together, these findings suggest that neuronal and synaptic alterations are key contributors to cognitive deficits in this model, and that D-serine may promote functional recovery primarily through modulation of neuronal and synaptic processes rather than through broad suppression of neuroinflammatory responses. Targeting neuronal resilience may therefore represent a complementary therapeutic strategy alongside immune modulation in anti-NMDAR encephalitis.
Ginsenoside Rg2 attenuates secondary brain injury following intracerebral hemorrhage by inhibiting NLRP3-mediated pyroptosis.
Sun H, Fu W, Yao Z … +12 more , Sun Y, Wang H, Ma W, Zuo S, Zhang Z, Feng S, Chen J, Wu Y, Cai M, Xu H, Dityatev A, Sun W
J Neuroinflammation · 2026 Mar · PMID 41888931 · Full text
BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype without effective therapy. Neuroinflammation, particularly driven by NLRP3 inflammasome–mediated pyroptosis, is a key contributor to secondary br...
BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype without effective therapy. Neuroinflammation, particularly driven by NLRP3 inflammasome–mediated pyroptosis, is a key contributor to secondary brain injury (SBI). Ginsenoside Rg2 (Rg2), a natural saponin with anti-inflammatory activity, has been reported to inhibit NLRP3, but its efficacy and mechanisms in ICH remain unclear. METHODS: In a collagenase-induced ICH mouse model, we evaluated the effects of Rg2 on neurological function, cerebral blood flow, hematoma expansion, neuronal injury, and inflammation. Mechanistic studies included RNA sequencing, western blotting, immunostaining, co-treatment with MCC950, and microglial depletion with PLX3397. Serum NLRP3 levels were analyzed in patients with ICH. RESULTS: Rg2 improved acute and long-term neurological and cognitive recovery, restored cerebral blood flow, reduced hematoma expansion, and alleviated neuronal damage. It suppressed central and peripheral inflammation, limiting microglial and astrocytic overactivation. Mechanistically, Rg2 directly targeted NLRP3 to selectively inhibit NLRP3 inflammasome activation and pyroptosis while sparing NLRC4 and AIM2. Partial microglial depletion abolished its benefit, and MCC950 co-treatment produced no additive effect. Serum NLRP3 levels correlated with ICH severity and were reduced by Rg2. Long-term treatment showed no organ toxicity. CONCLUSIONS: Rg2 confers robust neuroprotection against ICH by selectively targeting NLRP3-mediated pyroptosis, offering both acute and long-term benefits. These findings support Rg2 as a promising candidate for ICH and potentially for other NLRP3-related neuroinflammatory diseases.
Meningeal lymphatic dysfunction mediates postoperative sleep deprivation-induced cognitive decline via impaired neuroinflammatory clearance.
Huang B, Tu W, Zhou H … +16 more , Mo L, Yang Q, Sheng Y, Sun D, Meng B, Chi Z, Lv Y, Liu R, Xing X, Yuan H, Yang J, Hu F, Chen G, Chen J, Chen X, Lu B
J Neuroinflammation · 2026 Mar · PMID 41882759 · Full text
Postoperative sleep deprivation (PSD) exacerbates perioperative neurocognitive disorders (PND) through unresolved neuroinflammation, yet the underlying mechanisms remain elusive. Here, we aim to evaluate contribution of...
Postoperative sleep deprivation (PSD) exacerbates perioperative neurocognitive disorders (PND) through unresolved neuroinflammation, yet the underlying mechanisms remain elusive. Here, we aim to evaluate contribution of disregulation of the meningeal lymphatic vessels (MLVs) to PSD-induced cognitive decline. In a mosue model combining tibial fracture surgery with sleep deprivation, PSD induced spatial and contextual memory deficits, concurrent with hippocampal neuroinflammation and microglial activation. Crucially, PSD induced significant MLVs structural regression and functional impairment, which further limited drainage of inflammatory mediators (IL-1β, IL-6, and TNF-α) to deep cervical lymph nodes. Lymphatic ligation that suppressed cytokine trafficking to peripheral lymphatics amplifies hippocampal inflammation. Overexpression of vascular endothelial growth factor C (VEGF-C) by intracisternal delivery of AAV-VEGF-C to enhance MLVs function restored lymphatic drainage capacity, attenuated hippocampal neuroinflammation, and rescued PSD-induced cognitive decline. Our findings exhibit a MLVs-related pathological mechanism in PSD-related cognition impairment, showing that sleep loss disrupts meningeal lymphatic integrity, which further impairs inflammatory clearance and exaggrates neuroinflammation and neuronal dysfunction. Therapeutic targeting of restore MLVs’ function may thus offer a novel strategy to mitigate PND.
Dynamics of neutrophilia at the neurovascular unit arising from repeated pulmonary inflammation.
Chiang W, Li H, Le L … +13 more , David-Bercholz J, Caceres AI, Ahmad D, Squire E, Stecyk KS, Marrero M, Pereira A, Squire R, Lim C, McGrath JL, Majewska AK, Terrando N, Gelbard HA
J Neuroinflammation · 2026 Mar · PMID 41882669 · Full text
BACKGROUND: The role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune crosstalk between the periphery and the brain. This study...
