Journal of Neuroinflammation最新文献

{"title":"Complement inhibition targets a rich-club within the neuroinflammatory network after stroke to improve radiographic and functional outcomes.","authors":"Youssef M Zohdy, Tomas Garzon-Muvdi, Jonathan A Grossberg, Daniel L Barrow, Brian M Howard, Gustavo Pradilla, Firas H Kobeissy, Stephen Tomlinson, Ali M Alawieh","doi":"10.1186/s12974-024-03316-z","DOIUrl":"10.1186/s12974-024-03316-z","url":null,"abstract":"<p><p>Following recent advances in post-thrombectomy stroke care, the role of neuroinflammation and neuroprotective strategies in mitigating secondary injury has gained prominence. Yet, while neuroprotection and anti-inflammatory agents have re-emerged in clinical trials, their success has been limited. The neuroinflammatory response in cerebral ischemia is robust and multifactorial, complicating therapeutic approaches targeting single pathways. In this study, we aimed to characterize early inflammatory gene dysregulation following ischemic stroke using translational in-silico and in-vivo approaches. Using an in vivo ischemic stroke model, transcriptomic analysis revealed significant dysregulation of inflammatory genes. Graph theory analysis then showed a rich-club organization among stroke-related genes, with highly connected core nodes. The expression levels of the core genes identified within this network significantly explained radiological outcomes, including T2-signal hyperintensity (R² = 0.57, P < 0.001), mean diffusivity (R² = 0.52, P < 0.001), and mean kurtosis (R² = 0.65, P < 0.001), correlating more strongly than non-core genes. Similar findings were observed with functional and cognitive outcomes, showing R² values of 0.58, 0.7, 0.54, and 0.7 for neurological severity scores, corner tasks, passive avoidance, and novel object recognition tasks, respectively (P < 0.001). Using in-silico analysis, we identified a set of upstream regulators directly interacting with core network nodes, leading to simulations that highlighted C3-targeted therapy as a potential treatment. This hypothesis was then confirmed in vivo using a targeted C3 inhibitor (CR2-fH), which reversed gene dysregulation in the neuroinflammatory network and improved radiological and functional outcomes. Our findings underscore the significance of neuroinflammation in stroke pathology, supporting network-based therapeutic targeting and demonstrating the benefits of targeted complement inhibition in enhancing outcomes through modulation of the neuroinflammatory network core. This study's approach, combining graph theory analysis along with in-silico modeling, offers a promising translational pipeline applicable to stroke and other complex diseases.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"1"},"PeriodicalIF":9.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic reduction of neurocan in murine intracerebral hemorrhage lesions promotes oligodendrogenesis and functional recovery.","authors":"Hongmin Li, Samira Ghorbani, Olayinka Oladosu, Ping Zhang, Frank Visser, Jeff Dunn, Yunyan Zhang, Chang-Chun Ling, V Wee Yong, Mengzhou Xue","doi":"10.1186/s12974-024-03331-0","DOIUrl":"https://doi.org/10.1186/s12974-024-03331-0","url":null,"abstract":"<p><strong>Background: </strong>Intracerebral hemorrhage (ICH) causes prominent deposition of extracellular matrix molecules, particularly the chondroitin sulphate proteoglycan (CSPG) member neurocan. In tissue culture, neurocan impedes the properties of oligodendrocytes. Whether therapeutic reduction of neurocan promotes oligodendrogenesis and functional recovery in ICH is unknown.</p><p><strong>Methods: </strong>Mice were retro-orbitally injected with adeno-associated virus (AAV-CRISPR/Cas9) to reduce neurocan deposition after ICH induction by collagenase. Other groups of ICH mice were treated with vehicle or a drug that reduces CSPG synthesis, 4-4-difluoro-N-acetylglucosamine (difluorosamine). Rota-rod and grip strength behavioral tests were conducted over 7 or 14 days. Brain tissues were investigated for expression of neurocan by immunofluorescence microscopy and western blot analysis. Brain cryosections were also stained for microglia/macrophage phenotype, oligodendrocyte lineage cells and neuroblasts by immunofluorescence microscopy. Tissue structural changes were assessed using brain magnetic resonance imaging (MRI).