Pub Date : 2024-08-02DOI: 10.1186/s12974-024-03175-8
Monika Ayten, Tobias Straub, Lew Kaplan, Stefanie M Hauck, Antje Grosche, Susanne F Koch
Retinitis pigmentosa (RP), an inherited retinal disease, affects 1,5 million people worldwide. The initial mutation-driven photoreceptor degeneration leads to chronic inflammation, characterized by Müller cell activation and upregulation of CD44. CD44 is a cell surface transmembrane glycoprotein and the primary receptor for hyaluronic acid. It is involved in many pathological processes, but little is known about CD44's retinal functions. CD44 expression is also increased in Müller cells from our Pde6bSTOP/STOP RP mouse model. To gain a more detailed understanding of CD44's role in healthy and diseased retinas, we analyzed Cd44-/- and Cd44-/-Pde6bSTOP/STOP mice, respectively. The loss of CD44 led to enhanced photoreceptor degeneration, reduced retinal function, and increased inflammatory response. To understand the underlying mechanism, we performed proteomic analysis on isolated Müller cells from Cd44-/- and Cd44-/-Pde6bSTOP/STOP retinas and identified a significant downregulation of glutamate transporter 1 (SLC1A2). This downregulation was accompanied by higher glutamate levels, suggesting impaired glutamate homeostasis. These novel findings indicate that CD44 stimulates glutamate uptake via SLC1A2 in Müller cells, which in turn, supports photoreceptor survival and function.
{"title":"CD44 signaling in Müller cells impacts photoreceptor function and survival in healthy and diseased retinas.","authors":"Monika Ayten, Tobias Straub, Lew Kaplan, Stefanie M Hauck, Antje Grosche, Susanne F Koch","doi":"10.1186/s12974-024-03175-8","DOIUrl":"10.1186/s12974-024-03175-8","url":null,"abstract":"<p><p>Retinitis pigmentosa (RP), an inherited retinal disease, affects 1,5 million people worldwide. The initial mutation-driven photoreceptor degeneration leads to chronic inflammation, characterized by Müller cell activation and upregulation of CD44. CD44 is a cell surface transmembrane glycoprotein and the primary receptor for hyaluronic acid. It is involved in many pathological processes, but little is known about CD44's retinal functions. CD44 expression is also increased in Müller cells from our Pde6b<sup>STOP/STOP</sup> RP mouse model. To gain a more detailed understanding of CD44's role in healthy and diseased retinas, we analyzed Cd44<sup>-/-</sup> and Cd44<sup>-/-</sup>Pde6b<sup>STOP/STOP</sup> mice, respectively. The loss of CD44 led to enhanced photoreceptor degeneration, reduced retinal function, and increased inflammatory response. To understand the underlying mechanism, we performed proteomic analysis on isolated Müller cells from Cd44<sup>-/-</sup> and Cd44<sup>-/-</sup>Pde6b<sup>STOP/STOP</sup> retinas and identified a significant downregulation of glutamate transporter 1 (SLC1A2). This downregulation was accompanied by higher glutamate levels, suggesting impaired glutamate homeostasis. These novel findings indicate that CD44 stimulates glutamate uptake via SLC1A2 in Müller cells, which in turn, supports photoreceptor survival and function.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878880","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}
Pub Date : 2024-08-02DOI: 10.1186/s12974-024-03176-7
Kristina V Bergersen, Bill Kavvathas, Byron D Ford, Emma H Wilson
Background: Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood.
Main text: This study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed "chronic brain neutrophils" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies.
Conclusions: In conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.
