J Neuroinflammation [JOURNAL]
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200 papers
A central role for fibrinogen in promoting microglial repair of the hypoxia-disrupted blood-brain barrier.
Halder SK, Sapkota A, Milner R
J Neuroinflammation · 2026 Mar · PMID 41808179 · Full text
Building on our previous finding that a small fibrinogen peptide inhibits microglial repair of the hypoxia-disrupted blood-brain barrier (BBB), we directly evaluated the importance of fibrinogen in this process by studyi...
Building on our previous finding that a small fibrinogen peptide inhibits microglial repair of the hypoxia-disrupted blood-brain barrier (BBB), we directly evaluated the importance of fibrinogen in this process by studying these events in fibrinogen knockout (KO) mice. While young (4 months old) fibrinogen KO mice were still capable of mediating a vasculo-protective response to chronic mild hypoxia (CMH; 8% O2), the extent of vascular leak in these mice was much greater than wild-type (WT) mice. Consistent with this, fibrinogen KO mice displayed greatly reduced levels of hypoxia-induced microglial activation, proliferation, and aggregation around leaky blood vessels. Notably, defects in fibrinogen KO mice became more pronounced with age such that by 8-months old, a large fraction (3/8) of fibrinogen KO mice failed to survive 4 days CMH, and those that survived showed much greater loss of myelin and neurons compared to WT. Furthermore, under normoxic conditions, microglia in middle-aged (13 months old) fibrinogen KO mice were significantly less activated compared to WT, suggesting that slow fibrinogen leak across the age-weakened BBB might explain why microglia are more activated in aged mice. Finally, in vitro studies revealed that microglia readily attach to fibrinogen and that compared to other pro-adhesive ECM proteins such as fibronectin, fibrinogen promotes morphological transition into a polarized phenotype capable of greater levels of migration. Together, these observations demonstrate the importance of fibrinogen in promoting an effective microglial vasculo-protective response and suggest that pharmacological manipulation of fibrinogen-microglial interactions in the aged brain could hold therapeutic promise in the prevention or treatment of vascular dementia.
ApoE4 Drives Microglial Lipid Dysregulation in Alzheimer's Disease via Epigenetic Reprogramming of the Asxl1/LXRα-H3K4me3 Axis.
Lin L, Pan Z, Wei Z … +4 more , Jiang X, Lai Y, Chen M, Lin F
J Neuroinflammation · 2026 Mar · PMID 41808104 · Full text
BACKGROUND: The ε4 allele of apolipoprotein E gene (APOE) stands as the greatest genetic risk factor for late-onset Alzheimer’s disease (AD). Although microglia accumulating lipid droplets (LDAM) have been implicated in...
BACKGROUND: The ε4 allele of apolipoprotein E gene (APOE) stands as the greatest genetic risk factor for late-onset Alzheimer’s disease (AD). Although microglia accumulating lipid droplets (LDAM) have been implicated in AD pathogenesis, the mechanistic link between ApoE4 and microglial lipid dysregulation remains elusive. METHODS: We employed a multi-omics approach, combining snRNA-seq and locus-specific epigenetic analysis, alongside microglia-specific gene manipulation in ApoE-targeted replacement (TR) mice. Primary microglia were challenged with cholesterol to simulate lipid overload conditions. RESULTS: In mid-life ApoE4-TR mice, microglia within the dentate gyrus developed pronounced lipid droplet accumulation, concurrent with impaired Aβ clearance and a pro-inflammatory shift. snRNA-seq unveiled a unique microglial cluster in ApoE4 mice, enriched for lipid-metabolism genes and marked by the pronounced downregulation of the hub gene Asxl1. Mechanistically, ApoE4 attenuated the Asxl1–LXRα interaction, leading to reduced H3K4me3 occupancy at promoters of lipid-efflux genes such as Abca1. Crucially, CRISPR-mediated, microglia-specific overexpression of Asxl1 restored H3K4me3 levels, normalized cholesterol efflux, and rescued Aβ phagocytic deficits in vivo. CONCLUSIONS: Our findings define an epigenetic pathway whereby ApoE4 drives microglial dysfunction via the Asxl1–LXRα–H3K4me3 axis, fostering the LDAM phenotype. Enhancing Asxl1 function presents a promising therapeutic avenue for countering ApoE4-mediated pathogenesis in AD.
Targeting Apolipoprotein E4 rescues photoreceptor degeneration by inhibiting the disease-associated microglia activation in experimental retinal detachment.
Li X, Fan N, Yan Y … +3 more , Ren M, Wu H, Dong K
J Neuroinflammation · 2026 Mar · PMID 41803887 · Full text
Retinal detachment (RD) is a prevalent ocular disorder that leads to photoreceptor death and irreversible visual impairment. Following RD, microglia—the resident immune cells of the retina—become activated and participat...
