J Neuroinflammation [JOURNAL]
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200 papers
Correction: Comprehensive insight on immune landscape in intracerebral hemorrhage patients with single‑cell RNA sequencing: from blood to hematoma.
Du Y, Li G, Ji Z … +6 more , Wang D, Wu J, Liu Y, Kang K, Zhao X, Bian L
J Neuroinflammation · 2026 Apr · PMID 42021372 · Full text
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Microbiota as a regulator of brain vulnerability across lifespan and disease contexts.
Santerre M, Shcherbik N, Sawaya BE
J Neuroinflammation · 2026 Apr · PMID 42021371 · Full text
The gut microbiota influences brain health through inflammatory and metabolic pathways that regulate neurological vulnerability rather than directly causing specific diseases. This framework positions altered microbial c...
The gut microbiota influences brain health through inflammatory and metabolic pathways that regulate neurological vulnerability rather than directly causing specific diseases. This framework positions altered microbial composition as one among many environmental factors that modulate brain resilience across aging and disease contexts. Chronic low-grade inflammation driven by compositional and functional changes in the gut microbiota, intestinal barrier dysfunction, and alterations in bacterial metabolites contributes to systemic immune activation, affecting blood-brain barrier integrity, microglial function, and neuronal stress responses. These mechanisms operate across neurodegeneration, viral-associated cognitive decline, and brain tumor progression without constituting primary disease triggers. Aging amplifies microbiota-mediated inflammatory effects through progressive loss of microbial diversity and increased intestinal permeability. Evidence demonstrates associations between altered microbial composition and brain pathology, though these relationships reflect shared inflammatory pathways rather than direct microbial causation and are substantially confounded by diet, medication use, geographic variation, and disease-related behavioral changes. The vulnerability threshold framework proposed here is distinct from multi-hit models: rather than constituting an independent pathogenic insult, microbiota-derived signals modulate the quantitative threshold at which a given level of neurological stress produces clinical disease expression. This vulnerability-threshold model generates testable predictions: microbiota normalization should delay but not prevent neurodegeneration in high-genetic-risk individuals, and the severity of microbiota-associated inflammatory burden should predict the rate of progression rather than disease identity, predictions that longitudinal intervention trials can now begin to test.
Parkin regulates NLRP3 degradation through chaperone-mediated autophagy to suppress PANoptosis and protect dopaminergic neurons in Parkinson's disease.
Zheng D, Zhang H, Xie A … +10 more , Xiao H, Guan D, Xie Z, Luo J, Cao J, Lin T, Xing L, Xia T, Zou F, Chen J
J Neuroinflammation · 2026 Apr · PMID 42021324 · Full text
Parkinson's Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, a...
Parkinson's Disease (PD) is characterized by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). PANoptosis, a programmed inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, contributes to DA neuron degeneration in PD. The E3 ubiquitin ligase Parkin and the inflammasome sensor NOD-like receptor protein 3 (NLRP3) are known to play critical regulatory roles in DA neuron degeneration. However, whether Parkin modulated NLRP3 via chaperone-mediated autophagy (CMA) to inhibit PANoptosis remained unclear. To verify the above hypothesis, SN4741 cells and C57BL/6 mice were treated with rotenone to establish PD models. PANoptosis activation and DA neurons degeneration were observed in PD models, and these pathological manifestations were mitigated by the NLRP3 inhibitor MCC950. Besides, Parkin interacted with NLRP3, ubiquitinated its K353 residue, and then promoted NLRP3 degradation via CMA. Parkin overexpression or CMA activation alleviated DA neuron damage and PANoptosis, while K353R mutation abolished these effects. It was revealed that Parkin mediated CMA-dependent degradation of NLRP3 (targeting K353) to suppress PANoptosis and protect DA neurons in PD. CMA activators or NLRP3 inhibitors may serve as disease-modifying therapies for PD.
The SHIP1-inflammatory-lipid axis in Alzheimer's disease: from genetic risk to spatiotemporal mechanistic insights.
Xi R, Zheng X, Zhao J … +1 more , Fu Y
J Neuroinflammation · 2026 Apr · PMID 42021321 · Full text
The INPP5D gene, encoding the SHIP1 protein, has been identified as a prominent genetic risk factor for Alzheimer’s disease (AD). However, its multifunctional roles remain complex. SHIP1 serves as a pivotal integrative n...
