J Neuroinflammation [JOURNAL]
Sun
200 papers
Inhibition of endocannabinoid degradation in astrocytes reprograms glial reactivity and prevents seizure sequelae.
Zeng C, Gao F, Hu M … +6 more , Zhang J, Zhu D, Sun L, Lyu J, Pan M, Chen C
J Neuroinflammation · 2026 May · PMID 42192420 · Full text
BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by a pathological cascade of excitotoxicity that leads to neuroinflammation, progressive neuronal loss, and subseque...
BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by a pathological cascade of excitotoxicity that leads to neuroinflammation, progressive neuronal loss, and subsequent cognitive decline. Despite its prevalence, effective therapies remain lacking. Previous studies have demonstrated that the dysregulation of the endocannabinoid system contributes to epileptic activity. In particular, inactivation of monoacylglycerol lipase (MAGL), the key rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, suppresses seizures and reduces neuroinflammation. However, the cellular and molecular mechanisms underlying these protective effects remain unclear. METHODS: To dissect the cellular mechanisms underlying MAGL-mediated neuroprotection, we employed a kainic acid (KA)-induced status epilepticus model in mice with global, astrocyte-specific (aKO), and neuron-specific (nKO) deletion of mgll. We combined single-nucleus RNA sequencing (snRNA-seq) to map the transcriptomic landscape of glial responses with pharmacological interventions and AAV-mediated gene manipulation to validate key signaling pathways, as well as behavioral assays to assess functional recovery. RESULTS: We demonstrated that astrocyte-specific mgll deletion attenuated seizure susceptibility and hippocampal neuroinflammation, whereas neuron-specific, mgll deletion did not reproduce this broader protective phenotype. Transcriptomic profiling revealed that astrocytic MAGL deficiency fundamentally reshaped the glial response to injury by preventing the transition to pro-inflammatory reactive astrocyte states and suppressing the activation of disease-associated microglia (DAM). Mechanistically, we identified a signaling pathway in which the neuroprotective effects of MAGL inhibition depend on cannabinoid receptor 1 (CB1) activation and are mediated by downstream peroxisome proliferator-activated receptor γ (PPARγ) signaling. Genetic deletion of CB1 abolished the protective effects, whereas pharmacological blockade or AAV-mediated knockdown of PPARγ attenuated these effects. Furthermore, aKO mice exhibited reduced neuronal loss, preserved synaptic structural integrity and protection against post-seizure cognitive deficits. CONCLUSION: These findings reveal astrocytic MAGL as a crucial regulatory node after status epilepticus and support a model in which CB1-dependent mechanisms and astrocytic PPARγ-dependent regulation jointly contribute to 2-AG-mediated neuroprotection, attenuating neuroinflammation, preserving synaptic integrity, and reducing post-seizure behavioral deficits in this KA-induced SE model.
PVN regulates acinar cell-mediated inflammatory response via DMV projections to the acinar cell.
Fang H, Liu A, Yang JF … +12 more , Liu M, Zheng YY, Zhang HY, Guo JR, Luo PP, Yang DS, Wang R, Lai F, Chen QP, Xu T, Wang H, Ren ZH
J Neuroinflammation · 2026 May · PMID 42186091 · Full text
The central nervous system regulates glandular secretions by modulating visceral organ functions. However, the anatomical and functional connections between the brain and digestive enzyme-producing pancreatic acinar cell...
The central nervous system regulates glandular secretions by modulating visceral organ functions. However, the anatomical and functional connections between the brain and digestive enzyme-producing pancreatic acinar cells remain poorly defined. Using the hypertriglyceridemia-associated acute pancreatitis (HTGP) mouse model, we aimed to describe a functional transneuronal circuit connecting the hypothalamus to pancreatic acinar cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVN), and reaches the exocrine pancreas via acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVACh) to innervate acinar cells. Silencing of PVNOXT neurons suppresses digestive enzyme secretion and inhibits the inflammatory response in HTGP. Conversely, stimulation of these neurons induces inflammation by dysregulating secretory pathways in acinar cells. Single-cell RNA sequencing revealed that WD repeat and FYVE domain-containing 1 (Wdfy1), a gene expressed in the OXT neuron subpopulation, plays a critical role in the acinar cell-mediated inflammatory response, and its function is essential for the PVNOXT-DMVACh axis.
Semaglutide targets the Isg15-FUNDC1 axis: suppressing IFN-β overactivation and attenuating blood-brain barrier injury in diabetic intracerebral hemorrhage.
Wang Y, Kuang B, Chen Y … +10 more , Zou W, Zheng L, Zhang B, Shang T, Xu C, Xu Q, Li H, Hu Y, Zhao K, Kuang H
J Neuroinflammation · 2026 May · PMID 42186030 · Full text
BACKGROUND: Intracerebral hemorrhage complicated by diabetes mellitus (DM-ICH) is characterized by severe secondary injury of the blood-brain barrier (BBB) and poor clinical outcomes; however, targeted therapies remain l...