</p><p><strong>Results: </strong>The adeno-associated virus (AAV)-reduction of neurocan increased oligodendrocyte numbers and functional recovery in ICH. The small molecule inhibitor of CSPG synthesis, difluorosamine, lowered neurocan levels in lesions and elevated numbers of oligodendrocyte precursor cells, mature oligodendrocytes, and SOX2⁺ nestin⁺ neuroblasts in the perihematomal area. Difluorosamine shifted the degeneration-associated functional state of microglia/macrophages in ICH towards a regulatory phenotype. MRI analyses showed better fiber tract integrity in the penumbra of difluorosamine mice. These beneficial difluorosamine results were achieved with delayed (2 or 3 days) treatment after ICH.</p><p><strong>Conclusion: </strong>Reducing neurocan deposition following ICH injury is a therapeutic approach to promote histological and behavioral recovery from the devastating stroke.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"22 1","pages":"2"},"PeriodicalIF":9.3,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia and Immune cells interactions in multiple sclerosis cognitive impairment: a postmortem study.","authors":"Catarina Barros, Ainhoa Alberro, Adelaide Fernandes","doi":"10.1186/s12974-024-03326-x","DOIUrl":"10.1186/s12974-024-03326-x","url":null,"abstract":"<p><p>Multiple Sclerosis (MS), a neuroinflammatory disease of the central nervous system, is one of the commonest causes of non-traumatic disability among young adults. Impaired cognition arises as an impactful symptom affecting more than 50% of the patients and with substantial impact on social, economic, and individual wellbeing. Despite the lack of therapeutic strategies, many efforts have been made to understand the mechanisms behind cognitive impairment in MS patients. Here, we aimed to investigate whether microglia-derived synaptic elimination and immune interactions are exacerbated in MS patients with impaired cognition when compared to non-demented controls (NDC) and cognitively preserved MS patients, that may clarify the role of immune cell interplay in MS cognitive deficits. Postmortem hippocampal samples were obtained from NDCs and MS patients. Sixteen MS patients were categorized based on their cognitive status: preserved cognition (MSCP) and impaired cognition (MSCI). Immunohistochemistry studies were conducted to explore the density of microglia, their role in synaptic engulfment, and their interaction with CD8⁺ immune cells in the context of cognitive impairment in MS. In high synaptic density hippocampal regions, MSCI patients exhibited a massive presence of microglia cells actively engulfing both excitatory and inhibitory synapses, accompanied by morphological alterations. Additionally, there was an increased expression of the complement protein C1q particularly localized at inhibitory synapses within microglia cells, suggesting a preferential engulfment of complement-tagged inhibitory synapses in MSCI patients. Furthermore, in hippocampal lesions of MSCI patients, we detected a significant infiltration of microglia and CD8 T cells that may be contributing to the smouldering MS and cognitive deterioration. These findings demonstrate that cognitive deficits occurring in MS are associated with microglia engulfment of C1q-tagged inhibitory synapses, which may be driven by direct or indirect stimulation from CD8+ T cells.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"332"},"PeriodicalIF":9.3,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11689504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Th17 and effector CD8 T cells relate to disease progression in amyotrophic lateral sclerosis: a case control study.","authors":"Tatsuo Itou, Koji Fujita, Yuumi Okuzono, Dnyaneshwar Warude, Shuuichi Miyakawa, Yoshimi Mihara, Naoko Matsui, Hiroyuki Morino, Yusuke Kikukawa, Yuishin Izumi","doi":"10.1186/s12974-024-03327-w","DOIUrl":"10.1186/s12974-024-03327-w","url":null,"abstract":"<p><p>The immune system has garnered attention due to its association with disease progression in amyotrophic lateral sclerosis (ALS). However, the role of peripheral immune cells in this context remains controversial. Here, we conducted single-cell RNA-sequencing of peripheral blood