The INPP5D gene, encoding the SHIP1 protein, has been identified as a prominent genetic risk factor for Alzheimer’s disease (AD). However, its multifunctional roles remain complex. SHIP1 serves as a pivotal integrative node linking microglial immune activation with lipid metabolism. This review synthesizes current evidence on the SHIP1-inflammatory-lipid axis, elucidating how its phosphatase and scaffold functions modulate microglial homeostasis through the PI3K-Akt signaling pathway and the NLRP3 inflammasome. We propose a novel lipid‒lysosome‒inflammation cycle model in which SHIP1 deficiency initiates a self-perpetuating cascade of lipid sequestration and lysosomal impairment that fuels chronic inflammatory priming. Furthermore, we propose a stage-dependent duality of SHIP1, characterized by its transition from a beneficial homeostatic brake in early disease to a pathological checkpoint that hinders essential metabolic and phagocytic adaptation in advanced stages. This dysregulation leads to widespread multicellular network disruption across neurons and the neurovascular unit. Finally, we evaluate current pharmacological strategies and advocate for the precise spatiotemporal modulation of SHIP1 activity to disrupt the converging pathological axes and facilitate next-generation therapies for Alzheimer’s disease.
Type-1 interferons associated with microglial-mediated neuroinflammation in Alzheimer's disease.
Shippy DC, Sande ML, Ulland TK
J Neuroinflammation · 2026 Apr · PMID 42021305 · Full text
Type-1 interferons (IFN-1) are a pleiotropic group of cytokines initially known for their antiviral activity, but recent studies highlight a vital role of IFN-1 in central nervous system (CNS) homeostasis, brain aging, a...
Type-1 interferons (IFN-1) are a pleiotropic group of cytokines initially known for their antiviral activity, but recent studies highlight a vital role of IFN-1 in central nervous system (CNS) homeostasis, brain aging, and neurodegeneration. Alzheimer’s disease (AD) is an age-related neurodegenerative disorder with a complex etiology. The hallmark signs of AD that appear in the brain are amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Neuroinflammation facilitated primarily by microglia is known to drive amyloid and tau pathology, with evidence suggesting IFN-1 as a key player in AD pathogenesis. Activated microglia secrete IFN-1 in response to Aβ accumulation which activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) (JAK/STAT) pathway as well as the cyclic GMP–AMP synthase (cGAS)/stimulator of interferon genes (STING) (cGAS/STING) pathway, resulting in the expression of interferon-stimulated genes (ISGs). Implications of IFN-1 signaling during AD development include neuroinflammation, alterations in microglial morphology (microglial dysfunction), synapse/neuron loss, and cognitive impairment. Additionally, studies suggest blocking/attenuating the IFN-1 response results in reduced AD pathology and improved behavioral deficits. Here, we review the role of IFN-1 in AD pathogenesis. The ability to attenuate IFN-1, coupled with the well-established role of IFN-1 in AD pathogenesis, supports the notion that targeting this neuroinflammatory pathway may be a potential therapeutic strategy for AD.
Enhanced MIF/CD74 axis activity shapes B cell functioning following traumatic spinal cord injury.
Rubio S, Beckers L, Coenen H … +9 more , van Laake-Geelen CCM, Depreitere B, Bamps S, Cornips EMJ, Buelens E, Peuskens D, Deckers J, Somers V, Fraussen J
J Neuroinflammation · 2026 Apr · PMID 42021300 · Full text
A traumatic spinal cord injury (SCI) severely damages the nerve tissue of the spinal cord, often leading to long-term impairment of motor, sensory and autonomic functions. During a secondary injury phase, an inflammatory...
A traumatic spinal cord injury (SCI) severely damages the nerve tissue of the spinal cord, often leading to long-term impairment of motor, sensory and autonomic functions. During a secondary injury phase, an inflammatory immune response is initiated. Current evidence points toward involvement of B cells and the macrophage migration inhibitory factor (MIF)/CD74 axis in SCI pathology. This study aimed to map the complete MIF/CD74 axis across the immune system and analyze its impact on B cell function after traumatic SCI. Peripheral blood samples were obtained from a total cohort of 90 healthy controls (HC) and 70 SCI patients. SCI samples were collected longitudinally in the acute (0 weeks post-SCI), subacute (2 weeks post-SCI), intermediate (3–18 weeks post-SCI) and chronic (26–52 weeks post-SCI) phases post-injury. MIF levels in plasma of SCI patients and HC were measured using ELISA. Relative and absolute levels of immune and B cell subsets, as well as expression of members of the MIF/CD74 axis, were studied using high-dimensional flow cytometry. The functional relevance of MIF/CD74 axis signaling on B cell functions was investigated using in vitro blocking assays. SCI triggered an early immune cell reduction, characterized by decreased absolute numbers of total and MIF/CD74 axis-expressing B cells and immune cells. In contrast, the MIF/CD74 axis was upregulated as MIF receptor surface expression on B cell subsets, as well as frequencies of CD74+, CD44+ and CXCR4+ B cells, were increased during the subacute/intermediate phase post-SCI. MIF plasma levels were increased in SCI patients, yet MIF expression levels were reduced within circulating immune cells, suggesting that the injured spinal cord is the main source of MIF. Importantly, decreased B cell proliferation, activation and cytokine production were observed after blocking of CD74, CD44 or MIF in primary B cells of SCI patients and HC. The observed effects were more pronounced in SCI B cells, highlighting their stronger dependence on MIF/CD74 axis signaling. In conclusion, the complete MIF/CD74 axis plays an important role in post-SCI B cell responses. Our findings warrant further investigation of the MIF/CD74 axis as a potential target for immunomodulatory strategies in SCI treatment.