BACKGROUND: The role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune crosstalk between the periphery and the brain. This study aimed at understanding the early phases of crosstalk following repetitive inflammation to the lung and ensuing neuropathology. Such a model of frequent inflammatory injury to the lung is pertinent to understanding the focal neurologic risk of constant exposure to aerosolized environmental hazards leading to progressive pulmonary disease. METHODS: To model repeated pulmonary inflammation, we applied a three-dose regimen of intranasal (i.n.) lipopolysaccharide (LPS) in C57BL/6J mice and studied the impact on the inflammatory environment of the brain, with a specific focus on neutrophil dynamics at the neurovascular unit (NVU). Tissue and circulatory inflammatory profiles were screened via bronchoalveolar lavage (BAL) protein content and cellularity, transcript analysis of brain tissue, and flow cytometry of peripheral blood. Intravital two-photon microscopy (2PM) of the brain vasculature identified neutrophil dynamics at the NVU. Immunofluorescence validated neutrophil dynamics and identified neuroinflammatory hallmarks and peripheral immune factor interactions at the NVU. In vivo findings were corroborated and replicated in murine and human microphysiological systems (MPS) modeling the blood-brain barrier as a proxy demonstration of the translational relevance of our findings. RESULTS: 2PM of tdTomato-Ly6G+ neutrophils demonstrated increased levels of circulating neutrophils and corresponding engagement with cortical brain vasculature after the three-dose repeated i.n. exposure regimen. Neutrophilia at the NVU was corroborated with increased transcript levels of Ly6G and other pro-inflammatory markers. This coordination between endothelial pathophysiology and neutrophil phenotypes was recapitulated in separate murine and human MPS models. Systemic neutrophilia in the lung and circulation was found to be cotemporaneous to neutrophilia at the NVU based on the cellularity of BAL and peripheral blood samples collected at the same endpoints. Immunohistochemical analysis of brain tissue implicates temporal coordination between vascular surface adhesion molecules with changes in neutrophil dynamics from adhesion, crawling, stalling, and transmigration. Extravasation of neutrophils was accompanied by sustained paravascular deposition of fibrinogen and microgliosis up to 72 h after the final i.n. dosing. Microglia-associated effector functions for synaptic pruning and regulation of neutrophil activity demonstrated distinct temporal profiles in the hippocampus independent from transduction along the primary olfactory cortex. CONCLUSIONS: Our results identify systemic levels of neutrophilia accompanied by ingress and extravascular accumulation in brain parenchyma that correlated with sustained microglial activation. Pathology to the brain parenchyma is further complemented by the observation of paravascular fibrinogen deposition that alters synaptic metabolism. Thus, we highlight a key role for neutrophil signaling and ensuing neuroimmune interactions from the lung to the brain as a generalizable model of repeated respiratory exposure to inflammatory agents.
DNA methylation regulation of CYP450-lipid metabolism by high-altitude hypoxia: linking neuroinflammation to cognitive impairment.
Wang Q, Han J, Liu G … +7 more , Duan Y, Duo D, Zhu J, Lin Y, Xin Y, Li X, Li T
J Neuroinflammation · 2026 Mar · PMID 41862971 · Full text
Under high-altitude hypoxia, neuroinflammation contributes to cognitive impairment, though the underlying mechanisms remain unclear. In this study, we established rat and astrocyte models of hypoxic exposure. We found th...
Under high-altitude hypoxia, neuroinflammation contributes to cognitive impairment, though the underlying mechanisms remain unclear. In this study, we established rat and astrocyte models of hypoxic exposure. We found that hypoxia induced significant alterations in blood biochemistry, widespread neuronal and glial damage, and impaired spatial learning and memory in rats, which were associated with the abnormal accumulation of p-Tau and Aβ. Hypoxia also triggered neuroinflammation, increasing the levels of inflammatory mediators and activating microglia and astrocytes. Targeted metabolomics and molecular analyses revealed disrupted oxidized lipid metabolism, including reduced synthesis of key metabolites such as arachidonic acid derivatives, accompanied by downregulation of cytochrome P450 (CYP450) expression. In vitro, hypoxia enhanced astrocyte inflammation, promoted Aβ/p-Tau accumulation, increased apoptosis, and suppressed CYP450. Inhibition of CYP450 (particularly epoxygenase) exacerbates hypoxia-induced inflammatory responses and promotes abnormal accumulation of cognition-related proteins by negatively regulating the NF-κB inflammatory signaling pathway. Furthermore, CYP450 downregulation was associated with DNA methylation changes. These findings highlight the role of DNA methylation-mediated CYP450 and oxidative lipid metabolic dysregulation in hypoxia-induced neuroinflammation and cognitive deficits, offering new insights for the development of neuroprotective strategies targeting the CYP450-oxidized lipid axis.
TRIM21 promotes astrocyte-mediated neuroinflammation in experimental autoimmune encephalomyelitis by stabilizing RGMa via K33-linked ubiquitination.
Zhang S, Wang Z, Cheng R … +4 more , Yang X, Jiang A, Zhu L, Qin X
J Neuroinflammation · 2026 Mar · PMID 41857575 · Full text
Abnormal astrocytes activation contributes to disease progression in multiple sclerosis (MS), yet the regulatory mechanisms are not fully understood. Here, we found that repulsive guidance molecule a (RGMa) was significa...
