J Neuroinflammation [JOURNAL]
Sun
200 papers
Multi-dimensional decoding of the TSPO signal in animal models of neuroinflammation using fluorescence-conjugated DPA714.
Song H, Zhu Z, Xiao L … +16 more , Zhao Q, Li C, Lv A, Yu X, Gao Z, Lin J, Wang Y, Zhang Y, Zhang L, Li R, Yao S, Cui M, Lin Y, Fu Y, Yong VW, Li R
J Neuroinflammation · 2026 Jun · PMID 42343311 · Full text
UNLABELLED: Neuroinflammation is a core pathological process in multiple central nervous system diseases. Although positron emission tomography (PET) targeting the translocator protein (TSPO) (e.g., ¹⁸F-DPA-714) is widel...
UNLABELLED: Neuroinflammation is a core pathological process in multiple central nervous system diseases. Although positron emission tomography (PET) targeting the translocator protein (TSPO) (e.g., ¹⁸F-DPA-714) is widely used for in vivo inflammatory imaging, the cellular heterogeneity and functional states underlying its imaging signals remain unclear, severely limiting its mechanistic research and clinical translational value. This study used the multifunctional fluorescent TSPO probe (Cy5-PEG3-DPA714) to establish a multidimensional decoding framework that enables systematic analysis of the TSPO signal in neuroinflammation across in vivo, tissue, and single-cell levels. Multiple animal models demonstrated the probe’s ability to dynamically monitor acute and chronic neuroinflammation noninvasively in vivo. Histopathology confirmed that the TSPO signal mainly comes from activated Iba1 microglia. Using the probe’s fluorescence properties, we effectively isolated specific microglial subpopulations with distinct TSPO signaling profiles via flow cytometry. Single-cell analysis revealed that the TSPO signal is specifically enriched in a microglia subpopulation with TSPO probe. Importantly, this subpopulation shares features with disease-associated microglia (DAM), exhibiting a robust pro-inflammatory phenotype and significant metabolic reprogramming. Furthermore, we found that TSPO probe microglia are highly dependent on the Colony Stimulating Factor 1 Receptor (CSF1R) signal pathway, and selective elimination using the CSF1R inhibitor (PLX3397) reduces neuroinflammation. This study systematically decodes the TSPO signal in neuroinflammation through a multimodal approach, providing novel insights and tools for precision therapeutic strategies targeting specific pathological microglia subpopulations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03829-9.
The complement system in Alzheimer's disease: evaluating biomarker potential in a complex neuroimmune context.
Soni H, Sutherland GT, Hofer MJ
J Neuroinflammation · 2026 Jun · PMID 42337797 · Full text
Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these,...
Neuroinflammatory processes are increasingly recognised as important modulators of Alzheimer's disease (AD) progression, driving interest in immune-related biomarkers beyond classical pathological measures. Among these, the complement system has attracted attention because of its interactions with amyloid-β (Aβ) and tau pathology, genetic associations with AD risk, and evidence of activation within affected brain regions. However, these biological observations do not directly translate into straightforward biomarker signals. Complement activity is highly dynamic, spans multiple activation and regulatory states, and may reflect both central and peripheral immune processes. This complexity limits interpretation when complement markers are assessed in isolation, as age, systemic inflammation, vascular comorbidity, and blood-brain barrier integrity can influence measured levels. Current evidence does not support complement-derived biomarkers as stand-alone diagnostic classifiers comparable to established amyloid, tau, and neurodegeneration (AT(N)) measures. Their independent or additive value within multimodal biomarker frameworks remains unclear, partly because of cohort heterogeneity, incomplete assay harmonisation, uncertain tissue-source attribution, and limited longitudinal validation. This review critically evaluates complement-derived measures as biologically informative markers of neuroimmune activity in AD, distinguishing biological plausibility from analytical and clinical utility. We argue that their most defensible current role is within multimodal biomarker frameworks, where they may provide context-specific information on inflammatory state rather than function as independent diagnostic, staging, or treatment-monitoring tools. Progress toward clinical application will require rigorous standardisation, mechanistic clarification, and validation across large, longitudinal, and diverse cohorts.
Bortezomib-induced gastrointestinal dysfunction, peripheral neuropathy and neuroimmune signalling are influenced by the gut microbiota in mice.
Scott JS, Munir S, Lynn MA … +21 more , Duggan JA, Castro J, Harrington AM, Brierley SM, Schober G, Cash K, Gutschmidt B, Hutchinson MR, Yong A, Costello SP, Sikdar S, Tangseefa P, Hewett DR, Cross CB, Park SB, Ryan FJ, Zannettino ACW, Lynn DJ, Vandyke K, Wardill HR, Mrozik KM
J Neuroinflammation · 2026 Jun · PMID 42337655 · Full text
BACKGROUND: Peripheral neuropathy and gastrointestinal dysfunction are frequent, debilitating side effects of the neurotoxic myeloma drug bortezomib that reduce quality of life and adherence to optimal therapy. Therapeut...