Tet2 deficiency orchestrates Alzheimer's pathogenesis through oxidative mtDNA-driven cGAS-STING activation.
Hao JP, Cheng ZZ, Wang MY … +11 more , Zhu YP, Chen N, Zhu D, Zhang L, Li YL, Li L, Bai ZF, Xiao XH, Wang JB, Zhang L, Gao D
J Neuroinflammation · 2026 Apr · PMID 42015258 · Full text
Emerging evidence underscores the pivotal role of Ten-eleven translocation 2 (Tet2), as an epigenetic regulator with neuroprotective functions, yet its temporal dynamics and pathogenic contributions to Alzheimer’s diseas...
Emerging evidence underscores the pivotal role of Ten-eleven translocation 2 (Tet2), as an epigenetic regulator with neuroprotective functions, yet its temporal dynamics and pathogenic contributions to Alzheimer’s disease (AD) remain poorly understood. By integrating human longitudinal cohort data with experimental models, we demonstrated that Tet2 deficiency accelerated AD‑like neurodegeneration through oxidative stress-dependent cGAS-STING activation. Clinically, Tet2 loss-of-function carriers among Aβ-positive individuals exhibited significantly accelerated cognitive decline. In mice, Tet2 expression decreased with age and in late‑stage AD models, and constitutive Tet2‑mutant (Tet2mut) mice recapitulated AD-like behaviors and pathology by exacerbating neuroinflammation and impairing neurogenesis and synaptic plasticity. Crucially, Tet2 deficiency induced mitochondrial dysmorphology and heightened oxidative stress in the hippocampus, culminating in DNA damage and robust cGAS-STING activation. Mechanistically, integrative epigenomic analyses further revealed that Tet2 deficiency was associated with hypermethylation of antioxidant gene networks, thereby exacerbating oxidative stress and mitochondrial injury. Notably, antioxidant treatment with N-acetylcysteine (NAC) effectively alleviated oxidative damage, restored mitochondrial function and suppressed cGAS-STING signaling in Tet2-silenced microglia. In vivo, NAC administration in Tet2mut mice improved cognitive performance and synaptic plasticity while reducing neuroinflammation and neuronal loss through inhibition of cGAS-STING signaling. These findings delineate a previously unrecognized epigenetic-immune axis in AD, highlighting Tet2 enhancement and ROS modulation as promising therapeutic strategies.
Nociceptor neurons shape antiviral immunity.
Thomas I, Roger A, Rafei M … +3 more , Gee K, Talbot S, Basta S
J Neuroinflammation · 2026 Apr · PMID 42015248 · Full text
The nervous and immune systems cooperate to protect the host, yet the contribution of sensory neurons to antiviral immunity remains incompletely defined. Nociceptor neurons do more than relay pain: they detect viral prod...
The nervous and immune systems cooperate to protect the host, yet the contribution of sensory neurons to antiviral immunity remains incompletely defined. Nociceptor neurons do more than relay pain: they detect viral products and inflammatory cues through pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), and respond to mediators such as type I interferons (IFNs), tumor necrosis factor (TNF), and interleukin-1β (IL-1β). Upon activation, these fibres release neuropeptides and neurotransmitters, including calcitonin gene-related peptide (CGRP) and substance P (SP), while sympathetic catecholamines provide a parallel neural input that shapes vascular tone, leukocyte trafficking, and effector programmes across tissues. Viral infection can also engage neuro-glial circuits in sensory ganglia and, in some settings, spread directly to the central nervous system (CNS), as described for lymphocytic choriomeningitis virus (LCMV), herpes simplex virus (HSV), and selected influenza A virus (IAV) strains. Here, we synthesize evidence that nociceptors shape antiviral immunity in a context-dependent manner rather than exerting uniform control. Nav1.8⁺ afferents restrain excessive inflammation while supporting dendritic cell (DC) priming of CD8⁺ T cells during cutaneous HSV-1 infection; vagal TRPV1⁺ neurons, a subset of Nav1.8⁺ nociceptors, promote disease tolerance during influenza by tuning lung myeloid responses; CGRP signaling drives T helper (Th) 1 differentiation during acute LCMV infection; and sympathetic adrenergic inputs deepen CD8⁺ T cell exhaustion during chronic infection. Defining these neuro-immune circuits may reveal therapeutic opportunities, but species differences, circuit heterogeneity, and the pleiotropic effects of shared mediators will need to be resolved before these insights can be translated to human disease.