Abnormal astrocytes activation contributes to disease progression in multiple sclerosis (MS), yet the regulatory mechanisms are not fully understood. Here, we found that repulsive guidance molecule a (RGMa) was significantly upregulated in astrocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE). RGMa promoted the release of key inflammatory factors such as C-C motif chemokine ligand 2 (CCL2) from astrocytes. Through protein interaction screening, we identified the E3 ubiquitin ligase, tripartite motif-containing (TRIM) protein 21 (TRIM21), as a interaction protein of RGMa. Mechanistically, TRIM21 enhanced the stability of RGMa by catalyzing K33-linked ubiquitination at lysine 238 of RGMa in vitro. Astrocyte-specific knockdown of TRIM21 decreased the expression of both RGMa and CCL2, thereby effectively alleviating neurological deficits, inflammatory infiltration, and demyelination in acute EAE. Over-expression of RGMa reversed this protective effect in primary astrocytes. Notably, Quisinostat disrupted this signaling cascade by downregulating TRIM21 and consequently attenuating RGMa-mediated CCL2 induction, at least in part through TRIM21-dependent mechanisms, thereby exhibiting therapeutic potential for acute EAE. These results suggest that TRIM21-mediated stabilization of RGMa via K33-linked ubiquitination may represent a pathway contributing to astrocyte-mediated neuroinflammation, and might offer a potential target for MS intervention.
Obesity supersizes macrophage and neutrophil activation after stroke while lipid droplets play a protective role.
Bradshaw K, Holsten J, Hahn O … +7 more , Foltz A, Zera KA, Zhu L, Haarslev C, Wyss-Coray T, Peterson TC, Buckwalter MS
J Neuroinflammation · 2026 Mar · PMID 41857563 · Full text
Obesity is a major stroke risk factor. By 72 h after ischemia, obese mice exhibit greater stroke sizes, neuroinflammation, and motor deficits. However, the immune mechanisms driving these outcomes remain incompletely und...
Obesity is a major stroke risk factor. By 72 h after ischemia, obese mice exhibit greater stroke sizes, neuroinflammation, and motor deficits. However, the immune mechanisms driving these outcomes remain incompletely understood. To define how obesity reshapes the immune response to stroke, we performed single-cell RNA sequencing of immune cells in the blood and brain 72 h after stroke or sham surgery in control-diet and diet-induced obese mice. In the blood, macrophages and neutrophils from obese mice exhibited the most pronounced transcriptional changes under both sham and stroke conditions. These changes included Ly6c2-Cd68-Cx3cr1-enriched monocyte-derived transitioning macrophages and classic macrophage populations enriched in the lipid droplet gene perilipin-2 (Plin2) with one also enriched with foamy macrophage marker Cd36; chemotaxis-associated neutrophil subtypes enriched in Cxcl2 or Cxcr2; and interferon-signaling neutrophils. Obese mice after sham surgery exhibited minimal immune changes in the brain, but after stroke, we report substantial transcriptional changes in infiltrating monocyte-derived macrophages with high or intermediate Plin2 expression, interferon-signaling dendritic cells, and Cxcl2-enriched neutrophils. The obesity-induced changes in immune cells across both blood and brain are characterized by elevated lipid handling, inflammation, cellular stress, and notable coagulation pathways in the brain neutrophils. Co-expression analyses revealed that elevated Plin2, a hallmark of obesity, is positively correlated with lipid-related, immune, stress, and pro-thrombotic genes. We tested its role by stereotactically injecting Plin2 siRNA into the stroke. In non-obese mice, Plin2 knockdown increased infarct size and worsened motor outcomes despite reducing inflammatory markers (CD68, IFITM3, and TSPO), suggesting that early lipid droplet accumulation is neuroprotective and stimulates the immune response to stroke. In obese mice, Plin2 knockdown mildly worsened motor deficits while reducing obesity-elevated CD68. Collectively, these findings identify elevated lipid handling, neuroinflammation, cellular stress, and coagulation as key transcriptional features of obesity-exacerbated stroke outcomes while revealing a protective role for Plin2.
Single-cell RNA sequencing uncovers neutrophil clusters associated with autoimmune neuroinflammation.
Wang Y, Turbitt WJ, Zhou L … +11 more , Yan Z, Patel SB, Yang W, Li Z, Buckley JA, Mulia G, Welner RS, Meador WR, Raman C, Qin H, Benveniste EN
J Neuroinflammation · 2026 Mar · PMID 41851894 · Full text
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by multifocal inflammation and axonal degeneration, driven by innate and adaptive immune cells. The Janus K...
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by multifocal inflammation and axonal degeneration, driven by innate and adaptive immune cells. The Janus Kinase (JAK)/Signal Transducers and Activators of Transcription (STAT)/Suppressors Of Cytokine Signaling (SOCS) pathway regulates immune cell activity, with SOCS proteins functioning as negative regulators. Using the Experimental Autoimmune Encephalomyelitis (EAE) model of MS, our prior work demonstrated that mice lacking Socs3 in myeloid cells (Socs3ΔLysM) developed severe, brain-targeted EAE (btEAE), with increased cerebellar infiltration of activated neutrophils.To define neutrophil-specific roles, we generated mice with Socs3 deletion restricted to neutrophils (Socs3ΔLy6G). Following MOG-induced EAE, these mice exhibited clinical features identical to Socs3ΔLysM mice, including severe cerebellar demyelination, increased cerebellar infiltration of activated neutrophils and CD4+ T-cells, and clinical symptoms of both btEAE and classical EAE (cEAE), the latter involving the spinal cord (SC). Cerebellar neutrophils from Socs3ΔLy6G mice exhibited a primed, inflammatory phenotype with elevated reactive oxygen species, neutrophil extracellular traps (NETs) and heightened production of pro-inflammatory cytokines/chemokines. Neutrophil depletion alleviated btEAE, confirming their pathogenic role.Single-cell RNA Sequencing (scRNA-Seq) of cerebellum (CB) and SC neutrophils revealed five clusters in naïve and EAE mice, with expansion of two clusters (Neu2 and Neu4) in Socs3ΔLy6G mice with EAE. Neu2, Neu3 and Neu4 clusters showed high expression of Saa3, Il1b and Cxcl2, with Neu4 enriched in cytokine signaling pathways and inflammatory responses. Strikingly, Saa3 mRNA and protein expression were markedly increased in the CB and SC of Socs3ΔLy6G mice with EAE compared to controls. Translationally, the human orthologue SAA1 was significantly elevated in plasma from MS patients relative to healthy controls.Collectively, these findings demonstrate that Socs3 deficiency unleashes pathogenic neutrophil activity in Socs3ΔLy6G mice with EAE. They further demonstrate neutrophil heterogeneity within the inflamed CNS and define inflammatory transcriptional states, with Saa3/SAA1 as a potential biomarker and/or target in autoimmune neuroinflammation.