{"title":"Toxoplasma infection induces an aged neutrophil population in the CNS that is associated with neuronal protection.","authors":"Kristina V Bergersen, Bill Kavvathas, Byron D Ford, Emma H Wilson","doi":"10.1186/s12974-024-03176-7","DOIUrl":"10.1186/s12974-024-03176-7","url":null,"abstract":"<p><strong>Background: </strong>Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons that can have devastating consequences in the immunocompromised. In the immunocompetent individual, anti-parasitic effector mechanisms and a balanced immune response characterized by pro- and anti-inflammatory cytokine production establishes an asymptomatic infection that rarely leads to neurological symptoms. Several mechanisms are known to play a role in this successful immune response in the brain including T cell production of IFNγ and IL-10 and the involvement of CNS resident cells. This limitation of clinical neuropathology during chronic infection suggests a balance between immune response and neuroprotective mechanisms that collectively prevent clinical manifestations of disease. However, how these two vital mechanisms of protection interact during chronic Toxoplasma infection remains poorly understood.</p><p><strong>Main text: </strong>This study demonstrates a previously undescribed connection between innate neutrophils found chronically in the brain, termed \"chronic brain neutrophils\" (CBNeuts), and neuroprotective mechanisms during Toxoplasma infection. Lack of CBNeuts during chronic infection, accomplished via systemic neutrophil depletion, led to enhanced infection and deleterious effects on neuronal regeneration and repair mechanisms in the brain. Phenotypic and transcriptomic analysis of CBNeuts identified them as distinct from peripheral neutrophils and revealed two main subsets of CBNeuts that display heterogeneity towards both classical effector and neuroprotective functions in an age-dependent manner. Further phenotypic profiling defined expression of the neuroprotective molecules NRG-1 andErbB4 by these cells, and the importance of this signaling pathway during chronic infection was demonstrated via NRG-1 treatment studies.</p><p><strong>Conclusions: </strong>In conclusion, this work identifies CBNeuts as a heterogenous population geared towards both classical immune responses and neuroprotection during chronic Toxoplasma infection and provides the foundation for future mechanistic studies of these cells.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878904","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}
Pub Date : 2024-08-02DOI: 10.1186/s12974-024-03154-z
Nicolás Albornoz, Javiera Álvarez-Indo, Adely de la Peña, Eloisa Arias-Muñoz, Alanis Coca, Fabián Segovia-Miranda, Bredford Kerr, Mauricio Budini, Alfredo Criollo, María A García-Robles, Eugenia Morselli, Andrea Soza, Patricia V Burgos
Objective: Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases.
Methods: The levels of the immunoproteasome β5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome β5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of β5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay.
Results: Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the β5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA.
Conclusions: Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.
目的:肥胖症是一项重大的全球性健康挑战,其特点是慢性低度炎症和代谢失调。下丘脑是能量平衡的关键调节器,特别容易受到肥胖的有害影响。免疫蛋白酶体是一种专门的蛋白酶体复合物,与炎症和细胞稳态有关:方法:通过免疫染色、Western 印迹和蛋白酶体活性检测分析了高脂饮食(HFD)或普通饮食(CHOW)喂养的小鼠体内免疫蛋白酶体 β5i亚基的水平。我们还研究了自噬抑制对免疫蛋白酶体β5i亚基水平和AKT通路激活的影响。最后,通过共聚焦显微镜,我们利用流式细胞术和有丝分裂检测分析了β5i亚基抑制对线粒体功能的贡献:结果:通过使用高氟日粮喂养的肥胖小鼠模型,我们发现下丘脑 POMC 神经元中的免疫蛋白酶体水平升高。此外,我们还观察到下丘脑神经元细胞中的免疫蛋白酶体β5i亚基水平升高,而棕榈酸(PA)是高脂饮食中饱和脂肪的主要成分。值得注意的是,免疫蛋白酶体表达的增加与自噬的减少有关,而自噬是维持体内平衡和抑制炎症的关键细胞过程。在功能上,PA 破坏了胰岛素-葡萄糖轴,导致 AKT 磷酸化减少,免疫蛋白体上调导致细胞内葡萄糖水平升高,从而对胰岛素产生反应。从机理上讲,我们发现蛋白质 PTEN 是胰岛素信号转导的关键调控因子,它以免疫蛋白体依赖的方式减少了胰岛素信号转导。为了进一步研究这些发现的潜在治疗意义,我们使用了一种特异性免疫蛋白酶体抑制剂 ONX-0914。我们证实这种抑制剂能防止 PA 诱导的胰岛素-葡萄糖轴失衡。鉴于线粒体功能障碍与代谢紊乱之间的相互作用,我们探讨了 ONX-0914 对线粒体功能的影响。值得注意的是,在 PA 存在的情况下,ONX-0914 能保持线粒体膜电位并减少线粒体 ROS 的产生。此外,我们还发现 ONX-0914 在 PA 存在的情况下减少了有丝分裂:我们的研究结果有力地支持了免疫蛋白酶体在下丘脑神经元中的致病参与,以及高密度脂蛋白胆固醇诱发的肥胖和代谢紊乱。以免疫蛋白酶体为靶点是减轻肥胖对胰岛素-葡萄糖轴和细胞稳态有害影响的一种有前景的治疗策略。这项研究为了解肥胖相关代谢疾病的驱动机制提供了宝贵的见解,并为开发新型治疗干预措施提供了潜在的途径。