BACKGROUND: Intracerebral hemorrhage complicated by diabetes mellitus (DM-ICH) is characterized by severe secondary injury of the blood-brain barrier (BBB) and poor clinical outcomes; however, targeted therapies remain limited. Using single-cell RNA sequencing (scRNA-seq) in a dynamic rat model of ICH, we observed that brain microvascular endothelial cells (BMECs) exhibited a robust type I interferon (IFN-I)-mediated innate immune response at the peak of injury (day 3), paradoxically accompanied by decreased expression of interferon-stimulated gene 15 (Isg15). This study aimed to investigate the role of Isg15 deficiency in mitophagy impairment and IFN-β dysregulation in DM-ICH, and to evaluate the therapeutic potential of the GLP-1 receptor agonist semaglutide. METHODS: An in vivo DM-ICH model was established in male rats, alongside an in vitro model using the human cerebral microvascular endothelial cell line hCMEC/D3 exposed to high glucose and hemin (HG+Hemin). Brain injury was evaluated by measuring brain water content and neurological scores, while BBB integrity was assessed through Evans blue (EB) extravasation and transmission electron microscopy (TEM). ScRNA-seq, adeno-associated virus (AAV)- and siRNA-mediated interventions, co-immunoprecipitation (Co-IP), and cycloheximide (CHX) chase assays were utilized to systematically explore the molecular role of Isg15 and assess the effects of semaglutide on Isg15 regulation and BBB protection. RESULTS: ScRNA-seq data demonstrated that although IFN-I-related pathways were activated in BMECs at the injury peak, the key negative regulator Isg15 was specifically downregulated. This suppression was further exacerbated under DM-ICH conditions and was associated with severe BBB damage. Isg15 deficiency destabilized the mitophagy receptor FUNDC1, impairing mitophagy, triggering mitochondrial DNA (mtDNA) leakage into the cytosol, and subsequently inducing robust IFN-I-mediated inflammation. Mechanistically, Isg15 stabilized FUNDC1 by inhibiting proteasomal degradation independently of ISGylation. Semaglutide effectively upregulated Isg15 expression, reversing this pathological cascade, attenuating BBB disruption, and improving neurological function. CONCLUSIONS: This study provides the first evidence that the Isg15-FUNDC1-mitophagy axis protects BBB homeostasis following DM-ICH. Isg15 downregulation drives IFN-I-mediated vascular injury, whereas semaglutide protects the BBB by upregulating Isg15, offering a translational therapeutic strategy. However, the applicability of these findings to females warrants further research.
Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
Liu Y, Shi S, Zhang J … +5 more , Huang M, Wang M, Zhang T, Wang W, Xiang J
J Neuroinflammation · 2026 May · PMID 42185903 · Full text
Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise...
Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhance microglial α-syn clearance, resulting in reduced α-syn burden and improved PD-CI. Mechanistically, irisin activates integrin αV/β5-FAK axis to promotes microglial phagocytic uptake of α-syn, while concurrently stabilizing HMGB1 to facilitate autophagy-lysosome mediated degradation of internalized α-syn, thereby coupling phagocytic uptake to efficient degradation. In summary, these results highlight a dual-module irisin-integrin αV/β5 mechanism that couples microglial phagocytosis and autophagy-lysosome clearance to reduce α-syn burden and ameliorate PD-CI.
Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease.
Cao Y, Wang J, Li X … +5 more , Chen X, Xiong J, Wang T, Sun H, Wang Z
J Neuroinflammation · 2026 May · PMID 42178562 · Full text
BACKGROUND: Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates t...
BACKGROUND: Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates the role of the Ccl4-Ccr5 axis in microglia-mediated synaptic phagocytosis during CKD-associated cognitive decline. METHODS: A 5/6 nephrectomy rat model was established in rats to induce CKD, validated by renal function markers. Cognitive performance was evaluated through spatial, contextual, and recognition memory tests. Hippocampal cellular alterations were analyzed using single-cell RNA sequencing and immunofluorescence for microglial activation and synaptic density. The functional roles of Ccr5 were assessed via in vivo and in vitro CRISPR-mediated knockdown or overexpression, while Ccl4-Ccr5 interactions were confirmed by co-immunoprecipitation. RESULTS: CKD rats showed significant cognitive deficits, increased hippocampal microgliosis, and synaptic loss. Ccr5 knockdown reduced microglial synaptic engulfment, restored synaptic plasticity, and improved memory, whereas Ccr5 overexpression enhanced phagocytic activity. CONCLUSIONS: These findings demonstrate that Ccl4-Ccr5 signaling drives pathological synaptic elimination by microglia, linking systemic inflammation to cognitive decline in CKD. Targeting this pathway may provide a therapeutic approach to preserve neuronal function.
ERVK activity in CD8 T cell immune cell compartment in patients with ALS.
Sharma S, Cortés-Pérez C, Bird S … +4 more , Di Curzio D, Vandenakker A, Schellenberg K, Douville RN
J Neuroinflammation · 2026 May · PMID 42177561 · Full text
Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load...