BACKGROUND: Peripheral neuropathy and gastrointestinal dysfunction are frequent, debilitating side effects of the neurotoxic myeloma drug bortezomib that reduce quality of life and adherence to optimal therapy. Therapeutic strategies to manage these complications are limited. Here, we have developed a mouse model of bortezomib side effects to investigate the role of the gut microbiota in their development. METHODS: C57BL/6 specific pathogen-free (SPF), germ-free (GF) and ex-GF mice (colonised with healthy gut microbiota via faecal microbiota transplantation [FMT]) were treated with bortezomib (1 mg/kg) twice-weekly for two weeks. Neurotoxicity and neuroimmune signalling were assessed by serum neurofilament light chain (NfL) quantitation and real-time qPCR analysis of inflammatory markers in sensory and autonomic nerve ganglia, respectively. Faecal microbiota composition was characterised using 16S rRNA gene sequencing. Bortezomib side effects were assessed using behavioural phenotyping, von Frey mechanical sensitivity and rotarod testing, and FITC-dextran gut permeability and Evans Blue dye transit assays. RESULTS: Bortezomib-treated SPF mice displayed altered spontaneous behaviour and developed acute gastric retention, altered gastrointestinal motility and increased intestinal permeability, in the absence of intestinal micro-architecture changes. Concurrently, bortezomib induced sensory loss in, and increased grooming of, paws, and reduced motor performance, indicative of peripheral neuropathy. Bortezomib neurotoxicity was evidenced by elevated serum NfL levels and neuroimmune signalling in sciatic nerve dorsal root and vagal nerve nodose ganglia. In SPF mice, bortezomib altered gut microbiota composition with an acute decrease in microbial diversity and expansion of Lactobacillus gasseri. Notably, GF mice developed a milder symptom profile following bortezomib treatment compared with SPF mice, while FMT mice did not develop overt bortezomib side effects despite displaying evidence of nerve damage. CONCLUSIONS: This is the first study to model gastrointestinal side effects of bortezomib in rodents, implicating neuroimmune dysregulation of the vagus nerve. Our data show that the gut microbiota is not a primary driver of bortezomib side effects. However, the absence of a symptom profile in FMT mice suggests that, in GF mice, the gut microbiota beneficially modulates the host to protect against bortezomib side effects. Further studies are required to determine whether this can be harnessed to mitigate clinical complications of bortezomib.
Immunopathogenesis of neuropsychiatric systemic lupus erythematosus: current insights into inflammatory and thrombotic pathways.
Adamski I, Wardowska A
J Neuroinflammation · 2026 Jun · PMID 42337641 · Full text
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance, systemic inflammation, autoantibody production, and immune complex formation. Neuropsychiatric systemic lupus erythem...
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of immune tolerance, systemic inflammation, autoantibody production, and immune complex formation. Neuropsychiatric systemic lupus erythematosus (NPSLE) represents one of the most severe manifestations of the disease and may involve both the central and peripheral nervous systems. Its pathogenesis remains incompletely understood and reflects the interplay among systemic immune dysregulation, vascular injury, blood-brain and blood-CSF barrier dysfunction, and local neuroinflammatory processes.Current evidence supports two partially overlapping pathogenic pathways: an autoimmune-inflammatory and a thrombo-ischemic pathway. These mechanisms promote disruption of the blood-brain barrier, infiltration of immune cells into the central nervous system, activation of microglia, and neuronal dysfunction. Increasing evidence also highlights the role of neutrophil extracellular traps, complement activation, type I interferon signaling, and autoreactive lymphocytes in driving neuroinflammation.The heterogeneity of clinical manifestations and the diversity of underlying mechanisms make NPSLE a major diagnostic and therapeutic challenge. This review summarizes current knowledge on the immunopathogenesis of NPSLE, with particular attention to the strength of evidence supporting individual mechanisms. Human clinical studies provide important associative data, whereas animal models and cell-based systems offer mechanistic insight into selected pathways. We also discuss emerging biomarkers, limitations of current evidence, and potential therapeutic targets that may improve future diagnosis, stratification, and management of NPSLE.
PDZD8 overexpression alleviates early brain injury via regulating MERCs integrity after experimental subarachnoid hemorrhage.
Deng P, Wu X, Liu Y … +9 more , Song B, Liu X, Yang X, Luo H, Peng J, Li H, Wang Z, Wang Z, Li W
J Neuroinflammation · 2026 Jun · PMID 42337592 · Full text
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder with high acute mortality and long-term neurological disability, and early brain injury (EBI) characterized by mitochondrial dysfunction, oxidative...
Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disorder with high acute mortality and long-term neurological disability, and early brain injury (EBI) characterized by mitochondrial dysfunction, oxidative stress, and neuronal apoptosis is a pivotal determinant of poor prognosis. Mitochondria-endoplasmic reticulum contact sites (MERCs) are specialized membrane domains essential for maintaining cellular homeostasis via calcium trafficking and lipid exchange, but their regulatory mechanisms in SAH-induced EBI remain largely undefined. Here, we investigated the role and underlying mechanism of PDZD8, a core MERCs-stabilizing protein, in SAH pathogenesis using in vivo endovascular perforation models of male C57BL/6 mice and in vitro oxyhemoglobin (OxyHb)-challenged primary cortical neurons/HT22 cells, combined with PDZD8 overexpression, CRISPR/Cas9-mediated knockout, and C884A site-directed mutagenesis. Results demonstrated that PDZD8 was neuron-specifically downregulated at 48 h post-SAH, which closely correlated with MERCs structural disruption detected by transmission electron microscopy, impaired mitochondrial respiration analyzed via Seahorse assays, excessive reactive oxygen species production, and severe neuronal damage assessed by Nissl staining. PDZD8 overexpression preserved MERCs integrity, restored mitochondrial metabolic balance, mitigated oxidative stress, and ameliorated neurobehavioral deficits evaluated by modified neurological severity scores, rotarod, and open field tests. Mechanistically, SAH-induced PDZD8 downregulation was associated with enhanced global S-nitrosylation and post-translational regulation at cysteine 884 (C884), promoting its ubiquitination and proteasomal degradation, while C884A mutation abrogated this process. Our findings reveal a previously unrecognized mechanism involving S-nitrosylation-associated ubiquitination of PDZD8 in SAH-induced MERCs dysfunction and EBI, highlighting PDZD8 as a promising therapeutic target for SAH treatment.