{"title":"Targeting the immunoproteasome in hypothalamic neurons as a novel therapeutic strategy for high-fat diet-induced obesity and metabolic dysregulation.","authors":"Nicolás Albornoz, Javiera Álvarez-Indo, Adely de la Peña, Eloisa Arias-Muñoz, Alanis Coca, Fabián Segovia-Miranda, Bredford Kerr, Mauricio Budini, Alfredo Criollo, María A García-Robles, Eugenia Morselli, Andrea Soza, Patricia V Burgos","doi":"10.1186/s12974-024-03154-z","DOIUrl":"10.1186/s12974-024-03154-z","url":null,"abstract":"<p><strong>Objective: </strong>Obesity represents a significant global health challenge characterized by chronic low-grade inflammation and metabolic dysregulation. The hypothalamus, a key regulator of energy homeostasis, is particularly susceptible to obesity's deleterious effects. This study investigated the role of the immunoproteasome, a specialized proteasomal complex implicated in inflammation and cellular homeostasis, during metabolic diseases.</p><p><strong>Methods: </strong>The levels of the immunoproteasome β5i subunit were analyzed by immunostaining, western blotting, and proteasome activity assay in mice fed with either a high-fat diet (HFD) or a regular diet (CHOW). We also characterized the impact of autophagy inhibition on the levels of the immunoproteasome β5i subunit and the activation of the AKT pathway. Finally, through confocal microscopy, we analyzed the contribution of β5i subunit inhibition on mitochondrial function by flow cytometry and mitophagy assay.</p><p><strong>Results: </strong>Using an HFD-fed obese mouse model, we found increased immunoproteasome levels in hypothalamic POMC neurons. Furthermore, we observed that palmitic acid (PA), a major component of saturated fats found in HFD, increased the levels of the β5i subunit of the immunoproteasome in hypothalamic neuronal cells. Notably, the increase in immunoproteasome expression was associated with decreased autophagy, a critical cellular process in maintaining homeostasis and suppressing inflammation. Functionally, PA disrupted the insulin-glucose axis, leading to reduced AKT phosphorylation and increased intracellular glucose levels in response to insulin due to the upregulation of the immunoproteasome. Mechanistically, we identified that the protein PTEN, a key regulator of insulin signaling, was reduced in an immunoproteasome-dependent manner. To further investigate the potential therapeutic implications of these findings, we used ONX-0914, a specific immunoproteasome inhibitor. We demonstrated that this inhibitor prevents PA-induced insulin-glucose axis imbalance. Given the interplay between mitochondrial dysfunction and metabolic disturbances, we explored the impact of ONX-0914 on mitochondrial function. Notably, ONX-0914 preserved mitochondrial membrane potential and attenuated mitochondrial ROS production in the presence of PA. Moreover, we found that ONX-0914 reduced mitophagy in the presence of PA.</p><p><strong>Conclusions: </strong>Our findings strongly support the pathogenic involvement of the immunoproteasome in hypothalamic neurons in the context of HFD-induced obesity and metabolic disturbances. Targeting the immunoproteasome highlights a promising therapeutic strategy to mitigate the detrimental effects of obesity on the insulin-glucose axis and cellular homeostasis. This study provides valuable insights into the mechanisms driving obesity-related metabolic diseases and offers potential avenues for developing novel therapeutic interventions.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878903","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}
Background: Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system.
Methods: The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB-/- mice were generated, and relevant in vivo experiments were performed.
Results: Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB-/- mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage.
Conclusion: Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.