Endogenous retrovirus-K (ERVK) expression has been associated with Amyotrophic Lateral Sclerosis (ALS), and its viral proteins can be detected in affected brain and spinal cord tissues. Despite confirmation of ERVK load in the blood of patients with ALS, few studies have examined ERVK protein expression in immune cells. ERVK produces an enzyme called integrase (IN), which can cause DNA damage during the integration of viral DNA into the host genome. Given that genomic instability is a hallmark of ALS, we hypothesized that the ERVK IN enzyme may also be expressed in lymphoid and myeloid-derived immune cells of patients. Peripheral blood mononuclear cells (PBMC) were isolated from blood specimens using Ficoll isolation, and either flash-frozen for western blot analyses or affixed onto slides using the cytospin technique for subsequent confocal microscopy analysis. Image analysis of confocal micrographs revealed that ERVK IN expression was significantly elevated in CD3CD8 T cells from a subset of patients with ALS as compared to controls. CD3CD8 T cells in ALS exhibit enhanced number and size of ERVK IN puncta within the nucleus and at the plasma membrane. The DNA damage load, as measured by marker γH2AX, was strongly associated with ERVK IN levels in both controls and patients with ALS. Stratification of molecular data based on clinical parameters showed an association of elevated ERVK IN load in CD8 T cells from patients with ALS with lower ALSFRS-R and higher King's scores, as well as a significant decline in lung function metrics. In bulk PBMC from patients with ALS, ERVK IN was associated with expression of immune checkpoint marker PD-1, but not T cell exhaustion marker TOX. ERVK IN in CD14CD11b myeloid cells was also elevated, with ERVK cells exhibiting notable membrane ruffling typical of immune cell activation and increased expression of HLA-DR. However, ERVK IN expression in monocytes was not correlated with clinical metrics in patients with ALS. This work points to the use of ERVK IN in CD8 cytotoxic T cells as a blood biomarker for ALS clinical trials, especially those focused on testing the efficacy of antivirals as a therapeutic strategy for ALS.
Regulator of G protein signaling 10: a critical regulator of chronic systemic inflammation in parkinson's disease.
Posey JEJ, Menees KB, Tansey MG
J Neuroinflammation · 2026 May · PMID 42174683 · Full text
The inflammatory response mounted by the immune system is a protective process necessary for survival following exposure to insults. However, it must be tightly regulated to maximize efficient elimination of pathogens an...
The inflammatory response mounted by the immune system is a protective process necessary for survival following exposure to insults. However, it must be tightly regulated to maximize efficient elimination of pathogens and to minimize collateral damage to the host. Failure to maintain balance and resolve an inflammatory response can result in chronic systemic inflammation (CSI). CSI has been identified as a key factor in the pathogenesis of many diseases including neurodegenerative diseases (NDs). This review covers the growing relationship between CSI and NDs with a particular emphasis on Parkinson's disease (PD). Furthermore, we discuss the role of an important negative regulator of inflammatory responses: Regulator of G-protein Signaling-10 (RGS10), within the context of CSI and PD.
Sleep deprivation induces anxiety-like behaviors through IL-6 driven astrocyte-GABAergic neuron crosstalk in the PAG-ACC circuit.
Xu X, Wu Z, Hang W … +5 more , Mao S, Sun J, Xiong H, Zhu J, Ma D
J Neuroinflammation · 2026 May · PMID 42174628 · Full text
Sleep deprivation (SD) is associated with anxiety-like behaviors, yet the underlying molecular and neural circuit mechanisms remain unclear. Using a 24-hour SD paradigm in mice, we found that SD induced anxiety-like beha...
Sleep deprivation (SD) is associated with anxiety-like behaviors, yet the underlying molecular and neural circuit mechanisms remain unclear. Using a 24-hour SD paradigm in mice, we found that SD induced anxiety-like behaviors and increased interleukin-6 (IL-6) in blood and the periaqueductal gray (PAG), and PAG-targeted administration of IL-6 receptor antagonist rescued the anxiety-like behaviors. This increased IL-6 activated PAG astrocytes, as evidenced by morphological remodeling, increased calcium activity, and enhanced glutamate release. Astrocytic activation upregulated several genes associated with endoplasmic reticulum (ER) protein synthesis and processing, including neuronal mesencephalic astrocyte-derived neurotrophic factor (Manf). Knockdown of Manf in PAG neurons upregulated the GABA receptor α1 subunit (Gabra1), reduced the activity of GABAergic neurons projecting to the anterior cingulate cortex (ACC), and rescued anxiety-like behaviors. Chemogenetic inhibition of this PAG-ACC circuit prevented SD-induced anxiety-like behaviors, whereas its activation recapitulated the anxiety-like behaviors. Our study identifies an IL-6-astrocyte-Manf signaling axis in the PAG that drives anxiety-like behaviors via enhanced GABAergic neuronal output to the ACC. This PAG-ACC circuit may serve as a neuroimmune hub for SD-mediated anxiety-like behaviors and represents a potential therapeutic target.
Translational evidence for increased central amygdala IL-6 activity in alcohol dependence.
St Onge CM, Erikson C, Cruz B … +17 more , Borgonetti V, Hashimoto JG, Cucinello-Ragland JA, Fitzpatrick-Schmidt T, Rodriguez L, Khom S, Palmisano M, Vlkolinsky R, Oleata CS, Nadav T, Salem NA, Edwards S, Mayfield RD, Guizzetti M, Roberts AJ, Bajo M, Roberto M
J Neuroinflammation · 2026 May · PMID 42174622 · Full text
Alcohol use disorder (AUD) is one of the most prevalent mental health disorders worldwide yet effective therapeutics remain limited. Mounting evidence indicates that dysregulated immune signaling in the brain plays a rol...