Retinal detachment (RD) is a prevalent ocular disorder that leads to photoreceptor death and irreversible visual impairment. Following RD, microglia—the resident immune cells of the retina—become activated and participate in regulating inflammatory responses and tissue repair processes. A distinct microglial subtype, disease-associated microglia (DAM) emerges in stressed neuronal microenvironments. However, its specific contribution to photoreceptor degeneration remains poorly understood. Apolipoprotein E (ApoE), a major lipoprotein predominantly expressed in brain and ocular myeloid cells, has been implicated in modulating neurodegeneration within the central nervous system through influencing DAM activation. In this study, we employed an experimental mouse model of RD and observed upregulation of ApoE and DAM-related markers at three days following RD induction. Genetic deletion of ApoE significantly attenuated photoreceptor loss and suppressed neuroinflammatory responses after RD, accompanied by reduced DAM activation. Furthermore, modulation of the ApoE-Galectin-3 axis reduced TUNEL-positive cells and inhibited TLR4-dependent inflammatory cascades post-RD. Using humanized ApoE allele mice, we further elucidated that the ApoE4 isoform significantly downregulated DAM-associated markers (including Galectin-3, Spp-1 and Gpnmb), promoted photoreceptor survival, and attenuated retinal inflammation. In contrast, ApoE2 and ApoE3 conferred no protection benefit compared to wild-type mice after RD. Our findings indicate that ApoE-mediated DAM activation exacerbates photoreceptor degeneration after RD insult. Both ApoE deficiency and ApoE4 expression potentially mitigated RD-induced photoreceptor death and ameliorated neuroinflammatory pathways via suppression of DAM activation. Collectively, our study highlights ApoE4 as a promising therapeutic target for modulating microglial cells to promote neuronal survival in photoreceptor degeneration conditions.
CSF microtubule-associated protein 1 light chain 3A and 3B levels are associated with tau pathology and Alzheimer's disease risk through amyloid deposition and microglial signaling.
Guo HH, Su D, Song B … +14 more , Geng Z, Wang L, Wang W, Hu W, Li X, Li W, Zhang G, Fang M, Dai Y, Hu P, Wu X, Wang K, Wei L, Alzheimer’s Disease Neuroimaging Initiative
J Neuroinflammation · 2026 Mar · PMID 41795086 · Full text
BACKGROUND: Autophagy has recently attracted increasing attention for its critical involvement in Alzheimer’s Disease (AD) pathogenesis. However, the role of microtubule-associated protein 1 light chain 3 A (LC3A) and B...
BACKGROUND: Autophagy has recently attracted increasing attention for its critical involvement in Alzheimer’s Disease (AD) pathogenesis. However, the role of microtubule-associated protein 1 light chain 3 A (LC3A) and B (LC3B), key autophagic-associated proteins in cognitive decline, AD risk, and underlying pathology remain unclear. METHODS: This study included 568 participants from the Alzheimer’s Disease Neuroimaging Initiative with cerebrospinal fluid (CSF) measurements of LC3A and LC3B. We systematically assessed the associations of LC3A and LC3B with cognition, dementia risk, AD biomarkers, microglial activity, brain volume, and metabolism through both cross-sectional and longitudinal analyses. Additionally, subgroup analyses based on ATN classification were conducted to evaluate stage-specific effects, and Receiver operating characteristic (ROC) analyses were employed to explore the clinical predictive value of LC3A and LC3B. Finally, mediation models were used to investigate the potential mechanisms by which LC3A and LC3B affect AD pathology and cognition. RESULTS: Elevated CSF LC3A and LC3B levels were negatively associated with cognition, while positively associated with amyloid deposition, total tau (t-tau), phosphorylated tau (p-tau), progranulin (PGRN), and soluble Triggering Receptor Expressed on Myeloid Cells-2 (sTREM2) at baseline. Higher CSF LC3A and LC3B concentrations were linked to an increased risk of dementia, accelerated longitudinal cognitive decline, greater brain atrophy, faster accumulation of t-tau, and longitudinal associations with sTREM2. Individuals with TN+ exhibited significantly higher CSF LC3A and LC3B levels compared to those with TN−. Moreover, CSF LC3A alone could predict TN−/TN+ status with an area under the curve (AUC) of 0.903, which increased to 0.939 when combined with amyloid PET. Similarly, CSF LC3B alone yielded an AUC of 0.876, rising to 0.913 when combined with amyloid PET. Finally, amyloid deposition and microglial activation individually or jointly, mediated the effects of LC3A and LC3B on tau pathology and cognitive decline. CONCLUSIONS: CSF LC3A and LC3B, reflecting autophagic activation, are linked to elevated tau pathology and an increased risk of AD. They may jointly contribute to AD pathological progression alongside amyloid deposition and microglial activation. LC3A and LC3B as robust candidate biomarkers for monitoring pathological burden, stratifying disease risk, and informing clinical evaluation in AD.