{"title":"Inhibition of ANGPTL8 protects against diabetes-associated cognitive dysfunction by reducing synaptic loss via the PirB signaling pathway.","authors":"Xiaoyu Meng, Danpei Li, Ranran Kan, Yuxi Xiang, Limeng Pan, Yaming Guo, Peng Yu, Peiqiong Luo, Huajie Zou, Li Huang, Yurong Zhu, Beibei Mao, Yi He, Lei Xie, Jialu Xu, Xiaoyan Liu, Wenjun Li, Yong Chen, Suiqiang Zhu, Yan Yang, Xuefeng Yu","doi":"10.1186/s12974-024-03183-8","DOIUrl":"10.1186/s12974-024-03183-8","url":null,"abstract":"<p><strong>Background: </strong>Type 2 diabetes mellitus (T2D) is associated with an increased risk of cognitive dysfunction. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator in T2D, but the role of ANGPTL8 in diabetes-associated cognitive dysfunction remains unknown. Here, we explored the role of ANGPTL8 in diabetes-associated cognitive dysfunction through its interaction with paired immunoglobulin-like receptor B (PirB) in the central nervous system.</p><p><strong>Methods: </strong>The levels of ANGPTL8 in type 2 diabetic patients with cognitive dysfunction and control individuals were measured. Mouse models of diabetes-associated cognitive dysfunction were constructed to investigate the role of ANGPTL8 in cognitive function. The cognitive function of the mice was assessed by the Barnes Maze test and the novel object recognition test, and levels of ANGPTL8, synaptic and axonal markers, and pro-inflammatory cytokines were measured. Primary neurons and microglia were treated with recombinant ANGPTL8 protein (rA8), and subsequent changes were examined. In addition, the changes induced by ANGPTL8 were validated after blocking PirB and its downstream pathways. Finally, mice with central nervous system-specific knockout of Angptl8 and PirB<sup>-/-</sup> mice were generated, and relevant in vivo experiments were performed.</p><p><strong>Results: </strong>Here, we demonstrated that in the diabetic brain, ANGPTL8 was secreted by neurons into the hippocampus, resulting in neuroinflammation and impairment of synaptic plasticity. Moreover, neuron-specific Angptl8 knockout prevented diabetes-associated cognitive dysfunction and neuroinflammation. Mechanistically, ANGPTL8 acted in parallel to neurons and microglia via its receptor PirB, manifesting as downregulation of synaptic and axonal markers in neurons and upregulation of proinflammatory cytokine expression in microglia. In vivo, PirB<sup>-/-</sup> mice exhibited resistance to ANGPTL8-induced neuroinflammation and synaptic damage.</p><p><strong>Conclusion: </strong>Taken together, our findings reveal the role of ANGPTL8 in the pathogenesis of diabetes-associated cognitive dysfunction and identify the ANGPTL8-PirB signaling pathway as a potential target for the management of this condition.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878901","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}
Pub Date : 2024-08-01DOI: 10.1186/s12974-024-03181-w
Ju Zou, Jie Li, Xiaoxu Wang, Daolin Tang, Ruochan Chen
The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.
{"title":"Neuroimmune modulation in liver pathophysiology.","authors":"Ju Zou, Jie Li, Xiaoxu Wang, Daolin Tang, Ruochan Chen","doi":"10.1186/s12974-024-03181-w","DOIUrl":"10.1186/s12974-024-03181-w","url":null,"abstract":"<p><p>The liver, the largest organ in the human body, plays a multifaceted role in digestion, coagulation, synthesis, metabolism, detoxification, and immune defense. Changes in liver function often coincide with disruptions in both the central and peripheral nervous systems. The intricate interplay between the nervous and immune systems is vital for maintaining tissue balance and combating diseases. Signaling molecules and pathways, including cytokines, inflammatory mediators, neuropeptides, neurotransmitters, chemoreceptors, and neural pathways, facilitate this complex communication. They establish feedback loops among diverse immune cell populations and the central, peripheral, sympathetic, parasympathetic, and enteric nervous systems within the liver. In this concise review, we provide an overview of the structural and compositional aspects of the hepatic neural and immune systems. We further explore the molecular mechanisms and pathways that govern neuroimmune communication, highlighting their significance in liver pathology. Finally, we summarize the current clinical implications of therapeutic approaches targeting neuroimmune interactions and present prospects for future research in this area.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875118","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}
Pub Date : 2024-07-30DOI: 10.1186/s12974-024-03163-y
Simone Lista, Bruno P Imbimbo, Margherita Grasso, Annamaria Fidilio, Enzo Emanuele, Piercarlo Minoretti, Susana López-Ortiz, Juan Martín-Hernández, Audrey Gabelle, Giuseppe Caruso, Marco Malaguti, Daniela Melchiorri, Alejandro Santos-Lozano, Camillo Imbimbo, Michael T Heneka, Filippo Caraci
Background: Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD.