Alcohol use disorder (AUD) is one of the most prevalent mental health disorders worldwide yet effective therapeutics remain limited. Mounting evidence indicates that dysregulated immune signaling in the brain plays a role in AUD pathophysiology. Activation of pro-inflammatory pathways like the interleukin-6 (IL-6) pathway represents a potential point of convergence between synaptic dysfunction and motivational changes in AUD that remain undiscovered. Thus, using a translational neuroscience approach and well-established model of chronic alcohol intake, we investigated the cell-type specific role of IL-6 signaling in the central amygdala, a critical region in the development and maintenance of alcohol dependence. We demonstrate that chronic alcohol exposure recruits IL-6-related pathways in humans and rodents via astrocytic, neuronal, and microglial mechanisms, and that IL-6 inhibits central amygdala GABAergic transmission. Notably, systemic administration of an IL-6 receptor antibody decreased alcohol drinking in alcohol-dependent female mice. Collectively, our findings support IL-6 inhibition as a novel-neuroimmune-targeted therapeutic strategy to reduce excessive drinking in the context of AUD.
Liver-nervous system axis: pathways, dysregulation, and translational perspectives.
Hao D, Hu Y, Luo W … +3 more , Li S, Yan Y, Zhou J
J Neuroinflammation · 2026 May · PMID 42169124 · Full text
The liver and the nervous system form a dynamic bidirectional regulatory network through the liver-nervous system axis, which is crucial for maintaining metabolic homeostasis, immune balance, and the integrity of neural...
The liver and the nervous system form a dynamic bidirectional regulatory network through the liver-nervous system axis, which is crucial for maintaining metabolic homeostasis, immune balance, and the integrity of neural function in the body. However, the specific regulatory pathways between the liver and the nervous system, as well as their mechanisms in the development and progression of diseases, remain incompletely understood. Moreover, the dynamic regulatory mechanisms of the blood-brain barrier in the transport of liver metabolites are yet to be elucidated. Therefore, we have integrated the latest research advances in recent years in the fields of liver innervation, the neuroregulatory effects of liver-derived substances, and the trans-organ conduction of inflammatory mediators. Additionally, we incorporate clinical translational evidence from the application of β-blockers, vagus nerve stimulation, liver transplantation, and other interventions to systematically elucidate the coordinated regulatory patterns of the liver and the nervous system under physiological conditions, as well as the mechanisms of interactive disorders under pathological conditions. The aim is to clarify the interactions between the liver and the nervous system and their significance in physiological and pathological processes, thus providing a theoretical basis and potential therapeutic targets for future related research.
The Epidermal Growth Factor Receptor (EGFR) as a means of neuro-immune cross-conversation.
Gryksa K, Sibilia M, Rothhammer V … +2 more , Liston A, Zaiss DM
J Neuroinflammation · 2026 May · PMID 42169107 · Full text
The nervous and the immune system coevolved, and the crosstalk between both is critical for the maintenance of tissue homeostasis and mental health. In recent years, several examples have been revealed that the immune sy...
The nervous and the immune system coevolved, and the crosstalk between both is critical for the maintenance of tissue homeostasis and mental health. In recent years, several examples have been revealed that the immune system influences behaviour, emotions, pain and even such fundamental needs as hunger. Reciprocally, several examples have become apparent in which neuronal innervation regulates local immune responses, wound healing and immune-mediated tissue homeostasis. Such findings demonstrate how well these two networks are interconnected with each other to sustain the body's well-being. Nonetheless, the underlying mechanisms that orchestrate this interconnection remain poorly understood. The Epidermal Growth Factor Receptor (EGFR) signalling pathway exemplifies this connection, being involved in both neuronal development and maintenance as well as in immune regulation and immune mediated wound healing. Particularly two antagonistic and leukocyte-derived EGF-like growth factors, Amphiregulin and HB-EGF, have gained appreciation for their role in the regulation of local immune responses and the maintenance of tissue homeostasis. In this review, we highlight the role of these two leukocyte-derived growth factors in the regulation of the nervous system and their importance in the bi-directional crosstalk between the immune and nervous systems during tissue homeostasis and inflammation. Ultimately, we propose that under inflammatory conditions, these two leukocyte-derived growth factors may substitute typical neurotrophic factors in their function.
IL-1β-mediated interaction between Müller cells and microglia through CXCL1/5-CXCR2 aggravates visual dysfunction in experimental glaucoma.
Xin X, Han L, Qu Y … +6 more , Zhang L, Zhang X, Li J, Lei B, Wang YC, Wang Z
J Neuroinflammation · 2026 May · PMID 42169105 · Full text
PURPOSE: Glaucoma is an optic neuropathy characterized by progressive death of retinal ganglion cells (RGCs), ultimately leading to blindness. Increasing evidence demonstrates that interactions among retinal glial cells...