Gasdermin D-dependent neutrophil pyroptosis exacerbates Coxsackievirus A6-induced neuroinflammation through NET formation.
Hu Q, Li D, Xie Y … +9 more , Wang F, Sun T, Ji W, Zhu P, Long J, Yang H, Chen S, Jin Y, Duan G
J Neuroinflammation · 2026 Jun · PMID 42332748 · Full text
BACKGROUND: Coxsackievirus A6 (CVA6) is a nonenveloped, single-stranded RNA virus linked to neurological complications. Emerging evidence suggests neutrophil pyroptosis drives inflammation. However, the role of neutrophi...
BACKGROUND: Coxsackievirus A6 (CVA6) is a nonenveloped, single-stranded RNA virus linked to neurological complications. Emerging evidence suggests neutrophil pyroptosis drives inflammation. However, the role of neutrophil pyroptosis in CVA6 pathogenesis remains unexplored. METHODS: Ten-day-old wild-type (WT), Caspase-1 KO, and GSDMD KO mice were infected with a lethal dose of CVA6. For in vivo and in vitro studies, we used the caspase-1 inhibitor belnacasan, disulfiram, and anti-Ly6G antibody. We also generated neutrophil-specific PAD4-knockout mice (PAD4 Ne-KO) by deleting Padi4 under the S100A8 promoter. Post-infection, clinical scores, survival, and body weight were monitored. Brain tissues and bone marrow-derived neutrophils (BMDNs) were collected for analysis. Key methods included qPCR, Western blotting, histology/immunofluorescence, flow cytometry, and TEM to assess pyroptosis, inflammation, and immune cell infiltration. Findings were further validated using blood samples from HFMD patients. RESULTS: In this study, we investigated how the Caspase-1/GSDMD pathway mediates neutrophil extracellular trap (NET) release and drives CVA6-induced neuroinflammation. CVA6 infection increased neutrophil numbers in mouse brain and peripheral blood, along with elevated MPO-DNA-a NET marker. In BMDNs, degranulation and NET formation occurred by 24 hpi, accompanied by Caspase-1/GSDMD activation. Caspase-1 knockout prolonged survival and reduced GSDMD-N expression in brain neutrophils; pharmacological Caspase-1 inhibition decreased mature IL-1β and IL-18 in brain tissue and suppressed CVA6 replication in BMDNs. Together, in vitro and in vivo data indicate that Caspase-1/GSDMD activation and NETosis critically contribute to CVA6-induced brain injury. This was confirmed by GSDMD knockout or disulfiram-mediated GSDMD inhibition, both of which markedly reduced NET release and neuropathology. Notably, global neutrophil depletion worsened infection-suggesting a protective role-whereas neutrophil-specific PAD4 knockout improved survival. Clinically, GSDMD expression showed a significant positive correlation with NETosis markers in patient samples from CVA6-infected individuals. CONCLUSION: These findings enhance understanding of enteroviral pathogenesis, identify GSDMD as a promising therapeutic target, and provide a novel framework for developing precision interventions that reduce excessive inflammation without impairing essential host defenses.
Neuro-immune crosstalk in the tumor microenvironment: mechanisms and therapeutic implications for cancer immunotherapy.
Fan Z, Wang N, Zhang B … +6 more , Deng K, Fu J, Ma L, Li J, Xu Z, Guo Y
J Neuroinflammation · 2026 Jun · PMID 42324469 · Full text
The nervous system is a critical regulator of the tumor microenvironment (TME), extending beyond structural innervation to influence tumor initiation, progression, and therapeutic response. Neural regulation operates thr...
The nervous system is a critical regulator of the tumor microenvironment (TME), extending beyond structural innervation to influence tumor initiation, progression, and therapeutic response. Neural regulation operates through synapse-like interactions and paracrine, neurotransmitter-mediated, and electrochemical signaling, thereby shaping both malignant and stromal compartments. These signals modulate immune-cell phenotypes, promote T-cell exhaustion, and expand immunosuppressive populations, thereby contributing to immune evasion and resistance to immunotherapy. Emerging evidence highlights bidirectional crosstalk, whereby neural activity supports tumor growth, metastasis, metabolic reprogramming, and immune suppression, while tumor-derived signals reciprocally remodel neural activity. This dynamic crosstalk defines a neuro-immune-tumor regulatory network that represents an important layer of tumor biology. Despite recent advances, how neural, immune, and metabolic pathways are integrated within the TME remains incompletely understood. Cancer neuroscience has therefore emerged as an interdisciplinary field for elucidating these mechanisms and identifying therapeutic vulnerabilities. Targeting the neuro-immune axis through neuromodulation, neuroactive agents, and combination immunotherapy may improve immunotherapy efficacy and advance precision oncology.