mononuclear cells to comprehensively profile immune cells concerning the rate of disease progression in patients with ALS. Our analysis revealed increased frequencies of T helper 17 cells (Th17) relative to regulatory T cells, effector CD8 T cells relative to naïve CD8 T cells, and CD16^highCD56^low mature natural killer cells relative to CD16^lowCD56^high naïve natural killer cells in patients with rapidly progressive ALS. Additionally, we employed serum proteomics through a proximity extension assay combined with next-generation sequencing to identify inflammation-related proteins associated with rapid disease progression. Among these proteins, interleukin-17 A correlated with the frequency of Th17, while killer cell lectin-like receptor D1 (CD94) correlated with the frequency of effector CD8 T cells. These findings further support the active roles played by these specific immune cell types in the progression of ALS.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"331"},"PeriodicalIF":9.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11674182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CCR2 restricts IFN-γ production by hippocampal CD8 TRM cells that impair learning and memory during recovery from WNV encephalitis.","authors":"Shenjian Ai, Artem Arutyunov, Joshua Liu, Jeremy D Hill, Xiaoping Jiang, Robyn S Klein","doi":"10.1186/s12974-024-03309-y","DOIUrl":"10.1186/s12974-024-03309-y","url":null,"abstract":"<p><p>Central nervous system (CNS) resident memory CD8 T cells (T_RM) that express IFN-γ contribute to neurodegenerative processes, including synapse loss, leading to memory impairment. Here, we show that CCR2 signaling in CD8 T_RM that persist within the hippocampus after recovery from CNS infection with West Nile virus (WNV) significantly prevents the development of memory impairments. Using CCR2-deficient mice, we determined that CCR2 expression is not essential for CNS T cell recruitment or virologic control during acute WNV infection. However, transcriptomic analyses of forebrain CCR2⁺ versus CCR2^- CD8 T_RM during WNV recovery reveal that CCR2 signaling significantly regulates hippocampal CD8 T_RM phenotype and function via extrinsic and intrinsic effects, limiting expression of CD103, granzyme A and IFN-γ, respectively, and increasing the percentages of virus-specific CD8 T cells. Consistent with this, WNV-recovered Cd8a^creCcr2^fl/fl mice exhibit decreased recognition memory. Overall, these data implicate CCR2 signaling in the regulation of CD8 T_RM phenotype, including antiviral specificity and IFN-γ expression, highlighing a neuroprotective role for CCR2 in limiting CD8 T cell-mediated neuroinflammation and cognitive deficits, providing insights into potential therapeutic targets for CNS infections.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"330"},"PeriodicalIF":9.3,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142895475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prostanoid signaling in retinal cells elicits inflammatory responses relevant to early-stage diabetic retinopathy.","authors":"Amy K Stark, John S Penn","doi":"10.1186/s12974-024-03319-w","DOIUrl":"10.1186/s12974-024-03319-w","url":null,"abstract":"<p><p>Inflammation is a critical driver of the early stages of diabetic retinopathy (DR) and offers an opportunity for therapeutic intervention before irreversible damage and vision loss associated with later stages of DR ensue. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown mixed efficacy in slowing early DR progression, notably including severe adverse side effects likely due to their nonselective inhibition of all downstream signaling intermediates. In this study, we investigated the role of prostanoids, the downstream signaling lipids whose production is inhibited by NSAIDs, in promoting inflammation relevant to early-stage DR in two human retinal cell types: Müller glia and retinal microvascular endothelial cells. When cultured in multiple conditions modeling distinct aspects of systemic diabetes, Müller glia significantly increased production of prostaglandin E₂ (PGE₂), whereas retinal endothelial cells significantly increased production of prostaglandin F_2α (PGF_2α). Müller glia stimulated with PGE₂ or PGF_2α increased proinflammatory cytokine levels dose-dependently. These effects were blocked by selective antagonists to the EP2 receptor of PGE₂ or the FP receptor of PGF_2α, respectively. In contrast, only PGF_2α stimulated adhesion molecule expression in retinal endothelial cells and leukocyte adhesion to cultured endothelial monolayers, effects that were fully prevented by FP receptor antagonist treatment. Together these results identify PGE₂-EP2 and PGF_2α-FP signaling as novel, selective targets for future studies and therapeutic development to mitigate or prevent retinal inflammation characteristic of early-stage DR.