Airborne particulate matter and the lung-brain axis: unraveling the neuroinflammatory cascade from alveolar irritation to microglial activation.
Song S, Fan M, Feng R … +1 more , Zhao H
J Neuroinflammation · 2026 Mar · PMID 41840695 · Full text
BACKGROUND: Epidemiological evidence increasingly substantiates a correlation between chronic exposure to airborne environmental pollutants—specifically fine particulate matter (PM₂.₅) and diesel exhaust particles—and th...
BACKGROUND: Epidemiological evidence increasingly substantiates a correlation between chronic exposure to airborne environmental pollutants—specifically fine particulate matter (PM₂.₅) and diesel exhaust particles—and the prevalence of neurological disorders. While the respiratory consequences of these exposures are well-documented, the mechanisms by which pulmonary distress communicates pathogenic signals to the central nervous system remain complex and multifaceted. SCOPE & REVIEW: This review explores the "Lung-Brain Axis" as a critical conduit for neurotoxicity. We synthesize current findings on two primary pathways: (1) the direct translocation of ultrafine particles via the olfactory nerve and compromised blood-brain barrier (BBB), and (2) the indirect "spill-over" hypothesis, where pulmonary-derived pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6) and extracellular vesicles (EVs) propagate systemic inflammation that subsequently primes microglial activation in the brain. KEY MECHANISMS: We detail the molecular interplay between alveolar macrophages and the subsequent polarization of neuroimmune cells. Special attention is given to the role of the vagus nerve in sensing pulmonary inflammation and the potential involvement of lung-derived exosomes in transporting microRNAs that disrupt neuronal homeostasis. CONCLUSION: Understanding the specific molecular messengers of the lung-brain axis is essential for developing therapeutic strategies. Targeting the pulmonary inflammatory response may offer a novel prophylactic approach to mitigate the neurological burden of environmental pollution.
Longitudinal in vivo imaging of dynamic immune-vascular responses to meningeal cerebrovascular injury.
Kraus A, Prosper-Santiago JS, Potapova A … +3 more , Prevedel J, Castranova D, Weinstein BM
J Neuroinflammation · 2026 Mar · PMID 41840669 · Full text
Meningeal cerebrovascular injuries (mCVI) trigger prolonged bleeding and inflammation that contribute to long-term neurological dysfunction, yet the immune–vascular dynamics governing meningeal repair remain poorly under...
Meningeal cerebrovascular injuries (mCVI) trigger prolonged bleeding and inflammation that contribute to long-term neurological dysfunction, yet the immune–vascular dynamics governing meningeal repair remain poorly understood. Existing animal models limit direct observation of these processes due to invasive procedures and restricted optical access through opaque skulls. With a thin, translucent skull, the zebrafish provides an idea model for longitudinal imaging of mCVI sequelae in intact, unmanipulated animals. We have established an adult zebrafish model to investigate mCVI using precisely calibrated sonication to rupture meningeal blood vessels without breaching the skull or damaging the underlying brain. Using longitudinal live imaging of intubated adult zebrafish, we directly visualize vascular disruption, blood flow dynamics and preservation, angiogenic regrowth and pruning, and immune cell population dynamics over time in the same animal with unprecedented resolution. Together, these studies unveil the meninges as a dynamic immune–vascular niche and demonstrate that our newly developed zebrafish mCVI model provides a powerful platform for longitudinal live imaging, opening the door to new insights into chronic neuroinflammatory disease at CNS borders.
Microglial NCAM1 attenuates ischemic brain injury by inhibiting NF-κB-driven neuroinflammation through IκBα stabilization.
Yu Z, Yu L, Lu W … +3 more , Chen P, Yan H, Jiang Y
J Neuroinflammation · 2026 Mar · PMID 41827071 · Full text
Ischemic stroke is a devastating condition with limited treatment options, where neuroinflammation plays a pivotal role in secondary brain injury. Neural cell adhesion molecule 1 (NCAM1) is implicated in neural developme...
Ischemic stroke is a devastating condition with limited treatment options, where neuroinflammation plays a pivotal role in secondary brain injury. Neural cell adhesion molecule 1 (NCAM1) is implicated in neural development and plasticity, but its specific role in microglia during ischemic stroke remains unclear. Here, we demonstrate that microglial NCAM1 expression is significantly downregulated in the acute phase of ischemic stroke in both human patients and a mouse transient middle cerebral artery occlusion (tMCAO) model. Using microglia/macrophage-specific NCAM1-overexpressing CX3CR1Cre/ERT2 mice, we show that NCAM1 overexpression reduces infarct volume, improves neurological deficits, and enhances long-term functional recovery. Mechanistically, NCAM1 directly interacts with the E3 ubiquitin ligase TRIM67 via its cytoplasmic domain. This NCAM1-TRIM67 complex enhances K63-linked ubiquitination while suppressing K48-linked ubiquitination of IκBα, thereby stabilizing IκBα protein, preventing NF-κB p65 nuclear translocation, and ultimately inhibiting NF-κB-driven neuroinflammation and apoptosis. Furthermore, through molecular docking and high-throughput screening, we identified DB07993 as a potent NCAM1 agonist. DB07993 treatment mimicked the neuroprotective effects of NCAM1 overexpression in vitro and in vivo, primarily through activation of the NCAM1-TRIM67-IκBα axis. Our study unveils a novel regulatory mechanism where microglial NCAM1 serves as a critical brake on post-stroke neuroinflammation and identifies DB07993 as a promising lead compound for developing NCAM1-targeted stroke therapies.