OSBPL10 alleviates neuronal ferroptosis via lysosomal membrane repair in a PS-dependent manner after spinal cord injury.
Zhang H, Luo Y, Kang Y … +8 more , Huang D, Zhao T, Hu X, Di J, Yao S, Pang M, Liu B, Rong L
J Neuroinflammation · 2026 Mar · PMID 41794746 · Full text
Spinal cord injury (SCI) exerts severe adverse effects on patients, leading to impaired motor functions in segments remote from the injury site. Following SCI, lysosomes are damaged due to inflammatory microenvironment,...
Spinal cord injury (SCI) exerts severe adverse effects on patients, leading to impaired motor functions in segments remote from the injury site. Following SCI, lysosomes are damaged due to inflammatory microenvironment, and the repair of such damage requires a substantial supply of lipids. Studies have demonstrated that lipid transfer proteins (LTPs) play a pivotal role in the repair process of neuronal organelles. However, whether these proteins regulate functional recovery after SCI and their underlying mechanisms remain elusive. Through RNA sequencing and human cerebrospinal fluid enzyme-linked immunosorbent assay (ELISA) analyses, we verified that OSBPL10 is significantly downregulated in the acute phase of SCI and may serve as a protective factor against SCI. The Basso Mouse Scale (BMS), Nissl staining, and two-dimensional (2D) gait analysis were employed to evaluate functional recovery. Western blotting and immunofluorescence assays were performed to detect the expression changes of proteins associated with autophagy, ferroptosis, oxidative stress, and lysosomal membrane permeabilization (LMP) related proteins. Finally, molecular docking and rescue experiments using lipid synthesis inhibitors further confirmed that OSBPL10 ameliorate LMP by transferring PS to lysosomes, thereby promoting autophagic flux. Collectively, our findings conclude that OSBPL10 overexpression alleviates autophagic flux impairment, ferroptosis, and oxidative stress after SCI through PS-mediated lysosomal repair, thus facilitating post-injury neurological function recovery and holding promising potential for clinical application.
Sigma-1 receptor regulates HIV-1 and methamphetamine-induced endothelial/pericyte barrier impairment via strain-specific inflammatory responses and mitochondrial dysregulation.
Fattakhov N, Torices S, Becker S … +6 more , Joseph JA, Schmidlin S, Ngo A, Okoro A, Naranjo O, Toborek M
J Neuroinflammation · 2026 Mar · PMID 41792779 · Full text
BACKGROUND: Methamphetamine (METH) use disorder (MUD) is a frequent comorbidity among people with HIV-1 (PWH). While both METH and HIV-1 independently disrupt the brain microvascular system and promote neuroinflammation,...
BACKGROUND: Methamphetamine (METH) use disorder (MUD) is a frequent comorbidity among people with HIV-1 (PWH). While both METH and HIV-1 independently disrupt the brain microvascular system and promote neuroinflammation, the molecular mechanisms underlying their synergistic neurotoxicity remain unclear. The sigma-1 receptor (Sigma-1R) signaling pathway has been suggested as a potential target in METH misuse; however, its involvement in the impact of METH and/or HIV-1 infection on brain pericytes remains unknown. METHODS: Transwell co-cultures of human brain microvascular endothelial cells (HBMECs) and human brain vascular pericytes (HBVPs) were employed to assess the impact of combined METH exposure and infection with HIV-1 on barrier integrity. Moreover, mitochondrial functions, inflammatory mediators, oxidative stress markers, and the expression of interferon-stimulated genes were analyzed. RESULTS: HBVP infection with the CXCR4-tropic HIV-1 strain NL4-3, but not the CCR5-tropic JR-CSF strain, disrupted endothelial/pericyte barrier permeability, reduced transendothelial electrical resistance (TEER), and lowered claudin-5 expression, effects alleviated by pretreatment with Sigma-1R antagonist S1RA (10 µM). S1RA suppressed interleukin-6 (IL-6) release without affecting increased ROS levels and mitigated HIV-1 NL4-3 and METH co-induced proton leak and mitochondrial network fragmentation in a DRP1 phosphorylation-dependent manner. Importantly, METH enhanced replication of HIV-1 NL4-3, a process modulated by the CXCR4/CCL2 signaling pathway rather than Sigma-1R. CONCLUSIONS: The obtained results identify Sigma-1R antagonism as a potential therapeutic strategy to protect microvascular integrity in the context of HIV-1 infection and METH misuse. In addition, they reveal distinct mechanisms that may underly microvascular dysfunction in PWH who experience MUD.
APOE-mediated lipid transport prevents C1q-related synaptic loss after spinal cord injury via attenuating macrophage lipid stress.
Mulat Y, Ren Z, Nong C … +14 more , Fu C, Huo Y, Zhao M, Dai Y, Chen C, Wang P, Wang R, Zhang H, Hu Y, Lai P, Guo R, Jiang D, Peng Y, Lin H
J Neuroinflammation · 2026 Mar · PMID 41792769 · Full text
Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in...
Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of Apoe disrupts this intercellular lipid transport, culminating in pathological lipid retention that activates the Hippo signalling cascade and transcriptionally induces complement component C1q. This excess C1q aberrantly tags intact synapses for excessive microglial pruning, leading to significant synaptic loss and impaired locomotor function recovery. Direct blockade of C1q using neutralizing antibodies recapitulated these neuroprotective effects, confirming C1q as the critical mediator. Crucially, macrophage-specific APOE re-expression reverses this entire cascade, preserving synapses and restoring locomotor function (BMS score: 4.81 ± 0.21 (Apoe) vs. 1.75 ± 1.28 (NC); Incline plane: 69.24° ± 2.33° (Apoe) vs. 51.66° ± 5.14° (NC) in Apoe−/− mice). These findings identify the APOE-Hippo-C1q pathway in macrophages as a novel therapeutic target for SCI.
Systemic inflammation triggers local complement production in the mouse retina and RPE.
Spero V, Escher P, Braga-Lagache S … +2 more , Enzmann V, Zinkernagel M
J Neuroinflammation · 2026 Mar · PMID 41787550 · Full text
Systemic inflammation is increasingly recognized as a potential contributor in sight threatening retinal diseases such as Age-related Macular Degeneration (AMD). Yet, its impact on local eye immune responses and further...
Systemic inflammation is increasingly recognized as a potential contributor in sight threatening retinal diseases such as Age-related Macular Degeneration (AMD). Yet, its impact on local eye immune responses and further pathological processes remains poorly understood. This study aims to elucidate the effect of peripheral immune activation on the local complement system, a central component of innate immunity with a dual role in maintaining ocular homeostasis and mediating inflammation, in the mouse retina and retinal pigment epithelium (RPE). Using a systemic lipopolysaccharide (LPS) challenge and a high-resolution proteomic approach, we observed a significant increase in complement factor 3 (C3) production in the RPE and retina 24 h post-injection. Further analysis confirmed the local source of complement signaling in resident cells such as astrocytes and RPE, independently from blood-retina barrier disruption. These findings reveal a direct cross-talk between systemic immune activation and ocular complement activation, and highlight the potential implications of systemic inflammation in the pathogenesis of ocular diseases, underlining the importance of future research into targeted therapies for inflammation-driven conditions.
Spatiotemporal dynamics of brain pericytes in ischemic stroke.
Zhong X, Ye Z, Liu L … +8 more , Hui Z, Wang S, Zhang A, Zhu G, Zhao F, Li M, Zhang Z, Hu Y
J Neuroinflammation · 2026 Mar · PMID 41782032 · Full text
Pericytes constitute a vital component of the neurovascular unit (NVU) and play a pivotal role in the pathophysiology of ischemic stroke (IS). They perform a variety of critical functions, involving regulating cerebral b...
Pericytes constitute a vital component of the neurovascular unit (NVU) and play a pivotal role in the pathophysiology of ischemic stroke (IS). They perform a variety of critical functions, involving regulating cerebral blood flow (CBF), modulating inflammatory responses, exhibiting stem cell-like properties, and maintaining the integrity of the blood-brain barrier (BBB). During the hyperacute and acute phases of IS, pericytes undergo contraction, contributing to the no-reflow phenomenon (NRP) and compromising BBB integrity. Concurrently, their activation exacerbates neuroinflammation and secondary injury. In contrast, the subacute and chronic phases are characterized by pericyte-mediated reparative processes, including angiogenesis, vascular stabilization, immune modulation, and scar formation. Notably, distinct pericyte subpopulations residing within specific vascular segments, pre-capillary, capillary, and post-capillary, demonstrate unique spatial and temporal functional patterns within the infarct core, penumbra, and peri-infarct regions. By examining these multifaceted dynamics, this review also highlights the intricate characteristics of pericytes as a therapeutic target and investigates novel therapeutic approaches based on their spatiotemporal functional modulation, with the goals of improving microcirculatory disorders, protecting the BBB, decreasing inflammation, and promoting neural repairs.
HIV gp120 induces TREM1 expression through TLR-PGE₂ signalling in human monocyte-derived microglia.
Mahama A, Rawat P, Teodorof-Diedrich C … +2 more , Spector SA, Campbell GR
J Neuroinflammation · 2026 Mar · PMID 41782012 · Full text
Microglia serve as a long-lived reservoir for HIV in the brain and are resistant to the cytopathic effects of infection. As such, they pose a significant barrier to eradication strategies and contribute to chronic neuroi...