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"329"},"PeriodicalIF":9.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance.","authors":"Yang Yang, Guanjin Shi, Yanyan Ge, Shanshan Huang, Ningning Cui, Le Tan, Rui Liu, Xuefeng Yang","doi":"10.1186/s12974-024-03314-1","DOIUrl":"10.1186/s12974-024-03314-1","url":null,"abstract":"<p><p>A high-fat diet (HFD) induces obesity and insulin resistance, which may exacerbate amyloid-β peptide (Aβ) pathology during Alzheimer's disease (AD) progression. Branched-chain amino acids (BCAAs) accumulate in obese or insulin-resistant patients and animal models. However, roles of accumulated BCAAs and their metabolites, branched-chain keto acids (BCKAs), in the HFD-induced deterioration of AD and the underlying mechanisms remains largely unclear. In this study, APPswe/PSEN1dE9 (APP/PS1) transgenic mice were fed a HFD for 6 months, and the BCAAs content of the HFD was adjusted to 200% or 50% to determine the effects of BCAAs. The HFD-fed APP/PS1 mice accumulated BCAAs and BCKAs in the serum and cortex, which was accompanied by more severe cognitive deficits and AD-related pathology. The additional or restricted intake of BCAAs aggravated or reversed these phenomena. Importantly, BCAAs and BCKAs repressed microglial phagocytosis of Aβ in vivo and in BV2 cells, which might be relevant for triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction and autophagy deficiency. We found that BCAAs and BCKAs could bind to TREM2 in silico, in pure protein solutions and in the cellular environment. These molecules competed with Aβ for binding to TREM2 so that the response of TREM2 to Aβ was impaired. Moreover, BCAAs and BCKAs decreased TREM2 recycling in an mTOR-independent manner, which might also lead to TREM2 dysfunction. Our findings suggest that accumulated BCAAs and BCKAs contribute to the HFD-induced acceleration of AD progression through hypofunctional TREM2-mediated disturbances in Aβ clearance in microglia. Lowering BCAAs and BCKAs levels may become a potential dietary intervention for AD.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"327"},"PeriodicalIF":9.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory T cell expansion prevents retinal degeneration in type 2 diabetes.","authors":"María Llorián-Salvador, Daniel Pérez-Martínez, Miao Tang, Anna Duarri, Marta García-Ramirez, Anna Deàs-Just, Anna Álvarez-Guaita, Lorena Ramos-Pérez, Patricia Bogdanov, Jose A Gomez-Sanchez, Alan W Stitt, Cristina Hernández, Alerie G de la Fuente, Rafael Simó","doi":"10.1186/s12974-024-03323-0","DOIUrl":"10.1186/s12974-024-03323-0","url":null,"abstract":"<p><strong>Background: </strong>The global incidence of type 2 diabetes (T2D) is rapidly increasing, with retinopathy being its most common complication and a leading cause of preventable blindness. Although the precise mechanisms involved in the development of diabetic retinopathy (DR) are not fully understood, defective immunomodulation is a recognized key factor in its pathophysiology. Regulatory T cells (Treg) regulate inflammation and promote regeneration, and while they are known to have important anti-inflammatory and neuroprotective roles in other tissues, including central nervous system, their role in the diabetic retina remains largely unknown. The aim of the present study is to examine the effect of Treg expansion of retinal neurodegeneration, an early event in the pathogenesis of DR.