Opioid-induced transcriptional reprogramming of cerebrospinal fluid immune cells is associated with neuroinflammatory signaling in antiretroviral treated SIV-infected rhesus macaques.
Acharya A, Ambikan AT, Neogi U … +5 more , Lamberty BG, Callen S, Buch S, Fox HS, Byrareddy SN
J Neuroinflammation · 2026 Apr · PMID 42010620 · Full text
BACKGROUND: Opioid use is disproportionately high among People with HIV (PWH). Although combined antiretroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognit...
BACKGROUND: Opioid use is disproportionately high among People with HIV (PWH). Although combined antiretroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell RNA sequencing (scRNA-seq) of cerebrospinal fluid (CSF) immune cells to explore how opioid mediated transcriptomic alterations impact neuroinflammatory signaling among PWH using the SIV/rhesus macaque model. METHODS: Herein, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. RESULTS: We observed all major immune cells in CSF, including CD4 + TCM cells, CD4 + TEM cells, CD8+ naïve T cells, CD8 + TCM cells, CD8 + TEM cells, CD14 + Monocytes, CD16 + Monocytes, NK cells, and B cells. Additionally, we found that morphine-mediated relative increase in CD4 + TCM, Treg, and a reduction in CD8 + TEM cell population prior to SIV infection. Chronic use of morphine was associated with a Th1/Th2 T-cell imbalance with a dominance of the Th2 population. In CSF cells from morphine-dependent RMs, there was dysregulation of genes involved in T-cell receptor signaling pathways, apoptosis, PI3K-Akt signaling pathway, cellular senescence, oxidative phosphorylation, and multiple neurodegenerative disorders. The contribution of different cell populations in these processes evolved across disease stages. During the chronic stage of the disease, the expression of disease-associated microglia (DAM) signature genes were significantly up or down regulated in monocytes. Further, cell-cell receptor-ligand interaction analysis revealed altered number of intercellular interactions and signaling strength in morphine vs. saline-administered animals. Specifically, for the CD14 + monocyte populations, the intra/inter-cell communication involving ligand-receptor pairs, including APOE-TREM2, APP (TREM2 + TYROBP), APP-CD74, SPP1−(ITGA4 + ITGB1), and CCL signaling pathways, remains significantly altered in the morphine-dependent macaques. CONCLUSION: Chronic opioid exposure reprograms CSF immune cells, creating a Th1/Th2 T-cell imbalance and polarizing monocytes toward a DAM-like state. This cell type specific transcriptomic signature is associated with progressive neuroinflammatory signaling in morphine-dependent macaques, and may have implications for neuroinflammatory and neurodegenerative phenotypes observed in PWH.
Targeting microglial C1q alleviates blood-brain barrier disruption in the thalamus after cortical infarction.
Peng L, Chen M, Zuo X … +5 more , Wu X, Gong M, Qin Z, Sun W, Xu E
J Neuroinflammation · 2026 Apr · PMID 42010605 · Full text
Focal cerebral infarction induces secondary damages in non-ischemic remote brain regions, severely affecting the prognosis and life quality of stroke patients. Disruption of blood–brain barrier (BBB) contributes to secon...
Focal cerebral infarction induces secondary damages in non-ischemic remote brain regions, severely affecting the prognosis and life quality of stroke patients. Disruption of blood–brain barrier (BBB) contributes to secondary thalamic damage after distal middle cerebral artery occlusion (dMCAO). However, the underlying molecular mechanisms that initiate BBB disruption and aggravate secondary thalamic damage after dMCAO remain unclear. It has been well-established that the complement pathway involves in the maintaining BBB integrity in the brain. Herein, using bulk RNA-sequencing and proteomics, we found that the complement pathway was the most pronounced in the ipsilateral ventroposterior nucleus (VPN) of thalamus at 2 weeks after dMCAO. Furthermore, we demonstrated for the first time that complement C1q derived mainly from a subtype of microglia binds to CD93 on endothelial cells, leading to the upregulation of vascular cell adhesion molecule 1 (VCAM-1) and BBB disruption in ipsilateral VPN after dMCAO. Knockdown of microglial C1q could inhibit the C1q-CD93 interaction, decrease VCAM-1 expression and maintain BBB integrity in the VPN, thus mitigating secondary thalamic damage after dMCAO. Moreover, minocycline treatment exerted neuroprotective effects by downregulating both microglial C1q and endothelial VCAM-1, consequently alleviating BBB disruption and neuronal loss in ipsilateral VPN, and improving neurological outcomes after dMCAO. Taken together, this innovative study highlights the pivotal role in maintaining BBB integrity mediated by microglial C1q in ipsilateral VPN after dMCAO. This finding provides a novel therapeutic target for improving the long-term prognosis of ischemic stroke patients.