Microglia serve as a long-lived reservoir for HIV in the brain and are resistant to the cytopathic effects of infection. As such, they pose a significant barrier to eradication strategies and contribute to chronic neuroinflammation in people living with HIV. We previously identified that triggering receptor expressed on myeloid cells-1 (TREM1) is upregulated in HIV-infected human microglia and is associated with resistance to virus-associated cellular stress.In this study, we examined the upstream mechanisms by which the HIV-1 envelope protein gp120 induces TREM1 expression in human monocyte-derived microglia. We found that gp120 induces TREM1 transcription through Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) signalling, and that this process requires prostaglandin E₂ (PGE₂) signalling through prostaglandin E₂ receptor EP4. Inhibition of TREM1 increased apoptotic DNA fragmentation and cytotoxicity in gp120-exposed microglia, consistent with a functional contribution of TREM1 in modulating apoptotic signalling under these conditions.Together, these findings identify a TLR–PGE₂–TREM1 signalling axis that regulates innate immune responses and apoptotic marker modulation following HIV-1 envelope protein exposure. Given the contribution of long-lived microglia to HIV-associated neurocognitive disorders, the TREM1 pathway may represent a therapeutic target for modifying neuroinflammatory responses in the context of HIV infection.
Roseburia intestinalis ameliorates adolescent depression via GPR43‑dependent Treg cell expansion and suppression of neuroinflammation.
Liu J, Fu L, Tang Z … +8 more , Li X, Manglike AY, Wang X, Mo H, Liu G, Jiang L, Gao R, Wang J
J Neuroinflammation · 2026 Mar · PMID 41776666 · Full text
Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poor...
Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poorly understood. A growing body of evidence highlights the gut microbiota-brain axis as a key modulator of host emotional function, acting through interconnected immune, metabolic, and neural pathways. In the current work, a clinical study involving first-diagnosed adolescent depression patients was conducted and significant reductions in Roseburia intestinalis (R.i.) and its metabolite butyrate were identified. Therefore, we hypothesized that alterations in R.i. and butyrate may be involved in adolescent depression and may serve as novel therapeutic strategy. Intriguingly, transplantation of R.i. obviously retarded the chronic restraint stress (CRS)-induced depression in adolescent mice. Critically, this protective effect was completely abrogated by blocking the G protein-coupled receptor 43 (GPR43). Mechanistically, we delineated a novel “peripheral-central” regulatory cascade: R.i. robustly promoted the expansion of peripheral CD25⁺Foxp3⁺ regulatory T (Treg) cells, alleviating pathological inflammation in both of the colon (peripheral) and brain (central). Reciprocally, depletion of Treg cells completely abolished not only R.i.’s antidepressant effects but also its anti-inflammatory actions in the colon and brain in vivo. The in vitro study revealed that either the R.i. conditioned or heated culture medium obviously alleviated the LPS+corticosterone induced neuroinflammation in microglial cells, shifting reactive state toward a homeostatic state. Collectively, our study for the first time reveals that R.i. ameliorates adolescent depression-like changes through a GPR43-dependent, Treg-mediated mechanism. Given the unmet clinical need for clinical diagnosis and therapy of adolescent depression, the present study provided the potential translational values for the novel treatments, such as transplantation of R.i. or butyrate supplement, which represent promising therapeutic strategies.
Unknotting the crosstalk between COPD and neuroinflammation.
Firdous SM, Marick S, Pattanayak A … +2 more , Polley K, Roy SL
J Neuroinflammation · 2026 Mar · PMID 41776640 · Full text
COPD is a progressive respiratory illness that is mostly caused by air pollution, biomass fuel exposure, or long-term cigarette smoking. It is increasingly being referred to as a multisystem inflammatory disease rather t...
COPD is a progressive respiratory illness that is mostly caused by air pollution, biomass fuel exposure, or long-term cigarette smoking. It is increasingly being referred to as a multisystem inflammatory disease rather than a pulmonary-only one. As a result of chronic airway inflammation in COPD, pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α are released throughout the body, causing systemic oxidative stress. Cardiovascular disease, skeletal muscular atrophy, osteoporosis, metabolic syndrome, and neurological impairment manifested as depression, anxiety, and cognitive impairment are among the several comorbidities associated with this systemic inflammation. Similarly, neuroinflammation, which is characterized by the activation of astrocytes and microglia that produce cytokines and ROS, causing neuronal damage and altered brain function, is closely linked to COPD, according to limitations. The integrity of the blood-brain barrier is also negatively impacted by chronic hypoxemia and due to oxidative stress in COPD, which permits inflammatory chemicals to enter the central nervous system and cause neurodegeneration. The systemic neural inflammatory connection is evident in the higher levels of biomarkers such as CRP, IL-6, and TNF-α in COPD. Thus, understanding the lung-brain axis provides valuable insight into the broader impact of COPD, and therapeutic approaches that reduce inflammation and oxidative stress may improve neurological and respiratory outcomes, offering a more all-encompassing approach to COPD management.
The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.
Wang L, Wang F, Wang X … +8 more , Chen X, Li C, Shan K, Zhou H, Wu G, Xu Z, Kong X, Wei P
J Neuroinflammation · 2026 Mar · PMID 41776637 · Full text
The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and cen...