</p><p><strong>Methods: </strong>Treg expansion was achieved by co-injecting recombinant mouse IL-2 with anti-IL-2 monoclonal antibody or its isotype in db/db mice as an established model of T2D. Treg expansion was confirmed via flow cytometry in blood, spleen, and retina. Fundus angiography was performed in the days prior to animal sacrifice at 18 weeks. To study the effect of Tregs on retinal neurons, glia and vascular permeability, immunohistochemistry against Cone-Arrestin, PKCα, synaptophysin, ChAT, TH, GFAP, Iba-1, calbindin, Brn3a, RBPMS, isolectin B4, and albumin was used. Retinal VEGF levels were measured with a magnetic bead-based immunoassay, and NLRP3, Casp1, p20 and IL-18 were analyzed by Western Blot in retinal homogenates.</p><p><strong>Results: </strong>There was a significant decrease in Treg in db/db mice blood. When this deficiency was corrected in db/db mice by systemic Treg expansion, there was an effective protection against retinal neurodegenerative, gliotic, inflammatory changes and vascular leakage associated with T2D. Importantly, Treg expansion did not impact the T2D phenotype in db/db mice as evaluated by blood glucose, HbA1c and circulating insulin.</p><p><strong>Conclusion: </strong>Treg modulation in T2D offers a promising therapeutic approach to prevent early stages of DR. This strategy focuses on reducing neuroinflammation and mitigating the associated neuronal, glial, and vascular degenerative changes characteristic of DR.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"328"},"PeriodicalIF":9.3,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations of the IKZF1-IKZF2 tandem in immune cells of schizophrenia patients regulate associated phenotypes.","authors":"Iván Ballasch, Laura López-Molina, Marcos Galán-Ganga, Anna Sancho-Balsells, Irene Rodríguez-Navarro, Sara Borràs-Pernas, M Angeles Rabadan, Wanqi Chen, Carlota Pastó-Pellicer, Francesca Flotta, Wang Maoyu, Joaquín Fernández-Irigoyen, Enrique Santamaría, Ruth Aguilar, Carlota Dobaño, Natalia Egri, Carla Hernandez, Miqueu Alfonso, Manel Juan, Jordi Alberch, Daniel Del Toro, Belén Arranz, Josep M Canals, Albert Giralt","doi":"10.1186/s12974-024-03320-3","DOIUrl":"10.1186/s12974-024-03320-3","url":null,"abstract":"<p><p>Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients' peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenia-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 mRNA levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenia-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"326"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11658472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tension at the gate: sensing mechanical forces at the blood-brain barrier in health and disease.","authors":"Cathrin E Hansen, David Hollaus, Alwin Kamermans, Helga E de Vries","doi":"10.1186/s12974-024-03321-2","DOIUrl":"10.1186/s12974-024-03321-2","url":null,"abstract":"<p><p>Microvascular brain endothelial cells tightly limit the entry of blood components and peripheral cells into the brain by forming the blood-brain barrier (BBB). The BBB is regulated by a cascade of mechanical and chemical signals including shear stress and elasticity of the adjacent endothelial basement membrane (BM). During physiological aging, but especially in neurological diseases including multiple sclerosis (MS), stroke, small vessel disease, and Alzheimer's disease (AD), the BBB is exposed to inflammation, rigidity changes of the BM, and disturbed cerebral blood flow (CBF). These altered forces lead to increased vascular permeability, reduced endothelial reactivity to vasoactive mediators, and promote leukocyte transmigration. Whereas the molecular players involved in leukocyte infiltration have been described in detail, the importance of mechanical signalling throughout this process has only recently been recognized. Here, we review relevant features of mechanical forces acting on the BBB under healthy and pathological conditions, as well as the endothelial mechanosensory elements detecting and responding to altered forces. We demonstrate the underlying complexity by focussing on the family of transient receptor potential (TRP) ion channels. A better understanding of these processes will provide insights into the pathogenesis of several neurological disorders and new potential leads for treatment.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"325"},"PeriodicalIF":9.3,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142852982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}