PURPOSE: Glaucoma is an optic neuropathy characterized by progressive death of retinal ganglion cells (RGCs), ultimately leading to blindness. Increasing evidence demonstrates that interactions among retinal glial cells exacerbate retinal inflammatory responses, which is closely associated with RGC injury. However, the detailed mechanisms governing these glial cell interactions remain largely unknown. This study aims to investigate the possible roles and the potential mechanisms of interleukin-1β (IL-1β) in mediating the interaction between Müller cells and microglia in glaucoma. METHODS: The experimental glaucoma model of chronic ocular hypertension (COH) was established in adult male mice by injection of micro-magnetic beads into the anterior chamber. Western blotting, quantitative real-time polymerase chain reaction, immunofluorescence, transwell co-culture of glial cells, RNA sequence, swept-source optical coherence tomography-based imaging and flash visually evoked potentials were employed to investigate the underlying mechanisms about the interaction of Müller cells and microglia in retina after IL-1β stimulation, along with their impact on visual functions. RESULTS: We showed that in COH retinas, IL-1β activated Müller cells and microglia, and promoted the recruitment of microglia to the ganglion cell layer. Mechanistic studies revealed that activated Müller cells released C-X-C motif chemokine ligand 1/5 (CXCL1/5) through the NF-κB and p38 MAPK signaling pathways. These chemokines bond to CXC chemokine receptor 2 (CXCR2), inducing microglial activation and migration. This activation led to a significant increase in the expression of pro-inflammatory factors, which contributed to RGC death and subsequent visual function decline. Importantly, inhibition of the CXCL1/5-CXCR2 axis substantially reversed RGC loss and improved visual function. CONCLUSIONS: IL-1β plays a positive feedback role in glial cell interactions, amplifying retinal inflammatory responses and impairing visual function. These findings demonstrate that inhibiting the interaction between Müller cells and microglia effectively protects RGCs, offering a promising strategic approach for glaucoma prevention and treatment.
The insulin receptor inhibitor BMS-754807 alleviates neuroinflammation and Alzheimer's disease pathologies across human cellular and mouse models.
Lee HJ, Seok J, Kang S … +5 more , Oh S, Hwang JW, Kim YJ, Seo J, Hoe HS
J Neuroinflammation · 2026 May · PMID 42163277 · Full text
BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer....
BACKGROUND: BMS-754807 is a dual inhibitor of insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR) that is in phase II clinical trials for the treatment of HR-positive and HER2-negative breast cancer. Because IGF-1R signaling regulates inflammatory responses, pharmacological modulation of IGF-1R may have therapeutic potential for Alzheimer's disease (AD); however, the effects of BMS-754807 on neuroinflammatory responses/AD pathology and cognitive function have not been fully investigated. METHODS: We examined whether BMS-754807 modulates neuroinflammation and AD pathologies in multiple in vivo animal models and in vitro human models. BMS-754807 (20 mg/kg, i.p.) was systemically administered in wild-type mice challenged with LPS, 5xFAD mice, and PS19 transgenic mice. In addition, human-induced pluripotent stem cell (hiPSC)-derived microglia challenged with LPS and AD hiPSC-derived neurons were treated with 2.5 µM BMS-754807. For all models, the effects of BMS-754807 treatment were analyzed by real-time PCR, immunofluorescence staining, western blotting, ELISA, and/or activity assays. RESULTS: BMS-754807 treatment significantly decreased p-IGF-IR (on-target) levels, LPS-induced proinflammatory cytokine production, and reactive oxygen species levels; restored HO-1 expressions; and inhibited AKT/STAT3 signaling in BV2 microglial cells. Similarly, BMS-754807 treatment reduced LPS-evoked proinflammatory cytokine expressions in primary microglial cells and primary astrocytes. In addition, BMS-754807 administration mitigated LPS-stimulated gliosis, microglial/astrocyte-associated dynamics, STAT3/NF-κB phosphorylation, and potentially NLRP3 inflammasome in vitro and/or in WT mice. Moreover, BMS-754807 treatment suppressed LPS-mediated proinflammatory responses through IGF-1R and NLRP3 in BV2 microglial cells. In 5xFAD mice, BMS-754807 administration downregulated IGF-1R phosphorylation, microgliosis/astrogliosis-related dynamics, and AKT/P38/STAT3 pathway. Notably, BMS-754807 treatment also diminished LPS-induced proinflammatory cytokine levels and STAT3/NF-κB signaling in human microglial models. Furthermore, BMS-754807 treatment decreased Aβ40/Aβ42 levels in hiPSC-derived AD neurons, and increased short-term spatial memory and reduced Aβ plaque accumulation by decreasing β-secretase (BACE1) activity in 5xFAD mice. Finally, in hiPSC-derived AD neurons and PS19 mice, BMS-754807 treatment significantly attenuated tau hyperphosphorylation, CaMKIIα phosphorylation, and tau-mediated astroglial activation. CONCLUSIONS: Taken together, our results suggest that BMS-754807 exerts anti-inflammatory and potential disease-modifying effects by attenuating LPS/Aβ/tau-evoked glial activation and reducing Aβ and tau pathologies in both human cellular and mouse models of neuroinflammation and AD. Furthermore, BMS-754807 administration improved specific domains of cognitive function in vivo. These findings support pharmacological inhibition of IGF-1R as a potential therapeutic approach for neuroinflammation-associated diseases including AD.
Plasma proteome in LGI-1 autoimmune encephalitis.