Targeting the neuro-immune axis: immunological mechanisms and therapeutic strategies in male sexual dysfunction.
Hu Z, Luo J, Lou J … +3 more , Deng J, Gong ZT, Chen J
J Neuroinflammation · 2026 Jun · PMID 42323649 · Full text
Male sexual dysfunction (MSD) is a multifactorial condition in which traditional models focusing on vascular, endocrine, and psychogenic factors are insufficient. Emerging evidence highlights dysregulated crosstalk betwe...
Male sexual dysfunction (MSD) is a multifactorial condition in which traditional models focusing on vascular, endocrine, and psychogenic factors are insufficient. Emerging evidence highlights dysregulated crosstalk between the nervous and immune systems-the neuroimmune axis-as a potential unifying pathological substrate. This review synthesizes fragmented yet compelling evidence linking neural injury, chronic inflammation (both systemic and neurogenic), and immune dysregulation to the pathogenesis of MSD. We propose a novel integrative framework in which disruption of the neuro-immune axis serves as a convergent pathway for diverse etiologies, ranging from diabetic neuropathy to chronic pelvic pain. Central to this framework is the concept that immune-mediated processes exacerbate neural and vascular damage, creating a self-perpetuating cycle of dysfunction. Building on this mechanistic perspective, we explore the translational potential of neurosurgical and neuromodulatory strategies-such as sacral neuromodulation and vagus nerve stimulation-to restore neuroimmune homeostasis. Although direct clinical evidence in MSD remains limited, insights from related fields, including chronic pain and autoimmune disorders, provide a strong rationale for further investigation. This review aims to bridge mechanistic insights with therapeutic innovation, charting a course for future research into precision neuromodulation as a promising frontier for refractory MSD.
Early-life lung injury and the developing brain: a lung-brain axis perspective on neurodevelopmental disorders.
Li C, Wang F, Tang X … +8 more , Wang L, Liu C, Chen X, Lyu W, Li D, Li J, Kong X, Wei P
J Neuroinflammation · 2026 Jun · PMID 42321914 · Full text
Emerging evidence indicates that early-life lung injuries-including bronchopulmonary dysplasia, childhood asthma, recurrent respiratory infections, and environmental tobacco smoke exposure-are significantly associated wi...
Emerging evidence indicates that early-life lung injuries-including bronchopulmonary dysplasia, childhood asthma, recurrent respiratory infections, and environmental tobacco smoke exposure-are significantly associated with an increased risk of neurodevelopmental disorders such as cognitive impairment, autism spectrum disorder, attention-deficit/hyperactivity disorder, and emotional or behavioral affections. The developing brain is particularly vulnerable during infancy and childhood, and pulmonary insults during this critical window may disrupt normal neurodevelopment through multiple interconnected mechanisms along the lung-brain axis. These mechanisms include the hypoxia-oxidative stress axis, which impairs oligodendrocyte maturation and myelination; pulmonary microvascular injury leading to neuronal energy metabolism dysregulation; systemic inflammation-mediated disruption of the blood-brain barrier; and a cascade from pulmonary inflammation to neuroinflammation, characterized by microglial activation, synaptic dysfunction, and impaired myelination. Together, these pathways converge to produce long-lasting neurodevelopmental consequences. Understanding the lung-brain axis provides a novel theoretical framework for explaining this comorbidity and highlights the need to integrate neurodevelopmental risk assessment and early intervention into the clinical management of early-life lung diseases. Future research should focus on longitudinal cohorts, identification of critical developmental windows, and targeted therapeutic strategies that address both pulmonary and neurological health.
Tau knockout mitigates long-term cognitive impairment following neonatal sepsis via mechanisms involving dendritic structural remodelling and adult hippocampal neurogenesis.
Li H, Yu B, Wang B … +5 more , Sun L, Zhao C, Hu L, Yuan M, Wang H
J Neuroinflammation · 2026 Jun · PMID 42316395 · Full text
One of the leading causes of morbidity and mortality in newborns and preterm infants is neonatal sepsis, which is defined as a systemic inflammatory response caused by a suspected or confirmed infection that occurs durin...
One of the leading causes of morbidity and mortality in newborns and preterm infants is neonatal sepsis, which is defined as a systemic inflammatory response caused by a suspected or confirmed infection that occurs during the first month of life. Adolescents who survive neonatal sepsis often experience severe long-term cognitive impairment and unfavourable neurological outcomes. The foetal brain expresses the Tau protein, a neuronal microtubule-associated protein that is essential for modulating neuronal development, and negative neurodevelopmental effects are linked to aberrant Tau expression. In this study, we investigated the possible role of Tau in the long-term memory and cognitive function deficits caused by neonatal sepsis. We discovered that Tau silencing could attenuate the memory impairment in adolescents caused by early-life inflammation. Furthermore, Tau silencing ameliorated this loss of long-term memory and cognitive function by promoting dendritic structural remodelling in granule neurons and adult hippocampal neurogenesis (AHN) in the hippocampus dentate gyrus (DG). Together, these results suggest that Tau is a possible molecular target for treating neonatal sepsis-induced brain damage and that Tau may influence deficits in long-term memory and cognitive function caused by neonatal sepsis by interfering with the dendritic structure of granule neurons and AHN during neuronal development.