Tumor immunogenicity shapes CNS immune niches and CD8⁺ T cell fate in glioblastoma.
Asalla S, Ahumada OS, Krull JE … +9 more , Wang Y, Patel DN, Gupta V, Wieland A, Giglio P, Ma Q, Tedeschi A, Segal BM, Acharya N
J Neuroinflammation · 2026 Mar · PMID 41826987 · Full text
Immunotherapeutic strategies have largely failed in glioblastoma (GBM), in part because the spatial and temporal organization of anti-tumor immunity across central nervous system (CNS) compartments remains poorly defined...
Immunotherapeutic strategies have largely failed in glioblastoma (GBM), in part because the spatial and temporal organization of anti-tumor immunity across central nervous system (CNS) compartments remains poorly defined. Here, using longitudinal, compartment-resolved profiling of the deep cervical lymph nodes (dcLNs), cranial meninges, and tumor tissue in two preclinical GBM models of differing immunogenicity, we delineate how tumor immunogenicity shapes CNS immune engagement. Although early immune priming occurred in both models, as evidenced by similar temporal patterns of dcLNs activation, they diverged markedly at the CNS border. In the highly immunogenic setting, the meninges underwent profound immune remodeling, assembling dense CD3⁺/B220⁺ lymphoid aggregates indicative of robust local immune activation. By tracking T cell responses to an endogenous retroviral antigen expressed by both tumors, we detected antigen-specific CD8⁺ T cells in the meninges as well as the tumor bed, indicating that the meningeal compartment harbors tumor-reactive T cells and functions as an immunologically active site rather than serving as a passive inflammatory site. CD8⁺ T cell differentiation trajectories varied substantially with anatomical context and tumor immunogenicity. During intermediate tumor progression, meningeal CD8⁺ T cells were enriched for PD-1⁺TCF1⁺TIM3⁻ stem-like and, later, CD44⁺CD62L⁺ central-memory phenotypes, whereas tumor-infiltrating counterparts rapidly acquired cytotoxic programs, yielding PD-1⁺GzmB⁺ and TNF-α⁺ effectors. Although the full spectrum of CD8⁺ T cell states was present in both immunogenicity contexts, their distribution differed: highly immunogenic tumors maintained robust stem-like and memory reservoirs in the meninges, correlating with sustained polyfunctionality and delayed exhaustion intratumorally. In contrast, poorly immunogenic tumors showed diminished meningeal reservoirs and were dominated in the tumor bed by hyperactivated PD-1⁺GzmB⁻ populations prone to early terminal dysfunction. These findings support a model in which the meninges serve as a regenerative immune niche that sustains durable cytotoxic responses. Tumor immunogenicity also reshaped the myeloid landscape, with highly immunogenic tumors supporting heterogeneous macrophage and microglial states encompassing both activation- and regulation-associated features, whereas myeloid cells in poorly immunogenic tumors remained comparatively inert. Collectively, our work defines a spatiotemporal model in which tumor immunogenicity is a key architect of immune topology across CNS compartments, positioning the meninges as a critical site sustaining long-lived anti-tumor immunity.
Uncovering a new player in ischemic stroke: a study of intra-arterial interferon-gamma-producing CD14 myeloid cells in hyperacute stroke.
Hernandez K, Plautz EJ, Sharif S … +3 more , Jones N, Osiah N, Ortega SB
J Neuroinflammation · 2026 Mar · PMID 41826949 · Full text
Stroke triggers a rapid and complex immune response that is not yet fully understood, especially within hours after an ischemic infarct. Our previous study in stroke patients revealed a significant increase in interferon...
Stroke triggers a rapid and complex immune response that is not yet fully understood, especially within hours after an ischemic infarct. Our previous study in stroke patients revealed a significant increase in interferon-gamma (IFN-γ) immediately (hyperacute) and downstream of the ischemic ictus, within the arterial compartment. The present study investigated the source, inciting factors, and role of IFN-γ in a preclinical murine model. Stroke was produced using transient middle cerebral artery occlusion, and immune cells within the arterial vasculature distal to the occlusion (pre- and post-occlusion) were characterized using flow cytometry. Compared with the control samples, the post-occlusion samples presented an increase in IFN-γ+ and CD69+ cells, whereas no significant increase was detected in IL17+, IL4+, and CD25+ cells. Further analysis of the IFN-γ+ population revealed two novel attributes. First, interrogation of the identity of these IFN-γ+ cells revealed that the increase in IFN-γ production was largely driven by CD14+ myeloid cells in the post-occlusion sample, with negligible contributions from other canonical IFN-γ-producing cells (CD4, CD8, NK). Second, the IFN-γ+ cells exhibited two distinct clusters, an IFN-γlow and an IFN-γhi population. Further analysis revealed that the IFN-γ low population was largely composed of CD14+ myeloid cells, whereas the IFN-γhi population was dominated by CD4+ T-cells. To explore the conditions driving IFN-γ production, an in vitro ischemia model involving oxygen-glucose deprivation (OGD) was employed. Co-culturing of naïve splenocytes with OGD-treated CNS cells and OGD-derived supernatant resulted in a significant increase in IFN-γ+CD14+ cells, as compared to normoxic controls, an effect that coincided with marked loss of DAPI+ and NeuN+DAPI+ cells in mixed cortical (neuronal and glial) cultures. In summary, this study identified intra-arterial CD14+ myeloid cells as novel early sources of IFN-γ in the hyperacute phase of stroke, a role traditionally attributed to adaptive immune cells. Using in vivo and in vitro ischemia models, the findings reveal that injury-associated signals from CNS cells are sufficient to directly induce IFN-γ production in CD14+ myeloid cells, redefining early stroke immunopathology and uncovering a potential target for timely immunomodulation.