Wesselingh R, Seery N, Ko K … +29 more , Griffith S, Kazzi C, O'Brien WT, Giesler L, Rushen T, Ter Horst L, Halliday A, Forcadela M, Tan T, Skinner G, Ford H, Buzzard K, Duncan A, D'Souza W, McDonald S, Kalincik T, Seneviratne U, Macdonell R, Gillis D, Ramanathan S, Reddel SW, Blum S, Hardy TA, Malpas C, O'Brien TJ, Sanfilippo P, Butzkueven H, Monif M, Australian Autoimmune Encephalitis Consortium
J Neuroinflammation · 2026 May · PMID 42157263 · Full text
BACKGROUND: Leucine-rich glioma-inactivated antibody associated autoimmune encephalitis (LGI-1 AE) is a rare immune mediated neuroinflammatory disease resulting in seizures and cognitive impairment. LGI-1 AE can respond...
BACKGROUND: Leucine-rich glioma-inactivated antibody associated autoimmune encephalitis (LGI-1 AE) is a rare immune mediated neuroinflammatory disease resulting in seizures and cognitive impairment. LGI-1 AE can respond well to immunotherapy, however residual symptoms, particularly cognitive dysfunction may persist despite treatment. We have previously identified perturbations of peripheral innate immune cells (monocytes) in LGI-1 AE in the treated (chronic) phase of the disease. To further understand these peripheral changes, we performed a proteomic analysis of plasma from individuals with LGI-1 AE in the untreated (acute) and chronic phase of the illness. METHODS: High-throughput proteomic profiling was performed on plasma samples from nine acute and 27 chronic LGI-1 AE participants and 16 age- and sex-matched controls using the SomaLogic 11 k proteomic panel. Differentially expressed proteins (DEP) were identified using limma with false discovery rate (FDR) < 0.05. Bulk RNA sequencing was performed on isolated monocytes from ten of the participants with chronic LGI-1 AE and 28 controls. Differential gene analysis was performed using DESeq2 with FDR < 0.1. Pathway analysis was performed on the transcriptomic and proteomic datasets with gene set enrichment analysis using the Gene Ontology Biological Processes database and FDR < 0.05. RESULTS: The plasma analysis identified 215 overexpressed and 1015 suppressed proteins in the acute cohort compared with the healthy cohort. Upregulated proteins included proteins related to innate immune activation, chemoattractants for myeloid cells, components of the complement cascade as well as lymphocyte signalling and activation molecules. Significantly downregulated pathways included those related to autophagy. There were no significantly differentially expressed proteins (DEP) between the acute and chronic or chronic and control cohorts. Monocyte transcriptomic analysis revealed 18 upregulated and 170 downregulated genes, highlighting interleukin (IL)-6 and downstream IL-6 pathway signalling as key dysregulated pathways. CONCLUSIONS: This study identified IL-6 signalling and activation of the terminal complement cascade as potential pathophysiological immune mechanisms, highlighting opportunities for therapeutic repurposing using existing agents in LGI-1 AE. In addition, the observed suppression of autophagy- related pathways suggests a previously underappreciated mechanism that may contribute to disease pathogenesis, warranting further investigations into the role of autophagy dysregulation in CNS autoimmunity associated with LGI-1 AE.
Tissue-resident macrophages maintain choroidal homeostasis by complement dependent and independent mechanisms.
Gong J, Ghotbaldini S, Viniak R … +2 more , Rajesh A, Lavine JA
J Neuroinflammation · 2026 May · PMID 42152120 · Full text
BACKGROUND: Age-related macular degeneration (AMD) is characterized by disruption of the choriocapillaris (CC) and retinal pigment epithelium (RPE) dysfunction, leading to drusen accumulation. The CC and RPE form a tight...
BACKGROUND: Age-related macular degeneration (AMD) is characterized by disruption of the choriocapillaris (CC) and retinal pigment epithelium (RPE) dysfunction, leading to drusen accumulation. The CC and RPE form a tightly interdependent unit that maintains homeostasis where the CC supplies oxygen and nutrients to the RPE, while the RPE produces vascular endothelial growth factor (VEGF) to maintain the CC. Genetic studies link alternative complement pathway variants to AMD, and complement deposition on the CC increases during both aging and AMD. Macrophages express complement protein, receptors, and inhibitors, suggesting that they may be a missing link in understanding the role of complement in AMD. In support, previous groups have shown that macrophage depletion disrupts RPE-CC homeostasis, leading to AMD-like pathology, but the mechanism remains unclear. METHODS AND RESULTS: To investigate the role of macrophages in CC-RPE homeostasis, we generated Cx3cr1Csf1r and Ms4a3Rosa26 mice. In Cx3cr1Csf1r mice, tamoxifen administration induced diphtheria toxin receptor (DTR) expression, allowing ablation of all macrophages (many tamoxifen injections) or long-lived, tissue-resident macrophages (tamoxifen followed by a 3-4 week wash out period). Ms4a3Rosa26 mice were used to deplete monocyte-derived macrophages. Ablation of all macrophages caused decreased CC density, increased CC apoptosis, RPE disorganization, and membrane attack complex (MAC) accumulation. Tissue-resident macrophage ablation phenocopied this result while monocyte-derived macrophage ablation had no phenotype. Additionally, long-term depletion of tissue-resident macrophages led to formation of drusen-like sub-RPE deposits and retinal thinning, mimicking AMD pathology. Finally, pharmacologic depletion of all macrophages similarly reduced CC density to genetic ablation, but C3 mice showed an attenuated phenotype. CONCLUSIONS: These data demonstrate that long-lived, tissue-resident macrophages are essential for maintaining CC-RPE homeostasis while monocyte-derived macrophages are dispensable in this context. Further, ocular macrophage ablation led to MAC accumulation, while C3 mice were resistant to CC regression. Together, these findings suggest that tissue-resident choroidal macrophages maintain CC-RPE homeostasis partially by complement dependent mechanisms. Further, the loss of tissue-resident choroidal macrophages over time is a potential mechanism of AMD pathogenesis.