Neuroimmune programming of childhood trauma: comorbid mechanisms and developmental origins of depression and autoimmune diseases.
Wang J, Xu Q, Tang X … +3 more , Hu A, Zhang D, Liu Z
J Neuroinflammation · 2026 Apr · PMID 42001138 · Full text
Adverse childhood experiences (ACEs) represent a critical environmental trigger for the adult comorbidity of depression and autoimmune diseases. This review synthesizes evidence showing that ACEs induce persistent dysreg...
Adverse childhood experiences (ACEs) represent a critical environmental trigger for the adult comorbidity of depression and autoimmune diseases. This review synthesizes evidence showing that ACEs induce persistent dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system, thereby promoting a chronic low-grade inflammatory state. This state is characterized by elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α), immune cell dysfunction, and epigenetic modifications. Facilitated by microglial activation and monocyte-mediated disruption of the blood–brain barrier, this pro-inflammatory milieu disrupts central nervous system homeostasis, contributing to the pathogenesis of both depressive symptoms and autoimmune disorders. Aberrant neuroimmune crosstalk emerges as a core mechanism underlying this comorbidity. Future research must delineate developmental windows of vulnerability and the differential effects of adversity types to translate these insights into novel therapeutic strategies targeting the neuroimmune axis—such as anti-cytokine therapies or vagus nerve stimulation—for high-risk populations.
From parasite-induced immune activation to neuroinflammation and behavioral dysfunction: convergent mechanisms across protozoa and helminths: a review.
Sadek AM, Mahmoud RH
J Neuroinflammation · 2026 Apr · PMID 41998715 · Full text
BACKGROUND: Parasitic infections are increasingly linked to persistent neurological and psychiatric sequelae, yet the mechanistic routes from peripheral infection to altered brain function remain incompletely integrated...
BACKGROUND: Parasitic infections are increasingly linked to persistent neurological and psychiatric sequelae, yet the mechanistic routes from peripheral infection to altered brain function remain incompletely integrated across parasite groups. Emerging work suggests that parasites may influence the central nervous system indirectly through microbiota disruption and chronic immune activation, or directly through neurotropism, ultimately converging on neuroinflammation. MAIN BODY: Here, we synthesize human and experimental evidence that protozoan and helminth infections can remodel the microbiota–immune–brain axis and promote neuroinflammatory states associated with behavioral dysfunction. Across neurotropic (e.g., Toxoplasma gondii, Plasmodium spp., Trypanosoma spp.) and primarily intestinal parasites (e.g., Enterobius vermicularis, Toxocara spp., schistosomes, and Taenia solium–associated neurocysticercosis), convergent pathways include: (i) sustained peripheral cytokine production and immune-cell reprogramming; (ii) gut dysbiosis with increased microbial products and reduced short-chain fatty acids; (iii) increased intestinal permeability and enhanced immune-to-brain signaling; (iv) blood–brain barrier dysfunction and activation of microglia and astrocytes; and (v) downstream neurochemical and transcriptional remodeling, including perturbations in dopamine/serotonin/GABA-related signaling, indoleamine 2,3-dioxygenase–driven tryptophan catabolism, and infection-associated epigenetic and microRNA changes. Clinically, these cascades are associated with seizures, sleep disturbance, cognitive impairment, mood and anxiety symptoms, and under specific contexts psychosis-like phenotypes. CONCLUSIONS: We propose an integrative mechanistic model in which parasite-induced microbiota disturbance and chronic immune activation converge on glial activation and barrier dysfunction to shape brain circuitry and behavior. Defining shared neuroinflammatory nodes across parasitic diseases may reveal tractable biomarkers and host-directed therapeutic strategies to mitigate long-term neuropsychiatric risk.
Cannabis use by people with HIV is associated with an anti-inflammatory immunometabolic phenotype in monocyte-derived macrophages.
Ford MK, Halcrow PW, Laird AE … +15 more , Avalos BL, Boustani A, Spencer M, Melcher JI, Walter KC, Hong DD, Funk G, Searson EG, Le AA, Ellis RJ, Letendre S, Marcondes MCG, Schlachetzki JC, Iudicello J, Fields JA
J Neuroinflammation · 2026 Apr · PMID 41998680 · Full text
Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in...