CAR T cell therapy in autoantibody-mediated neurological disorders: a promising strategy.
Wen M, Zheng R, Zhang H … +8 more , Goldberg SY, Jian Z, Gao Y, Cheng R, Wen L, Zhao Y, Kenderian SS, Shang P
J Neuroinflammation · 2026 Mar · PMID 41821047 · Full text
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising approach for B cell-driven neurological autoimmune disorders, particularly those characterized by pathogenic autoantibodies that targe...
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising approach for B cell-driven neurological autoimmune disorders, particularly those characterized by pathogenic autoantibodies that target key neural structures. These conditions, including neuromyelitis optica spectrum disorder, myasthenia gravis, Lambert-Eaton myasthenic syndrome, MOG antibody-associated disease, anti-NMDA receptor encephalitis, Diacylglycerol lipase alpha antibody associated encephalitis, stiff person syndrome, and multiple sclerosis, can be categorized based on their primary autoantigens into (1) extracellular antigen-associated (e.g., AQP4, AChR, NMDAR, MOG, VGCC), (2) intracellular antigen-associated (e.g., GAD65, DAGLA), or (3) unidentified antigenic origin (as seen in multiple sclerosis). This distinction is essential for guiding therapeutic strategies and exploring novel principles represented in distinct treatment approaches and their corresponding therapeutic outcomes. MAIN BODY: In this review, we propose a classification of CAR T cell therapies designed for different target antigens, including: CD19/20/BCMA-directed CAR T cells targeting general B cell-mediated pathogenesis, regulatory T cells modified with CARs, and the design of chimeric autoantibody receptors (CAARs) to selectively deplete pathogenic B cells directly associated with disease progression while preserving immune tolerance. We further discuss preclinical and clinical advancements, key challenges such as safety concerns and neurotoxicity, and the future landscape of CAR T applications in neuromyelitis optica spectrum disorder, myasthenia gravis, Lambert-Eaton myasthenic syndrome, MOG antibody-associated disease, anti-NMDA receptor encephalitis, Diacylglycerol lipase alpha antibody associated encephalitis, stiff person syndrome, and multiple sclerosis according to the latest research, case and trial data. CONCLUSION: CAR T cell therapy potentially offers a highly specific and effective method with thorough elimination of autoreactive B cells, representing a rapidly evolving field with the potential to transform the treatment of autoimmune neurological disorders. As CAR T technology advances, it holds the potential to become a groundbreaking immunoablative strategy with so-far disclosed controllable side effects; however, further long-term follow-up data are still needed to validate its application in autoimmune disorders.
Sex specific effects of adoptive Tregs transfer on the brain and periphery in maternal immune activation offspring rescuing immune dysregulation.
Rose D, Moreno RJ, Osman H … +4 more , Rowland ME, Silverman J, Ciernia A, Ashwood P
J Neuroinflammation · 2026 Mar · PMID 41821031 · Full text
Autism spectrum disorder (ASD) is characterized by atypical communication, social interactions, and restricted interests. In ASD, there are dysfunctional immune regulatory control mechanisms that can lead to immune activ...
Autism spectrum disorder (ASD) is characterized by atypical communication, social interactions, and restricted interests. In ASD, there are dysfunctional immune regulatory control mechanisms that can lead to immune activation. Notably lower frequencies of regulatory T cells (Tregs) and reduced immunosuppressive cytokines are reported and associated with more impaired behaviors impacting both individuals with autism and their families. Therefore, therapeutic approaches that enhance immune regulation may offer substantial benefits. Using the maternal immune activation (MIA) model, we investigated whether adoptive transfer of wildtype Tregs into MIA offspring recipients could rescue immune activation, brain transcriptome changes and behaviors exhibited in adult MIA offspring. We also aimed to explore potential sex-differences in responses. In male but not female MIA offspring, Tregs transfer reduced the frequency of T helper (TH)-17 (RORγT⁺ CD4⁺) T cells in both the mesenteric lymph node (MLN) and spleen. Moreover, the frequency of CD25⁺Foxp3⁺ T cells was increased in the MLN and spleen of male but not female MIA offspring following Tregs transfer. Splenocytes from male MIA offspring receiving Tregs showed reduced production of inflammatory cytokines (e.g., IL-6 and TNFα) following PMA/Ionomycin stimulations. In contrast, female MIA offspring that received Tregs exhibited different cytokine profiles characterized by increased production of cytokines, including GM-CSF, IFNγ, and IL-10. In the brain, bulk mRNA sequencing in the cerebellum, frontal cortex, and hippocampus revealed that Tregs-treated male MIA offspring had differentially expressed genes involved in neurodevelopmental disorders, synaptic function, and epigenetic regulation. Minimal gene expression differences were observed in female counterparts. There was significant improvement in self-grooming behaviors in males MIA offspring that received Tregs. In females, social novelty improved after Tregs treatment. In summary, adoptive Tregs transfer reduced systemic inflammation, brain transcription and behavior alterations in a sex dependent manner in the context of MIA. These findings suggest that adoptive Tregs transfer may represent a viable therapeutic avenue for mitigating systemic inflammation and comorbidities associated with MIA and neurodevelopmental disorders such as ASD.