A novel interoceptive subfornical organ to infralimbic cortex mechanism relays airway inflammation effects on fear extinction.
Allgire E, McAlees JW, Ahlbrand RA … +14 more , Mancz E, Vollmer LL, Winter A, McMurray KMJ, Maile L, Sanders B, Ryan WG, Pool AH, Ifergan I, Wohleb ES, Davidson S, McCullumsmith RE, Lewkowich IP, Sah R
J Neuroinflammation · 2026 May · PMID 42152094 · Full text
There is growing interest in the impact of internal body states on the brain and behavior. The detrimental effects of chronic lung inflammation on mental health are well recognized; however, underlying mechanisms are not...
There is growing interest in the impact of internal body states on the brain and behavior. The detrimental effects of chronic lung inflammation on mental health are well recognized; however, underlying mechanisms are not known. Here, using a murine model of allergic asthma we report compromised fear extinction in mice with severe but not mild airway inflammation (AI); an effect abolished by anti-interleukin-17 A (IL-17 A) antibodies. Investigation of innate immune cells, microglia as-well-as transcriptomic signatures in the subfornical organ (SFO), a brain interoceptive node lacking a traditional blood-brain-barrier, revealed significant alterations in severe AI mice. IL-17 Receptor A (IL-17RA) was expressed in SFO microglia and upregulated in severe AI mice. Notably, ablation of microglial IL-17RA improved fear extinction in severe AI mice. Furthermore, we identified direct SFO projections to the infralimbic (IL) cortex, a key area regulating extinction. Importantly, chemogenetic inhibition of the SFO-IL circuit led to improved fear extinction in severe AI mice. Collectively, we report a unique body-to-brain interoceptive mechanism engaging the SFO microglia and an SFO-to-IL circuit, through which airway inflammatory mediators compromise fear extinction. Beyond asthma, our findings are relevant to other pulmonary pathologies (e.g. bacterial pneumonia, ARDS, COVID-19) highlighting a risk for cortical dysfunction and fear pathologies such as PTSD.
Chronic activity-based anorexia triggers a glial response in the hippocampus independent of intestinal epithelial toll-like receptor 4.
Rousseau L, Demangeat T, Salaün C … +12 more , Queguiner C, Guérin C, Bôle-Feysot C, Maiga O, Tiffay A, Léon F, Cornaille L, Ribet D, do Rego JC, do Rego JL, Langlois L, Coëffier M
J Neuroinflammation · 2026 May · PMID 42152085 · Full text
Anorexia nervosa is characterized by maladaptive eating behavior and psychiatric comorbidities, which could be explained by a neuroinflammation. A gut dysbiosis could link gastrointestinal alterations to central dysfunct...
Anorexia nervosa is characterized by maladaptive eating behavior and psychiatric comorbidities, which could be explained by a neuroinflammation. A gut dysbiosis could link gastrointestinal alterations to central dysfunctions, particularly via the toll-like receptor 4 (TLR4), which has been shown to play a key role in the activity-based anorexia (ABA) model. We aimed to evaluate the neuroinflammation and its behavioral consequences in the ABA model, and to decipher the role of the microbiota-gut-brain axis, and more specifically of TLR4, in these alterations of the central nervous system. We show that chronic restriction is more strongly associated with gut inflammation, cecal microbiota alteration and neuroinflammatory processes in the hippocampus than acute restriction. The hippocampal glial response is characterized by a loss of astrocyte density, and an increased number of deramified microglia. We further demonstrate that these alterations are independent of TLR4 expressed by intestinal epithelial cells. In conclusion, our results highlight that the chronicity of ABA-associated undernutrition alters the response of glial cells in the hippocampus that is linked with changes in microbiota composition, highlighting the importance of faster diagnosis and treatment of AN.
Lung microbiota-derived deoxyinosine alleviates TBI-aggravated sepsis-induced lung injury via the S100A9/RAGE pathway.
Wang B, Gu A, Yang Y … +3 more , Liu X, Liu R, Wang Y
J Neuroinflammation · 2026 May · PMID 42152078 · Full text
Traumatic brain injury (TBI) frequently leads to severe systemic complications, with pulmonary dysfunction acting as a major determinant of poor prognosis in survivors. While the lung microbiota is increasingly recognize...