Chronic neuroinflammation is associated with comorbidities in people with HIV (PWH) on antiretroviral therapy (ART). While cannabis use is associated with reduced neuroinflammation and neurocognitive impairment (NCI) in PWH, the underlying mechanisms are unknown. To address this gap in knowledge, we analyzed monocyte-derived macrophages (MDMs) from a cohort of 50 PWH and 33 people without HIV (mean age: 61.9 years), categorized by frequency of cannabis use (naïve/low, moderate, daily). We performed immunocytochemistry, RNA sequencing, and qPCR on MDMs and quantified related biomarkers in donor plasma. In this cohort study, daily cannabis use in PWH was associated with less global neurocognitive deficits, and with an anti-inflammatory immunometabolic-phenotype in MDMs characterized by (1) a metabolic shift from glycolysis to oxidative phosphorylation, (2) higher mitochondrial numbers, (3) altered cytokine profiles (pro-inflammatory downregulation, anti-inflammatory upregulation), and (4) higher brain-derived neurotrophic factor (BDNF) expression. These cellular changes were corroborated by a plasma biomarker profile in PWH including (1) lower levels of growth differentiation factor 15 and soluble triggering receptor expressed on myeloid cells 2, and (2) higher mature BDNF/precursor BDNF ratios that correlated with better cognition. Thus, cannabis use may mitigate NCI in PWH by immunometabolically reprogramming MDM function towards an anti-inflammatory and neuroprotective state.
Therapeutic targeting of blood-derived protein infiltration to modulate neuroinflammation in cerebellar ataxia.
Park SM, Kim SS, Cho E … +11 more , Lee GB, Lee JM, Kim DW, Kim JH, Kim JE, Choi GE, Lee HW, Suk K, Yoon JH, Kim S, Kim SR
J Neuroinflammation · 2026 Apr · PMID 41992320 · Full text
Neuroinflammation is one of the key drivers of spinocerebellar ataxia type 2 (SCA2), yet the role of prothrombin-derived proteins in its pathogenesis remains unclear. Here, we show that prothrombin-derived proteins, thro...
Neuroinflammation is one of the key drivers of spinocerebellar ataxia type 2 (SCA2), yet the role of prothrombin-derived proteins in its pathogenesis remains unclear. Here, we show that prothrombin-derived proteins, thrombin and prothrombin kringle-2 (pKr-2), are elevated in the plasma of patients with cerebellar ataxia (CA) and in the cerebellum of SCA2 mice. Intervention strategies, reinforcing the blood–brain barrier (BBB) with caffeine administration and inhibiting thrombin/pKr-2 production through oral administration of rivaroxaban, attenuated cerebellar infiltration of prothrombin-derived proteins, neuroinflammation, and motor deficits in SCA2 mice, whereas pKr-2 upregulation exacerbated neuronal damage and behavioral impairments. These findings reveal a distinct peripheral proteomic signature linked to a cerebellar pathogenic pathway and suggest that limiting the entry of prothrombin-derived proteins into the cerebellum may represent a critical therapeutic approach in CA.
CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators.
Duggan MR, Jacobsen E, Yang S … +11 more , Zeng X, Kandala S, Joynes CM, Karikari TK, Nimgaonkar VL, Kamboh MI, Snitz BE, Ferrucci L, Yolken R, Ganguli M, Walker KA
J Neuroinflammation · 2026 Apr · PMID 41992251 · Full text
Immune processes play complex roles in Alzheimer’s disease and related dementias (ADRD), but it remains unclear whether host defenses against common microbes also contribute to ADRD, and what underlying mechanisms may ac...
Immune processes play complex roles in Alzheimer’s disease and related dementias (ADRD), but it remains unclear whether host defenses against common microbes also contribute to ADRD, and what underlying mechanisms may account for these relationships. Using antibody and plasma proteomic data from the Monongahela-Youghiogheny Healthy Aging Team study (n = 1,003; mean age = 78.0 yrs; follow up 7.6 yrs), the present study detected accelerated decline across a variety of cognitive domains and altered plasma abundance of FLT1 (also known as Vascular Endothelial Growth Factor Receptor 1) among participants with elevated cytomegalovirus (CMV) titers. After analyses in the Baltimore Longitudinal Study of Aging (n = 323) and the UK Biobank (n = 956) revealed CMV titer associations with higher cross-sectional cognition and greater cognitive decline were moderated by plasma FLT1 abundance, we leveraged two-sample Mendelian Randomization to uncover causal roles for host immune responses to CMV, including limiting brain amyloidosis. Using multi-cohort proteomic signatures of CMV antibody levels and plasma FLT1, bioinformatic analyses suggested that host immune responses to CMV may impact neurologic health through alterations in lymphocytic immunoregulatory cascades, with circulating FLT1 abundance capturing the extent to which these effects may be transmitted across the blood–brain-barrier. In addition to detecting pleiotropic associations of CMV titers with neurocognitive outcomes, our findings highlight FLT1 as an important molecular moderator of these effects, and extend our understanding of the biological basis by which host immune responses to common microbes may contribute to ADRD.
Repetitive trans-spinal magnetic stimulation promotes repair in inflammatory spinal cord injury through sex-dependent immune modulation.