Immune imbalance between T helper 1, T helper 17 and regulatory T cells fuels amyotrophic lateral sclerosis pathogenesis: disease trajectory, diagnosis and therapeutic implications.
Sligar C, Sluyter R, Ooi L
J Neuroinflammation · 2026 Mar · PMID 41821014 · Full text
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumul...
Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease, causing motor neuron loss and with limited treatment options. Although traditionally considered non-immune in origin, accumulating evidence implicates the adaptive immune system, particularly CD4+ T cell subsets, as key modulators of disease progression. Among these, T helper (Th)1 and Th17 cells are elevated in ALS blood, cerebrospinal fluid and central nervous system tissues, and drive pro-inflammatory cascades. By contrast, regulatory T cells (Tregs) suppress pathogenic inflammation and maintain immune homeostasis; however, in ALS, both Treg number and suppressive function decline, with remaining Tregs showing reduced FOXP3 (the master transcription factor governing Treg function) expression and impaired regulatory capacity. Integrating human and preclinical evidence, we describe how ALS-associated proteins can act as autoantigens that trigger adaptive immune responses, and how Th1/Th17 amplification and Treg insufficiency couple to microglial activation, blood–brain barrier disruption, and motor neuron degeneration, to impact disease trajectory. Convergent signalling pathways and their intersection with metabolic stress provide a mechanistic link between the adaptive immune response and neurodegeneration. We outline biomarker frameworks, spanning immune cell phenotypes, cytokine signatures and transcriptional readouts that define alterations in Th1, Th17 and Treg responses in ALS. Finally, we address the emerging immunomodulatory therapeutic approaches, including the targeted blockade of specific cytokines and signalling pathways, augmentation of Treg number and function, and attenuation of Th1/Th17 activity, while preserving protective Tregs using selective small-molecule approaches. Collectively, the evidence we provide establishes adaptive T cell imbalance as a central, targetable driver of ALS neuroinflammation and provides a rationale for biomarker-guided therapeutics designed to rebalance adaptive immunity and slow disease progression.
Bile acid scaffold engineering reveals an androstane-triol derivative as a potent immunomodulator with therapeutic efficacy in EAE.
Calvo-Barreiro L, Boutitah-Benyaich I, Eixarch H … +2 more , Espejo C, Gabr MT
J Neuroinflammation · 2026 Mar · PMID 41814398 · Full text
BACKGROUND: Neuroinflammation driven by dysregulated adaptive and innate immune responses plays a central role in the pathogenesis of multiple sclerosis and related autoimmune disorders of the central nervous system. Whi...
BACKGROUND: Neuroinflammation driven by dysregulated adaptive and innate immune responses plays a central role in the pathogenesis of multiple sclerosis and related autoimmune disorders of the central nervous system. While bile acids are increasingly recognized as endogenous immunomodulators, their therapeutic exploitation has been limited by modest potency and incomplete mechanistic understanding. Here, we report the rational engineering of a bile acid-derived scaffold that yields a potent small molecule immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis, a preclinical model of multiple sclerosis. METHODS: A focused series of bile acid-based compounds was established, leading to the identification of an androstane-triol derivative, BA59. The immunomodulatory activity of BA59 was evaluated using in vitro T cell differentiation assays and ex vivo immune profiling in EAE. Therapeutic efficacy was assessed in mice with established EAE. Flow cytometry was used to characterize peripheral immune populations, including effector T cells, regulatory T cells, and antigen-presenting cells. Disease progression was monitored using clinical scoring and cumulative disease burden analyses. RESULTS: BA59 treatment significantly attenuated disease severity and cumulative disease burden when administered therapeutically after the onset of clinical signs. Immunophenotyping revealed that BA59 treatment shifted the peripheral immune profile toward a regulatory state. Specifically, we observed a reduction in pro-inflammatory populations relative to IL-10-producing T cells, alongside an expansion of CD39+ regulatory T cells and CD4 + T cells expressing the immune checkpoints CTLA-4, PD-1, and TIM-3. Furthermore, BA59 reprogrammed antigen-presenting cells toward a tolerogenic phenotype, characterized by enhanced PD-L1 expression. CONCLUSIONS: This study identifies BA59 as a first-in-class androstane-triol immunomodulator that ameliorates experimental autoimmune encephalomyelitis through coordinated regulation of T cell balance, immune checkpoints, and antigen-presenting cell function. Our findings highlight bile acid scaffold engineering as a viable strategy for developing small molecule therapeutics that reprogram neuroinflammatory immune circuits, offering a promising translational approach for multiple sclerosis and related neuroinflammatory diseases.
Integrated omics reveal the effects of vitamin D deficiency on gut microbiota and plasma metabolism in experimental autoimmune uveitis.
Chen Z, Zhang W, Deng Y … +4 more , Zhang Y, Su G, Wang Y, Yang P
J Neuroinflammation · 2026 Mar · PMID 41814341 · Full text
Vitamin D deficiency (VD-deficiency) has been implicated in various autoimmune diseases, including uveitis, yet its mechanistic role remains unclear. Emerging evidence suggests that gut microbial dysbiosis and metabolic...