Traumatic brain injury (TBI) frequently leads to severe systemic complications, with pulmonary dysfunction acting as a major determinant of poor prognosis in survivors. While the lung microbiota is increasingly recognized as a critical regulator of pulmonary immune homeostasis, the specific mechanisms by which TBI remotely remodels the lung microenvironment to exacerbate secondary insults, such as sepsis-induced acute lung injury (ALI), remain poorly understood. To investigate this mechanism, we established a murine model combining controlled cortical impact with LPS-induced sepsis and analyzed bronchoalveolar lavage fluid by 16S rRNA sequencing and untargeted metabolomics. We further conducted microbiota depletion and transplantation experiments to establish causality, alongside molecular docking, Co-IP (co-immunoprecipitation), and transgenic mouse models to elucidate molecular pathways. Our results demonstrate that TBI significantly disrupts the lung microbiota, characterized by a reduction in Corynebacterium, and decreases the levels of the metabolite deoxyinosine. Microbiota transplantation from TBI mice worsened sepsis-induced lung injury in recipients, whereas deoxyinosine administration alleviated tissue damage by promoting the polarization of alveolar macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Mechanistically, deoxyinosine binds directly to S100A9, competitively inhibiting its interaction with the Receptor for Advanced Glycation End Products (RAGE), which subsequently suppresses downstream NF-κB signaling. This study identifies a novel brain-lung axis interaction mediated by microbiota-derived deoxyinosine and highlights the S100A9/RAGE pathway as a promising therapeutic target for preventing post-TBI multi-organ dysfunction.
ABCA1-mediated lipid efflux restrains oxidative stress and neuroinflammation after spinal cord injury.
Shao Y, Liu J, Zhao J … +10 more , Xue K, Wu X, Cao H, Bao R, Sun Q, Zhang Y, Gao P, Luo M, Chen J, Yin G
J Neuroinflammation · 2026 May · PMID 42141417 · Full text
Spinal cord injury (SCI) triggers a persistent inflammatory microenvironment that contributes to secondary tissue damage and neurological dysfunction. However, the metabolic mechanisms sustaining activation of lesion-ass...
Spinal cord injury (SCI) triggers a persistent inflammatory microenvironment that contributes to secondary tissue damage and neurological dysfunction. However, the metabolic mechanisms sustaining activation of lesion-associated phagocytes remain incompletely understood. Here, we identify lipid-laden microglia/macrophages as a metabolically stressed inflammatory state that emerges after SCI and investigate the role of lipid efflux in regulating this process. Single-nucleus and immune-enriched transcriptomic analyses revealed coordinated upregulation of cholesterol transport and inflammatory pathways in lesion-associated phagocytes. Among lipid transporters, the ATP-binding cassette transporter ABCA1 was consistently induced across post-injury stages. Conditional deletion of ABCA1 in Cx3cr1-lineage cells led to excessive lipid droplet accumulation, enhanced reactive oxygen species production, sustained pro-inflammatory cytokine expression, and impaired locomotor recovery following SCI. To therapeutically target this pathway, we performed structure-guided virtual screening and identified the small molecule Z231 as an ABCA1-binding compound. Pharmacological activation of ABCA1 reduced lipid accumulation, suppressed oxidative stress and inflammatory gene expression, and partially restored mitochondrial metabolic balance in microglia exposed to myelin debris. In vivo, systemic Z231 administration attenuated inflammatory signaling and improved functional recovery after SCI. Together, these findings identify ABCA1-mediated lipid efflux as a key regulator of microglial metabolic stress and neuroinflammation after spinal cord injury, and suggest that targeting lipid handling pathways may represent a potential therapeutic strategy for SCI.
IL-1-mediated vitreous inflammation as an early indicator of retinal ganglion cell loss following acute optic nerve injury.
Chang S, Fan W, Wu J … +8 more , Xu L, Lee VA, Zhang C, Kronenberg EP, Xu W, Yang H, Zhang HF, Liu X
J Neuroinflammation · 2026 May · PMID 42135831 · Full text
BACKGROUND: Retinal ganglion cell (RGC) degeneration in optic neuropathies is often preceded by neuroinflammatory changes, yet the earliest in vivo indicators of this process remain poorly defined. Vitreous hyperreflecti...
BACKGROUND: Retinal ganglion cell (RGC) degeneration in optic neuropathies is often preceded by neuroinflammatory changes, yet the earliest in vivo indicators of this process remain poorly defined. Vitreous hyperreflective foci (VHRFs) emerging within 24 h following optic nerve crush (ONC) might represent a promising early in vivo indicator of RGC loss. METHODS: VHRFs were longitudinally tracked by visible-light optical coherence tomography (vis-OCT) imaging post-ONC. Whole-eye sectioning, immunohistochemistry, and confocal imaging revealed the identity and migration of the VHRFs. RNAscope in situ hybridization detected cytokine mRNA expression, and IL-1 signaling was pharmacologically inhibited by intracameral administration of an IL-1 receptor antagonist: Anakinra post-ONC. Statistical differences between experimental groups were assessed by Student's t-test, one-way and two-way ANOVA. RESULTS: Longitudinal vis-OCT imaging revealed that VHRFs emerged as early as 6 h post-injury and peaked before the significant RGC loss. The VHRFs corresponded to activated amoeboid cells undergoing vertical migration from the outer to inner retina and horizontal movement toward the optic nerve head area. Similar amoeboid cells were also observed in the anterior segment, suggesting a global ocular inflammatory response to the ONC injury. Elevated IL-1β expression was detected in vitreous amoeboid cells, and blockade of IL-1 signaling significantly reduced VHRFs, suppressed microglial migration, and delayed RGC loss. CONCLUSIONS: Our findings identify VHRFs as a previously unrecognized early danger signal for RGC degeneration and highlight IL-1-mediated inflammation as a tractable early therapeutic target for preventing RGC degeneration and vision loss.
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