Microglial IRF7-induced lipophagy impairment aggravates lipid droplet overload and impedes neurological recovery after ischemic stroke.
Yin J, Li Y, Miao YL … +9 more , Song XF, Cheng Y, Zhai YJ, Ren J, Yang CH, Zhang HF, Zhang XN, Yang LJ, Fan YY
J Neuroinflammation · 2026 Jun · PMID 42310673 · Full text
Lipid droplet (LD) accumulation in microglia results in a dysfunctional and proinflammatory state after ischemic stroke and worsens neurological outcomes; yet how this accumulation is regulated remains unclear. Interfero...
Lipid droplet (LD) accumulation in microglia results in a dysfunctional and proinflammatory state after ischemic stroke and worsens neurological outcomes; yet how this accumulation is regulated remains unclear. Interferon regulatory factor 7 (IRF7) is an immune regulatory factor whose role in lipid metabolism and autophagy has been increasingly studied in peripheral tissues. However, the role of IRF7 in microglial lipophagy (a selective autophagic process that targets LDs) and poststroke functional recovery remains unexplored. In this study, using a mouse photothrombotic ischemia (PTI) model, we observed that microglia in the peri-infarct region displayed persistent lipophagy impairment and LD accumulation for up to 21 days. Reanalysis of the single-cell RNA sequencing (scRNA-seq) dataset revealed that an Irf7 microglial MG1 subcluster (disease-associated microglia) was significantly associated with autophagy and lipid metabolism poststroke. Furthermore, microglial Irf7 conditional knockout (Irf7 cKO) mice exhibited a significant rescue of lipophagy impairment and an alleviation of the ensuing LD accumulation in microglia, accompanied by enhanced synaptic plasticity and motor functional recovery during the subacute phase poststroke. Consistently, in the 15-month-old distal middle cerebral artery occlusion (dMCAO) model, Irf7 cKO mice also displayed similar improvements. Similar results were also observed in vitro. Mechanistically, Gnai2 was identified as a positively regulated transcriptional target of IRF7. In BV2 cells and primary microglia, Gnai2 knockdown mitigated lipopolysaccharide (LPS)-induced lipophagy impairment, thereby reducing LD accumulation. This treatment also increased the level of phosphatidylcholine (PC), a key lipid for stabilizing small LDs as well as promoting autophagosome formation and autophagic flux. Consistently, microglial Irf7 deletion or knockdown attenuated stroke- or LPS-induced PC reduction both in vivo and in vitro. Furthermore, exogenous supplementation with CDP-choline, an intermediate in PC synthesis, alleviated LD accumulation and lipophagy impairment, thereby improving motor function. Additionally, delayed administration of an inhibitor of stimulator of interferon genes (STING, an upstream target of IRF7) replicated the beneficial effects observed in Irf7 cKO mice, and its effects were not further enhanced by microglial Irf7 deletion. Taken together, these novel findings reveal that persistent impairment of microglial lipophagy is a key contributor to poststroke LD accumulation, and that IRF7 is involved in this process through direct transcriptional activation of Gnai2, which reduces the PC levels. Suppressing IRF7 with a STING inhibitor is a potential strategy for modulating microglial lipid metabolism and promoting functional recovery following stroke.
HMGB1-mediated endoplasmic reticulum stress in monocyte-derived dendritic cells regulates CD4+ T cell immune responses in myasthenia gravis.
Zhang Q, Gu Z, Li Y … +10 more , Yang M, Ma X, Pan X, Bi Z, Lin J, Gui M, Wang F, Zhang M, Li Z, Bu B
J Neuroinflammation · 2026 Jun · PMID 42304385 · Full text
INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disorder characterized by immune dysregulation at the neuromuscular junction. Monocyte-derived dendritic cells (moDCs) are increasingly recognized as key drivers of M...
INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disorder characterized by immune dysregulation at the neuromuscular junction. Monocyte-derived dendritic cells (moDCs) are increasingly recognized as key drivers of MG pathogenesis; however, the mechanisms that govern their dysfunction remain incompletely understood. METHODS: This study integrated human genetics, patient immunophenotyping, and therapeutic evaluation in the experimental autoimmune myasthenia gravis (EAMG) model. Monocytes were isolated and differentiated into moDCs to assess the effects of HMGB1 and its inhibitor, 18α-glycyrrhetinic acid (18α-GA), on the expression profiles, phenotypes, and functions of moDCs. Therapeutic efficacy was further assessed in EAMG using 18α-GA, HMGB1 neutralizing antibody, and adoptive transfer of 18α-GA-induced tolerogenic moDCs. RESULTS: Mendelian randomization (MR) analyses revealed bidirectional causality between MG and moDCs. MG patients exhibited elevated plasma HMGB1 levels and mature phenotypes of moDCs. Mechanistically, HMGB1 activated the IRE1α/XBP1 and NF-κB pathways in moDCs through the engagement of TLR4, thereby inducing endoplasmic reticulum (ER) stress, promoting the activation of moDCs, and driving an imbalance in CD4+ T cell immune responses. Through a multitargeted mechanism of action, 18α-GA effectively inhibited both the IRE1α/XBP1 and NF-κB pathways in moDCs, thereby blunting ER stress and driving the differentiation of moDCs toward tolerogenic phenotypes. The minimal effective dose of 18α-GA alleviated EAMG by counteracting HMGB1-driven, moDC-mediated CD4+ T cell dysfunction, and showed better therapeutic performance compared with HMGB1 neutralizing antibody. Moreover, the adoptive transfer of 18α-GA-induced tolerogenic moDCs was effective in treating EAMG. CONCLUSIONS: HMGB1-mediated ER stress reprogrammed moDCs via the IRE1α/XBP1 and NF-κB pathways to promote pathogenic CD4+ T cell responses in MG. Targeting the HMGB1-ER stress axis in moDCs could restore immune balance and represent a promising therapeutic strategy for MG.