The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.
Interferon-induced protein IFIT3 as a molecular nexus of neuroinflammation in Alzheimer's disease and HIV-associated neurocognitive disorders.
Das RK, Sahoo N, Roy D … +5 more , Nguyen L, Rodrigo H, Duttaroy AK, Fields JA, Roy U
J Neuroinflammation · 2026 Mar · PMID 41772634 · Full text
Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammatio...
Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammation, amyloid deposition, and immune dysregulation. However, the precise molecular connections between these disorders remain unclear. Here, we identify IFIT3 as a critical shared mediator of neuroinflammatory responses in both AD and HAND. Using complementary approaches, including neuronal and microglial cell cultures, the APP/PS1 mouse model, and human postmortem brain tissues, we demonstrate consistent IFIT3 upregulation in response to amyloid-beta (Aβ) and HIV-1 exposure, with notably enhanced expression under combined conditions. Treatment with combination antiretroviral therapy (cART) partially mitigated IFIT3 induction. Additionally, siRNA-mediated silencing of IFIT3 significantly reduced key inflammatory mediators, including mitochondrial antiviral signaling protein (MAVS), nuclear factor-κB, and proinflammatory cytokines. Clinically, elevated IFIT3 expression was associated with early HAND and progressively increased across advancing AD Braak stages. Together, these findings identify IFIT3 as a potential molecular bridge between HAND and AD, highlighting its promise as both a biomarker and a therapeutic target for inflammation-driven neurodegeneration.
Sublytic pyroptosis blocks Schwann cell remyelination through caspase-1-mediated Tyro3 cleavage.
Lu X, Han Y, Li D … +9 more , Li S, Li Z, Li Y, Liu Q, Liu Y, Morrison MH, Zha X, Wang F, Tao Y
J Neuroinflammation · 2026 Feb · PMID 41761334 · Full text
BACKGROUND: Inflammasomes canonically trigger pyroptotic cell death through GSDMD-mediated membrane rupture. This study investigates a distinct sublytic pyroptosis in Schwann cells following peripheral nerve injury, wher...
BACKGROUND: Inflammasomes canonically trigger pyroptotic cell death through GSDMD-mediated membrane rupture. This study investigates a distinct sublytic pyroptosis in Schwann cells following peripheral nerve injury, where inflammasome activation causes functional impairment without extensive cell death. METHODS: Using a mouse sciatic nerve transection-repair model combined with in vitro and in vivo analyses, we examined NLRP3 inflammasome activation and cell fate. Primary Schwann cell cultures and RSC96 cells were used for biochemical assays, while ultrastructural analyses were performed on sciatic nerve segments. RESULTS: Despite NLRP3 inflammasome activation, Schwann cells showed minimal GSDMD cleavage and maintained membrane integrity, resulting in low cell death rates (~ 8% in primary mouse Schwann cells and ~ 2–3% in RSC96 rat Schwann cells). However, these surviving cells failed to transition from repair to myelinating phenotype. Activated Caspase-1 directly cleaves Tyro3 receptor at Asp495, detaching the intracellular kinase domain and abolishing receptor function. This proteolytic inactivation disrupts the Gas6-Tyro3-Fyn signaling axis essential for Schwann cell myelination. Combined treatment with Caspase-1 inhibitor VX-765 and Gas6 prevented Tyro3 cleavage, restored downstream signaling, and promoted expression of myelin transcription factors Oct6 and Krox20 as well as myelin basic protein (MBP). In vivo application significantly enhanced myelin thickness, axon regeneration, and functional recovery assessed by sciatic function index and electrophysiology. CONCLUSIONS: Sublytic pyroptosis represents a novel inflammasome-mediated proteolytic receptor inactivation as a previously unrecognized mechanism, distinct from classical pyroptosis. Targeting this pathway with VX-765 and Gas6 represents a promising therapeutic strategy for peripheral nerve regeneration.
Microglia-T cell interactions drive α-synuclein pathology in a Parkinson's disease mouse model.
Ohtake Y, Norikami N, Hong B … +3 more , Manabe K, Itokazu T, Yamashita T
J Neuroinflammation · 2026 Feb · PMID 41761326 · Full text
Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is characterized by motor dysfunction, progressive dopaminergic (DA) neuron loss in the substantia nigra, and the pathological accumulation...
Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, is characterized by motor dysfunction, progressive dopaminergic (DA) neuron loss in the substantia nigra, and the pathological accumulation of α-synuclein (αSyn) aggregates within Lewy bodies. Emerging evidence suggests that neuroinflammation and adaptive immunity may contribute to PD pathogenesis. To investigate the underlying mechanisms, we adapted a PD model combining AAV-mediated αSyn overexpression with intranigral injection of αSyn fibrils, which enabled us to analyze the temporal sequence of pathological and immune responses over a defined time course. The model recapitulated key features of PD, including αSyn phosphorylation, motor deficits, and nigral DA neurodegeneration, alongside early-stage microglial activation and T cell infiltration. Furthermore, T cell deficiency markedly reduced these pathological changes and attenuated microglial activation, and pharmacological depletion of microglia suppressed T cell accumulation in the brain and mitigated PD pathology. Notably, microglia-associated chemokine induction remained detectable despite T cell deficiency, whereas pro-inflammatory cytokine induction was attenuated, suggesting amplification of neuroinflammation through T cell–microglia interactions. These findings underscore the crucial role of T cell–microglia crosstalk in accelerating PD pathogenesis, and suggest that targeting this early immune–glial interplay may help mitigate PD-related neuroinflammation and neuronal degeneration.
IL-18 binding protein attenuates neuroinflammation and cognitive decline in Alzheimer's disease.
Hong DK, Jeon SH, Kang M … +4 more , Lee S, Liu X, Ahn EH, Kang SS
J Neuroinflammation · 2026 Feb · PMID 41761230 · Full text
Neuroinflammation in Alzheimer’s disease (AD) extends beyond a secondary response to amyloid-β plaques and neurofibrillary tangles, representing a fundamental driver of disease pathogenesis. The NLRP3 inflammasome has em...
Neuroinflammation in Alzheimer’s disease (AD) extends beyond a secondary response to amyloid-β plaques and neurofibrillary tangles, representing a fundamental driver of disease pathogenesis. The NLRP3 inflammasome has emerged as a central mediator of neuroinflammation in AD, highlighting the importance of understanding its downstream effectors. Interleukin-18 (IL-18), a key proinflammatory cytokine activated by NLRP3 inflammasome, plays a crucial role in innate immunity and neuroinflammatory responses in neurodegenerative diseases and aging. However, its specific contribution to AD pathogenesis remains poorly understood. IL-18 binding protein (IL-18 BP), an endogenous inhibitor that suppresses IL-18-mediated inflammatory responses including IFNγ production, presents a potential therapeutic molecule, yet its regulatory role in AD has not been thoroughly investigated. This study aims to examine whether IL-18 and IL-18 BP are associated with neuroinflammation and neurodegeneration in AD progression and investigate the preventive effects of IL-18 BP in AD. Employing postmortem brain tissues of AD patients and AD mouse models, we confirmed that IL-18 and related proinflammatory signaling were activated in the absence of IL-18 BP in both AD patients and mice, including C/EBPβ transgenic mice, 3xTG (APP Swedish, MAPT P301L, PSEN1M146V), and 5xFAD (familial AD mutation) mice. Administration of IL-18 BP into the hippocampus alleviated inflammation and cognitive impairment during AD pathology progression in 3xTG mice compared to the vehicle administration group. These results suggest that IL-18 BP might be a new target for AD prevention by regulating IL-18-induced proinflammatory reactions and AD pathologies.
Kynurenine pathway dysregulation in major depressive disorder: the convergence of excitotoxicity, neuroinflammation, and oxidative stress.
O'Regan G, Plummer Z, Christie BR … +2 more , Shultz SR, Allen J
J Neuroinflammation · 2026 Feb · PMID 41749295 · Full text
Major depressive disorder (MDD) has traditionally been linked to deficient serotonergic neurotransmission, chronic stress, and heightened inflammation. Compelling evidence implicates the kynurenine pathway (KP), activate...
Major depressive disorder (MDD) has traditionally been linked to deficient serotonergic neurotransmission, chronic stress, and heightened inflammation. Compelling evidence implicates the kynurenine pathway (KP), activated by inflammatory cytokines and stress-related signals, as a critical mediator connecting these factors. The KP degrades tryptophan, the metabolic precursor of serotonin, into neuroactive metabolites called kynurenines, such as quinolinic acid and kynurenic acid. Patients with MDD exhibit KP dysregulation, often marked by an overproduction of quinolinic acid, an N-Methyl-D-aspartic acid receptor (NMDAR) agonist that drives excitotoxicity, alongside reduced production of kynurenic acid, an NMDAR antagonist that protects from excitotoxicity and has anti-inflammatory effects. This review examines dysregulation of the KP in MDD, emphasizing KP metabolites – particularly quinolinic acid and kynurenic acid – as biomarkers and mediators of excitotoxicity, neuroinflammation, and oxidative stress, and discusses the therapeutic efficacy of antidepressants that modulate this pathway. Understanding KP dysregulation could inform the development of targeted interventions that address the underlying biological drivers of MDD, offering new hope for patients who do not respond to conventional treatments.
Lcn2 deficiency leads to long-lasting social impairments independent of maternal immune activation.
Pekala M, Zawiślak S, Romanis S … +9 more , Nader K, Dzwonek J, Cabaj A, Madecka A, Puścian A, Knapska E, Pawlak R, Kaczmarek L, Kalita K
J Neuroinflammation · 2026 Feb · PMID 41742209 · Full text
Maternal infection during pregnancy is a well-established risk factor for neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain poorly understood. Lipocalin-2 (Lcn2), an innate immune protei...