Vitamin D deficiency (VD-deficiency) has been implicated in various autoimmune diseases, including uveitis, yet its mechanistic role remains unclear. Emerging evidence suggests that gut microbial dysbiosis and metabolic disturbances may serve as critical intermediates linking VD-deficiency and autoimmune disease pathogenesis. Here, using an experimental autoimmune uveitis (EAU) model induced in B10RIII mice, we demonstrate that VD-deficiency exacerbates EAU severity, accompanied by enhanced Th1 and Th17 responses, suppressed regulatory T cells, and disruption of both intestinal and blood–retinal barrier integrity. Integrated microbiota and metabolomic profiling revealed a coordinated pattern of gut dysbiosis, characterized by enrichment of opportunistic pathogens and depletion of beneficial commensals, together with host metabolic reprogramming in VD-deficient EAU mice. KEGG analysis highlighted disruption of vitamin-related pathways, particularly the vitamin digestion and absorption pathway. Mechanistically, VD-deficiency associated disturbances were linked to LRAT downregulation in retinal pigment epithelial (RPE) cells, accompanied by a pro-inflammatory intraocular microenvironment characterized by increased IL-6 and CXCL family chemokines expression. Gain- and loss-of-function studies in complementary in vivo and in vitro RPE-based models further demonstrated that LRAT functions as a negative regulator of retinal inflammatory responses, with LRAT knockdown enhancing, whereas LRAT overexpression suppressing, the production of IL-6, CXCL1, CXCL2, and CXCL8. Collectively, our findings suggest that VD-deficiency exacerbates autoimmune uveitis by disrupting effector–regulatory T cell balance and compromising blood–retinal barrier and intestinal integrity, accompanied by considerable alterations in gut microbiota and systemic metabolism, while identifying LRAT as a potential regulator linking VD-deficiency to retinal inflammatory amplification.
Molecular mechanisms and therapeutic potential of tryptophan metabolism in gut-brain signaling transduction: a narrative review.
Zhang J, Zhou Y, Mei X … +9 more , Yan S, Mao J, Li Y, Bian Z, Li L, Ji D, Lu T, Chen J, Su L
J Neuroinflammation · 2026 Mar · PMID 41814325 · Full text
As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together reg...
As an essential amino acid, tryptophan (Trp) serves as a pivotal mediator in gut-brain axis (GBA) communication through three primary metabolic pathways: kynurenine (Kyn), indole, and serotonin (5-HT), which together regulate neuroimmune and neuroendocrine homeostasis via the vagus and spinal afferent nerves, circulatory system, and hypothalamic-pituitary-adrenal (HPA) axis. This review systematically examines Trp metabolism’s critical roles in GBA, emphasizing molecular pathways, rate-limiting enzymes, and receptor-mediated signaling. We discuss the bidirectional interplay between gut microbiota and host Trp metabolism, encompassing microbial modulation of host enzyme activities such as indoleamine 2,3-dioxygenase and direct production of bioactive indole derivatives like indole-3-propionic acid. Characteristic disruptions in Trp metabolism patterns are identified across GBA-associated disorders including irritable bowel syndrome, inflammatory bowel disease, depression, Alzheimer’s disease, schizophrenia and Parkinson’s disease, marked by aberrant neurotoxic to neuroprotective metabolite ratios and enzymatic dysregulation. The aryl hydrocarbon receptor (AhR) emerges as a molecular hub connecting Trp metabolites to GBA functions, with distinct metabolites eliciting opposing effects through AhR activation. Therapeutic strategies targeting Trp metabolism are critically evaluated, including fecal microbiota transplantation, probiotic supplementation, metabolite administration, and enzyme inhibitors. Future research directions address mechanistic gaps and translational challenges in restoring GBA homeostasis via Trp pathway modulation.
Enhanced myelination potential of human mature oligodendrocytes by TNF and IFNG combination.
Mohammadnia A, Cui QL, Yaqubi M … +9 more , Blaszczyk GJ, Weng C, Hall JA, Dudley R, Stratton JA, Zandee S, Kennedy TE, Srour M, Antel JP
J Neuroinflammation · 2026 Mar · PMID 41808190 · Full text
Initial phases of multiple sclerosis (MS) are characterized by recurrent focal inflammation within the central nervous system associated with demyelination and variable subsequent remyelination, indicating that both inju...
Initial phases of multiple sclerosis (MS) are characterized by recurrent focal inflammation within the central nervous system associated with demyelination and variable subsequent remyelination, indicating that both injury and repair are ongoing within the same microenvironment. An array of pro-inflammatory molecules including tumor necrosis factor α (TNF) and interferon γ (IFNG) are implicated as contributing to oligodendrocyte (OL) lineage cell injury in MS and its models. Using OL lineage cells derived from human surgical samples, we observed that TNF and IFNG in combination enhanced ensheathment of synthetic nanofibers by mature OLs compared to those observed under control conditions or in the presence of individual cytokines, reaching levels comparable to those of A2B5+ late-stage progenitor cells. The combination reversed the individual cytokine mediated inhibition of A2B5+ cell ensheathment. Molecular analysis of the mature OL population identified increased expression of myelination relevant genes in the cytokine combination treated cells, of STAT and IRF transcription factors (TFs) that regulate many of these genes, and of mature OL structural genes (MOBP and CNP). TNF and IFNG combination also reduced expression of OPC signature genes in the mature OLs compared to IFNG alone. The combination effect on ensheathment was reversed using a JAK/STAT pathway inhibitor. The combination of TNF and IFNG induced a stronger immune signature in mature OLs compared to individual cytokines. These results emphasize the complex positive and negative interplay of inflammatory responses in the CNS and the potential for therapeutic modulation.
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