Human iPSC-derived neurons stimulated with IFNγ present HLA class I-restricted antigens to cytotoxic CD8 T cells.
Clarkson BD, Pucci S, Overlee BL … +7 more , Shrestha RB, Mangalaparthi KK, Raja R, Shang P, Curtis M, Pandey A, Howe CL
J Neuroinflammation · 2026 Jun · PMID 42304380 · Full text
Multiple sclerosis lesions are dominated by clonally expanded CD8 T cells within an IFNγ-rich inflammatory microenvironment and neurons may be targets of these effector cells. However, the peptide antigens that CD8 T cel...
Multiple sclerosis lesions are dominated by clonally expanded CD8 T cells within an IFNγ-rich inflammatory microenvironment and neurons may be targets of these effector cells. However, the peptide antigens that CD8 T cells recognize on neurons are largely undefined. Neurons constitutively express low levels of HLA class I, and whether inflamed human neurons are competent to present a class I ligandome, what that ligandome contains, and whether presentation has functional consequences for autoreactive CD8 T cells remain open questions. Here we combine human iPSC-derived neural aggregates (HNAs), HLA class I immunoprecipitation coupled to LC-MS/MS immunopeptidomics, and microfluidic co-culture assays to map IFNγ-induced HLA class I presentation by neurons and to test antigen-specific cytotoxicity. IFNγ stimulation induced HLA class I upregulation in HNAs and enabled recovery of a canonical 8-12-mer class I ligandome enriched for 9-mers. Neuron-restricted expression of a synapsin-driven polyepitope cassette yielded presentation of defined exogenous 9-mer peptides on donor HLA class I molecules and, in the presence of IFNγ, elicited activation of autologous antigen-specific CD8 T cells and antigen-dependent neurite injury. Across four donors, comparative immunopeptidomics identified IFNγ-associated neural peptide repertoires that were distinct from those of matched fibroblasts and enriched for predicted HLA-B binding peptides. β2-microglobulin deletion ablated peptide recovery, and neuron-restricted reconstitution enabled identification of candidate neuron-derived peptides, including recurrent neurofilament light (NEFL)-derived peptides detected across donors. Together, these findings establish a human iPSC-derived platform for studying inflammatory neuronal HLA class I antigen presentation and antigen-dependent CD8 T cell engagement.
A brain-lung circuit drives LPS-induced lung injury via sympathetic neutrophil axis.
Ren S, Yang S, Liu B … +9 more , Zhang Q, Zhao Z, Meng Y, Shao Q, Deng X, Bian J, Cao L, Mo F, Wang J
J Neuroinflammation · 2026 Jun · PMID 42298686 · Full text
Acute respiratory distress syndrome (ARDS) is a fatal complication of sepsis. However, the neural mechanisms underlying the exacerbation of pulmonary inflammation during systemic infection remain largely undefined. We em...
Acute respiratory distress syndrome (ARDS) is a fatal complication of sepsis. However, the neural mechanisms underlying the exacerbation of pulmonary inflammation during systemic infection remain largely undefined. We employed an intraperitoneal lipopolysaccharide (LPS)-induced systemic inflammatory lung injury model and found that systemic inflammation strongly activates corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN), whereas bilateral subdiaphragmatic vagotomy abolished this response. Chemogenetic inhibition of CRH neurons alleviated lung injury and the formation of neutrophil extracellular traps (NETs), whereas chemogenetic activation of CRH neurons exacerbated pathological damage through sympathetic efferent signaling. Additionally, in patients with septic ARDS, β2-adrenergic receptor (ADRB2) expression was upregulated on neutrophils, and ADRB2 signaling delayed neutrophil apoptosis through the PI3K/Akt pathway, whereas ADRB2 blockade promoted neutrophil apoptosis and attenuated lung injury. In summary, we delineate a dysregulated neuroimmune axis in LPS-induced lung injury: systemic inflammatory signals activate the vagal afferent-PVN-sympathetic circuit, which in turn drives a neutrophil-mediated ADRB2-PI3K/Akt signaling pathway that amplifies lung injury. Our study reveals a mechanistic basis for neuroregulatory intervention and indicates that targeting this Brain-lung pathway may offer new therapeutic strategies for ARDS.
Nipah virus infects the brain and triggers neuronal and glial damage in a hamster model.
Valerdi K, Saito T, Paroha R … +6 more , Littlefield K, Plante J, Plante K, Valdebenito S, Maruyama J, Eugenin E
J Neuroinflammation · 2026 Jun · PMID 42298683 · Full text
Nipah virus (NiV) is distributed in South-East Asia and the Western Pacific, with currently active outbreak sites. NiV causes an acute febrile illness with high mortality (40-70%), encephalitis, and long-term disability...