Semprez F, Ziane I, Du A … +9 more , Istre I, Dupuis L, Moncomble L, Neveu P, Raimond C, Fernandes A, Dorange J, Delarue Q, Guérout N
J Neuroinflammation · 2026 Apr · PMID 41987271 · Full text
Spinal cord injuries (SCI), whether traumatic or inflammatory such as transverse myelitis (TM), are characterized by severe neuroinflammation, demyelination, and long-term disabilities. Current treatments remain limited,...
Spinal cord injuries (SCI), whether traumatic or inflammatory such as transverse myelitis (TM), are characterized by severe neuroinflammation, demyelination, and long-term disabilities. Current treatments remain limited, highlighting the need for novel non-invasive therapeutic approaches. Repetitive magnetic stimulation (RMS) has emerged as a promising strategy, but its mechanisms and efficacy in inflammatory contexts remain poorly described. Here, we investigated the effects of RMS applied as trans-spinal RMS (rTSMS) in a mouse model of focal spinal cord demyelination induced by lysophosphatidylcholine (LPC). When applied one day after LPC injection, rTSMS reduced inflammation, demyelination, and fibroglial scar formation, while promoting early locomotor recovery in both sexes. In contrast, when treatment was initiated three days after LPC injection, corresponding to the peak of motor deficits, rTSMS conferred tissue protection and functional benefits only in female mice. RNA sequencing analyses revealed sex-dependent immune modulation: in females, rTSMS primarily regulated adaptive T cell–related pathways, whereas in males, it mainly targeted innate immune responses such as neutrophil activity and phagocytosis. Complementary in vitro experiments using microglial and macrophage cultures further demonstrated that RMS modulates transcriptomic responses differently depending on cell type and inflammatory state. Specifically, RMS attenuated IL-1–induced pro-inflammatory signaling in macrophages and completely abolished these effects in microglia. Altogether, our findings establish rTSMS as a non-invasive therapy capable of reducing neuroinflammation and demyelination in inflammatory SCI, with pronounced sex-dependent effects. By uncovering distinct immune pathways engaged in male and female mice, this study provides mechanistic insights into rTSMS action and opens perspectives for its translational use in neuroinflammatory diseases.
RNA-binding proteins: a comprehensive review of multifaceted regulatory mechanisms in neuroinflammation and implications in the pathogenesis of neurological disorders.
Zheng M, Li M, Liu S … +2 more , Guan R, Liu X
J Neuroinflammation · 2026 Apr · PMID 41987206 · Full text
Neuroinflammation stands as a cornerstone pathological hallmark across a spectrum of neurological disorders, drawing intensified scientific scrutiny owing to its profoundly intricate and multi-layered regulatory networks...
Neuroinflammation stands as a cornerstone pathological hallmark across a spectrum of neurological disorders, drawing intensified scientific scrutiny owing to its profoundly intricate and multi-layered regulatory networks. At the heart of this complexity, RNA-binding proteins (RBPs) emerge as masterful post-transcriptional orchestrators, exerting precise control over a vast array of neuroinflammatory cascades. Mounting evidence underscores that RBPs transcend their classical roles in RNA sensing and innate immune recognition, actively shaping pivotal biological pathways—ranging from inflammatory signal transduction and programmed cell death to metabolic reprogramming, epigenetic remodeling and dynamic crosstalk with non-coding RNAs. Furthermore, the functional versatility of RBPs is amplified by nuanced alterations in their nucleocytoplasmic trafficking, stress granule formation, post-translational modifications, and RNA-binding specificities, all of which intricately fine-tune their regulatory impact within the neuroinflammatory milieu. Strikingly, the cell type-specific actions of RBPs in neurons, microglia, and astrocytes unveil a sophisticated tapestry of molecular specialization, offering transformative insights into their context-dependent functions. Abnormal function of RNA-binding proteins is closely related to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, RNA-binding proteins are involved in various pathological processes, including central nervous system infections, stroke, high-altitude cerebral hypoxia, and traumatic brain injury. This review systematically organizes the multifaceted regulatory mechanisms of RNA-binding proteins in neuroinflammation. It deeply explores their key roles in the occurrence and development of nervous system diseases. The review aims to construct a comprehensive theoretical framework and provide a scientific basis for developing new diagnostic methods and targeted therapeutic strategies.
Inflammasomes in glioblastoma.
Govindarajan V, Jackson Q, Ramsoomair CK … +4 more , Aramburu M, de Rivero Vaccari JP, Keane RW, Shah AH
J Neuroinflammation · 2026 Apr · PMID 41987196 · Full text
Glioblastoma (GBM) is the most common primary malignancy of the brain with a poor prognosis. Despite advances in therapeutics, the gold standard of treatment remains maximal safe resection followed by temozolomide and ra...