Maternal infection during pregnancy is a well-established risk factor for neurodevelopmental disorders (NDDs), yet the underlying molecular mechanisms remain poorly understood. Lipocalin-2 (Lcn2), an innate immune protein, is highly upregulated during infection, known to affect neuronal and glial function. This study investigates the role of Lcn2 in shaping brain development, particularly after maternal immune activation (MIA). To mimic maternal infection, pregnant mice received intraperitoneal injections of either lipopolysaccharide (LPS) or saline on embryonic days 16 to 18 to model infection during the second trimester of pregnancy in humans. We first showed that Lcn2 mRNA was expressed in the fetal brain and that MIA significantly upregulated Lcn2 mRNA in the hippocampus and neocortex of both sexes. To assess functional relevance, we employed Lcn2 heterozygous females to generate wild-type and Lcn2 KO offspring from the MIA and control groups. Both female and male offspring underwent a battery of behavioral assays. Strikingly, both Lcn2 deletion and MIA independently led to social deficits and increased repetitive behaviors, hallmark features of NDDs, but their combination did not produce additive effects, suggesting a shared or converging mechanism. These alterations were specific to social and repetitive behavior, as no deficits were observed in the learning and memory task. To investigate potential shared molecular mechanisms, we quantified pro-inflammatory cytokine levels in the placenta and fetal forebrain at 4 h after the final LPS injection. No genotype-dependent differences were observed in IL-6, TNF-α, or IL-1β expression. However, RNA sequencing analysis revealed an overlapping group of differentially expressed genes in the Lcn2 KO and MIA groups, indicating convergence on similar transcriptional pathways that may underlie the observed behavioral phenotypes. Together, these findings reveal a previously unrecognized role for Lcn2 in brain development and suggest that while Lcn2 may not directly mediate the damaging effects of maternal immune challenge, it intersects with critical developmental pathways that shape social behavior.
Colitis-associated gut-vagus-brain signaling integrates tumorigenesis and neuroinflammation: comparative regulation by vagotomy and atropine.
Yun D, Yang C, Wang X … +8 more , Zhou L, Jia M, Liang J, Hu X, Niu L, Mo F, Wang J, Liu Z
J Neuroinflammation · 2026 Feb · PMID 41731594 · Full text
BACKGROUND: Colitis-associated cancer (CAC) is frequently accompanied by neuropsychiatric comorbidities, yet the underlying gut-brain signaling pathways remain elusive. Emerging evidence highlights the gut-brain axis, pa...
BACKGROUND: Colitis-associated cancer (CAC) is frequently accompanied by neuropsychiatric comorbidities, yet the underlying gut-brain signaling pathways remain elusive. Emerging evidence highlights the gut-brain axis, particularly the vagus nerve, as a pivotal mediator linking gastrointestinal pathology with neuropsychiatric dysfunction. This study aimed to dissect the dual roles of vagal signaling in a murine CAC model and to evaluate the therapeutic potential of the muscarinic antagonist atropine on CAC. METHODS: The azoxymethane/dextran sulfate sodium (AOM/DSS) was adopted to induce CAC mice model. We employed unilateral vagotomy and pharmacological intervention with atropine, a muscarinic antagonist, in CAC mice. We assessed colon tumorigenesis, intestinal inflammation, anxiety/depression-like behaviors, and neuroinflammation of CAC mice under vagotomy and atropine treatment. Vagotomy and retrograde viral tracing were used to verify the essential role of vagus nerve signaling in activating neurons in brain regions linked to inflammation-induced depression and anxiety, thereby clarifying the gut-neuro-brain circuit mechanism. RESULTS: The findings revealed that CAC progression was associated with depression- and anxiety-like behaviors. Vagotomy significantly alleviated these behaviors, reduced c-fos expression in the NTS and lateral habenula/ midbrain-hindbrain boundary (LHb/MHb), and retrograde tracing confirmed a functional gut–NTS–LHb/MHb circuit activated by intestinal inflammation. Moreover, vagotomy improved CAC-induced behavioral deficits by reducing GFAP expression, alleviating neuroinflammation, though it failed to inhibit tumor growth or intestinal inflammation. In contrast, atropine treatment not only improved behavioral deficits but also reduced tumor number, downregulated cholinergic signaling and tumor markers, suppressed intestinal pro-inflammatory cytokines, and markedly ameliorated depression- and anxiety-like behaviors. CONCLUSION: These findings demonstrate the vagus nerve as a key gut-brain pathway linking CAC to depression and anxiety. Vagotomy disrupts inflammation-driven signaling, whereas atropine preserves anti-inflammatory vagal activity, positioning it as a promising therapeutic strategy for CAC-related anxiety and depression.
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