Nipah virus (NiV) is distributed in South-East Asia and the Western Pacific, with currently active outbreak sites. NiV causes an acute febrile illness with high mortality (40-70%), encephalitis, and long-term disability among survivors. Currently, there are no effective therapeutic or preventive interventions, and its potential for explosive spread resulted in its designation as a pathogen of international epidemiological concern. However, the pathophysiology of NiV-induced encephalitis remains unclear. Using a hamster model of NiV infection, we demonstrated that NiV targets several brain areas, such as the cortex and the hippocampus, infecting neurons, astrocytes, and blood-brain barrier cells. NiV infection also induced glial activation, including both microglia and astrocytes, leading to vascular and neuronal compromise and parenchymal lesions. Overall, NiV demonstrates a marked tropism for the central nervous system, resulting in major damage and death.
Astrocyte β-catenin suppression by HIV and methamphetamine drives senescence and dysfunction of MEGF10-dependent phagocytosis, neuronal support, and BBB integrity.
Jana A, Narasipura SD, Szczerkowski J … +2 more , Mamede JI, Al-Harthi L
J Neuroinflammation · 2026 Jun · PMID 42298681 · Full text
Astrocytes are essential regulators of central nervous system (CNS) homeostasis, and their dysfunction can amplify neuroinflammation and neurodegeneration. HIV and methamphetamine (Meth) are known to downregulate β-caten...
Astrocytes are essential regulators of central nervous system (CNS) homeostasis, and their dysfunction can amplify neuroinflammation and neurodegeneration. HIV and methamphetamine (Meth) are known to downregulate β-catenin signaling and induce astrocyte senescence, but whether this senescent state is functionally pathogenic and contributes directly to neuroinflammatory processes remains unclear. Here, we investigated how senescent astrocytes respond across prototypical astrocytic functions.In vitro, human iPSC-derived astrocytes infected with HIV and/or exposed to Meth developed a senescence phenotype (increased p16) accompanied by reduced expression of the phagocytic receptor MEGF10 and impaired engulfment of apoptotic neurons. HIV/Meth exposure also shifted astrocyte secretomes toward proinflammatory profiles (IL-6, CCL2, CXCL1, and ICAM-1), and astrocyte-conditioned media decreased neuronal PSD95 and NFL and disrupted endothelial adherens and tight junction proteins (VE-cadherin, occludin, claudin-5), resulting in increased monocyte transmigration. Mechanistically, pharmacologic activation or lentiviral expression of active β-catenin protected astrocytes from senescence, preserving MEGF10 expression and phagocytic capacity under HIV/Meth exposure, while MEGF10 overexpression independently restored phagocytosis. In a human-mouse chimera model (NSG mice xenotransplanted with human iPSC-derived astrocytes), HIV infection and/or Meth administration increased p16 and reduced MEGF10 expression in engrafted human astrocytes, recapitulating in vitro findings.Together, these studies demonstrate that HIV and Meth suppress β-catenin signaling to drive a functionally disruptive astrocyte senescence program linked to impaired MEGF10-dependent phagocytosis, diminished neuronal support, and compromised blood-brain barrier integrity. Restoring β-catenin signaling and preserving MEGF10 function emerge as rational strategies to prevent astrocyte-driven neuroinflammation and neuropathogenesis in HIV/Meth co-morbidity.
Shared transcriptomic signatures in perilesional and contralesional cortex after ischemic stroke.
Betz D, Alers VA, Kenwood M … +8 more , Zuurbier KR, Coimbra R, Rhoton P, Plautz EJ, Douglas PM, Ramirez DMO, Stowe AM, Goldberg MP
J Neuroinflammation · 2026 Jun · PMID 42298604 · Full text
Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Experimental models have identified repair-associated processes in both the ipsilesional and contralesional...
Stroke induces a transient period of heightened plasticity during which functional recovery is most pronounced. Experimental models have identified repair-associated processes in both the ipsilesional and contralesional cortex, indicating that stroke recovery involves regions both remote and near the lesion. However, most transcriptional studies have focused on the infarct core and peri-lesional cortex (PLC), leaving it unclear whether comparable molecular responses occur in the contralesional cortex (CLC), a region that undergoes substantial remodeling in the absence of direct tissue injury, necrosis, or widespread cellular infiltration. In addition, potential sex-dependent differences in these responses remain incompletely defined, despite known influences of biological sex on post-stroke inflammation and vascular remodeling. To address these gaps, we performed bulk RNA-sequencing of the PLC and CLC at 7 days after photothrombotic stroke, a subacute time point associated with the initiation of repair, in male and female mice. Despite distinct positions relative to the lesion, both regions exhibited robust upregulation of inflammatory signaling, including cytokine-, astrocyte-, and myeloid-lineage-associated pathways. The CLC did not demonstrate a distinct region-specific transcriptional profile; instead, shared signatures between PLC and CLC included genes strongly associated with reactive microglial phenotypes. This shared neuroinflammatory response was largely conserved across sexes. Consistent with these findings, male and female mice exhibited comparable corticospinal tract axonal sprouting originating from the CLC at 6 weeks post-stroke. Together, these findings support a shared neuroinflammatory transcriptional response as a prominent early feature of cortical regions associated with post-stroke plasticity.
Neuroglial P2Y receptor signalling differentially contributes to inflammatory neurodegeneration.