Glioblastoma (GBM) is the most common primary malignancy of the brain with a poor prognosis. Despite advances in therapeutics, the gold standard of treatment remains maximal safe resection followed by temozolomide and radiation therapy, with the inter- and intratumoral heterogeneity of GBM making effective management challenging. As a result, the search for mechanisms underlying this heterogeneity has been paramount. The immunosuppressive and anti-inflammatory microenvironment of GBM has been of particular interest in recent years. Inflammasomes are protein complexes responsible for initiation of pro-inflammatory cascades and a specialized form of regulated cell death known as pyroptosis in response to noxious cellular stimuli. Inflammasomes play a critical role in several disease processes, including multiple sclerosis and traumatic brain injury. However, their role in GBM pathogenesis and regulation in the tumor microenvironment remains poorly understood. Here, we describe the current status of investigations into inflammasomes, their role in GBM pathogenesis, and their potential as therapeutic targets.
Serum and CSF cytokine profile impact clinical phenotype in pediatric MOGAD.
Ohashi E, Kohyama K, Mori T … +12 more , Matsuda S, Nishida H, Miyama S, Hayakawa I, Abe Y, Yamada N, Suzuki M, Matsubara K, Fukuoka M, Inoue T, Kuki I, Sakuma H
J Neuroinflammation · 2026 Apr · PMID 41981669 · Full text
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has a broad spectrum of clinical phenotypes, including acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myel...
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has a broad spectrum of clinical phenotypes, including acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM), and cerebral cortical encephalitis (CCE). Although these conditions exhibit diverse outcomes and require different treatment options for relapse prevention, no biomarkers have been identified to distinguish the clinical phenotypes. This study aimed to investigate the properties of cytokines and chemokines in the serum and cerebrospinal fluid (CSF) of patients with MOGAD and to determine whether they are associated with the clinical phenotype. METHODS: In this retrospective cohort study, we analyzed cytokines and chemokines in paired serum and CSF samples obtained during the acute phase before treatment from patients with MOG-IgG positivity, classified into five clinical phenotypes (ADEM, CCE, ON, TM, and “others”). RESULTS: Of the 50 patients diagnosed with MOGAD, 19 (38%) were diagnosed with ADEM, 9 (18%) with CCE, 3 (6%) with ON + TM, 9 (18%) with ON, and 10 (20%) with others. Overall, the CSF levels of Th17-related (including IL-6, CXCL8, G-CSF, IL-17, and IL-21) and B cell-related (including CXCL13, BAFF, and APRIL) cytokines/chemokines were elevated in pediatric patients with MOGAD compared with non-inflammatory neurological disease controls. Phenotype-stratified analyses of ADEM, CCE, and ON demonstrated higher CSF IL-6 and CXCL8 levels in encephalitic phenotypes (ADEM/CCE) than in ON. By contrast, no significant difference in the CSF-to-serum ratio (C/S ratio) for each cytokine was observed among the three phenotypes. Only the CXCL13 C/S ratio correlated with the ΔMOG-IgG C/S ratio. CONCLUSION: Pediatric patients with MOGAD showed limited phenotype-specific heterogeneity in their cytokine/chemokine profiles. Nevertheless, leptomeningeal inflammation was more prominent in patients with encephalitic presentations. Additionally, intrathecal MOG-IgG synthesis may be linked to intracranial inflammatory activity, which could inform future prospective studies using stratified treatment approaches.
Barrier breakdown: lung-brain crosstalk in systemic inflammation.
Villalba N, Beard RS, Yuan SY
J Neuroinflammation · 2026 Apr · PMID 41981636 · Full text
The lung and brain engage in a dynamic, bidirectional communication that influences immune homeostasis both locally and systemically, shaping overall health and disease progression. Lung infection is increasingly recogni...
The lung and brain engage in a dynamic, bidirectional communication that influences immune homeostasis both locally and systemically, shaping overall health and disease progression. Lung infection is increasingly recognized for its role in triggering or exacerbating neurological dysfunction, ultimately worsening clinical outcomes. Although the brain is shielded by the blood-brain barrier (BBB), it remains vulnerable to secondary injury during pulmonary infection, primarily through lung-driven systemic inflammation, immune cell activation, and the release of cytokines, chemokines, and other circulating mediators. This review explores the biological and immunological mechanisms underlying lung-to-brain communication, with a focus on cerebral alterations following pulmonary bacterial infection. We examine the contributions of circulating mediators such as degradation products of the endothelial glycocalyx (eGC), endothelial proteins, inflammatory cytokines, and others originating from the lung and impacting the central nervous system (CNS). We highlight emerging insights into how lung-triggered systemic inflammation causes neurological sequelae, including cognitive deficits and behavioral changes. Finally, we discuss recent experimental findings and clinical evidence that advance our understanding of the detrimental interplay between pulmonary inflammation and brain dysfunction. We then outline the clinical relevance, therapeutic translation and opportunities for future research. The mediators discussed here point to emerging therapeutic targets and highlight the clinical challenges of preventing long-term neurological complications of bacterial lung infections.
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