Schubert C, Lopes Fonseca R, Hadjilaou A … +11 more , Vieira V, Degenhardt K, Seemann AL, Hakimy A, Sonner JK, Ludewig P, Magnus T, Schneider M, Müller CE, Hirnet D, Friese MA
J Neuroinflammation · 2026 Jun · PMID 42288884 · Full text
Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocy...
Extracellular adenosine triphosphate (ATP) and diphosphate (ADP) act as key signalling molecules in the central nervous system (CNS) and regulate neuroinflammatory responses through purinergic receptors. Although astrocytes and neurons undergo profound changes in signalling and metabolism during inflammation, the contribution of specific purinergic pathways to inflammation-induced neurodegeneration remains unclear. Here we show that the ADP/ATP-activated Gq-coupled receptor P2Y drives astrocyte-mediated neurotoxicity in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Using plasma membrane-targeted luciferase reporter mice, we demonstrate that extracellular ATP levels are increased during acute EAE. This was accompanied by elevated astrocytic P2ry1 expression, which is also observed in inflammatory MS lesions. In vivo, pharmacological inhibition or astrocyte-specific deletion of P2Y reduced disease severity, astrocytosis, and neuronal loss, whereas neuron-specific deletion exerted only modest effects. Mechanistically, astrocytic P2Y signalling promoted cytokine-induced ERK activation, inflammatory gene expression, and metabolic reprogramming in vitro. In contrast to supernatants from stimulated P2Y-deficient astrocyte culture, supernatants derived from stimulated P2Y-proficient astrocytes reduced neuronal viability, demonstrating neurotoxic effects mediated by astrocyte-derived factors. In contrast, neuronal P2Y signalling primarily contributed to oxidative stress and mitochondrial dysfunction. Together, these findings identify astrocytic P2Y as a key regulator of neuroinflammatory damage and a potential therapeutic target.
TREM2 restrains myeloid inflammasome activation to protect against photoreceptor degeneration.
Wang T, Su L, Szczepan M … +5 more , Wang X, Gregg AT, Guo J, Smith LEH, Sun Y
J Neuroinflammation · 2026 Jun · PMID 42288845 · Full text
Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbat...
Myeloid cells, including infiltrating macrophages and resident microglia, are critical regulators of retinal homeostasis and respond rapidly to photoreceptor stress. Dysregulated myeloid responses, however, can exacerbate retinal degeneration. Triggering receptor expressed on myeloid cells 2 (TREM2) modulates phagocytosis, metabolism, and inflammatory signaling, yet its role in retinal degeneration remains incompletely understood. Here, we investigated TREM2 function in the retinal degeneration 10 (rd10) mouse model of inherited retinal degeneration, characterized by progressive photoreceptor loss and robust myeloid cell activation. TREM2 expression was upregulated in degenerating retinas, and global TREM2-deficiency in rd10 mice exhibited accelerated photoreceptor cell death, reduced outer nuclear layer thickness, disrupted retinal pigment epithelium integrity, and altered microglial spatial dynamics. Single-cell transcriptomics revealed that TREM2-positive microglia express APOE-associated and interferon-primed programs. Global TREM2 deficiency was associated with increased inflammasome-related signaling in retinal myeloid cells, including elevated cleaved caspase-1, cleaved gasdermin D, and mature interleukin-1β, linking amplified immune priming to pyroptotic signaling. Genetic or pharmacological inhibition of gasdermin D significantly mitigated photoreceptor loss in global TREM2-deficient rd10 retinas, demonstrating a functional contribution of inflammasome-associated responses to disease exacerbation. Together, these findings support a protective role for TREM2-associated immune regulation in the degenerating retina and identify downstream inflammasome pathways as potential therapeutic targets in retinal degenerative diseases.
C1q-CD44 interactions regulate microglial phagocytosis, proliferation, and migration.
Sakthivel PS, Villegas AJ, Lakatos A … +6 more , Kaipa M, Lopez JM, Ling A, Elrachid ZH, Karam J, Anderson AJ
J Neuroinflammation · 2026 Jun · PMID 42286716 · Full text
Microglia, the immune cells of the central nervous system (CNS), quickly respond to neurodegeneration by proliferating and migrating to areas of disease, phagocytosing debris, and releasing cytokines to initiate inflamma...
Microglia, the immune cells of the central nervous system (CNS), quickly respond to neurodegeneration by proliferating and migrating to areas of disease, phagocytosing debris, and releasing cytokines to initiate inflammation. Critically, the mechanisms underlying these microglial functions remain only partly understood. One molecular regulator of interest is complement protein C1q, the initiator molecule of the complement cascade that increases 300-fold in healthy aging and accumulates with neurodegeneration. We have previously reported that exogenous C1q treatment alters inflammatory gene expression and cell function in human induced pluripotent stem cell-derived microglia (iMG). Here, we test the hypothesis that C1q induced cell changes are modulated by novel C1q receptor, CD44. We first confirmed expression of five novel C1q receptors at the RNA and protein levels, and then validated C1q-receptor binding on the iMG cell surface using proximity ligation assay. Based on these results, we selected CD44 as an initial target and generated CD44 knockout iMG to test the role of CD44 in the iMG response to C1q. We demonstrate that C1q-CD44 interactions regulate changes in microglial phagocytosis, proliferation, and migration. These data suggest C1q interacts with CD44 to modulate microglial functions that are critical to health and disease, thus informing future directions to test whether these interactions are altered in neurodegenerative disease.
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