Main body: Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ ("A"), tau ("T"), and neurodegeneration ("N"), by incorporating a novel inflammatory component ("I").
Conclusions: The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.
背景:最近对早期阿尔茨海默病(AD)进行的抗淀粉样蛋白-β(Aβ)单克隆抗体(包括莱卡奈单抗和多那奈单抗)试验表明,这些药物的临床疗效有限,而且使用这些药物会带来严重不良反应的巨大风险。因此,探索辅助治疗方法似乎至关重要。全基因组关联研究发现,AD 与几个与免疫反应相关的 AD 风险基因(包括但不限于 CD33 和 TREM2)之间存在密切关联。在此,我们对目前有关候选神经炎症生物标志物及其在描述AD病理生理学特征方面的作用的知识进行了批判性回顾:主要内容:神经炎症被认为是AD发病机制的关键和促成因素。神经炎症很可能在AD的早期阶段就已存在,并与Aβ的沉积同时发生,这一事实加强了精确定义神经炎症事件的顺序和性质的必要性。此前,许多涉及抗炎药物的临床试验都对早期和轻度至中度 AD 产生了不利的结果。虽然这些失败的原因尚不清楚,但可能包括干预的时间和选择的目标。事实上,在我们的综述中,我们观察到了AD大脑神经炎症过程的阶段依赖性。神经胶质细胞的初始激活可抵消大脑早期的 Aβ 沉积,而小胶质细胞功能状态的下调则发生在疾病晚期。为解决这一问题,需要个性化的神经炎症调节疗法。可靠的血液神经炎症生物标志物的出现,尤其是作为反应性星形胶质细胞标志物的胶质纤维酸性蛋白的出现,可能有助于根据 ATI(N) 生物标志物框架对 AD 患者进行分类。这扩展了传统的 Aβ("A")、tau("T")和神经变性("N")分类,加入了新的炎症成分("I"):本综述概述了目前有关潜在神经炎症生物标志物的知识,重要的是强调了纵向分析的作用,因为需要纵向分析来准确监测大脑炎症的动态变化。在考虑将抗炎治疗干预措施用于临床评估之前,需要这种精确的时间和地点信息。我们建议,有效的抗神经炎症疗法应特别针对小胶质细胞和星形胶质细胞,同时考虑患者的个体 ATI(N)状态。
{"title":"Tracking neuroinflammatory biomarkers in Alzheimer's disease: a strategy for individualized therapeutic approaches?","authors":"Simone Lista, Bruno P Imbimbo, Margherita Grasso, Annamaria Fidilio, Enzo Emanuele, Piercarlo Minoretti, Susana López-Ortiz, Juan Martín-Hernández, Audrey Gabelle, Giuseppe Caruso, Marco Malaguti, Daniela Melchiorri, Alejandro Santos-Lozano, Camillo Imbimbo, Michael T Heneka, Filippo Caraci","doi":"10.1186/s12974-024-03163-y","DOIUrl":"10.1186/s12974-024-03163-y","url":null,"abstract":"<p><strong>Background: </strong>Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits and their use comes with a significant risk of serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD and several AD risk genes related to immune response, including but not restricted to CD33 and TREM2. Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers and their role in characterizing the pathophysiology of AD.</p><p><strong>Main body: </strong>Neuroinflammation is recognized to be a crucial and contributing component of AD pathogenesis. The fact that neuroinflammation is most likely present from earliest pre-stages of AD and co-occurs with the deposition of Aβ reinforces the need to precisely define the sequence and nature of neuroinflammatory events. Numerous clinical trials involving anti-inflammatory drugs previously yielded unfavorable outcomes in early and mild-to-moderate AD. Although the reasons behind these failures remain unclear, these may include the time and the target selected for intervention. Indeed, in our review, we observed a stage-dependent neuroinflammatory process in the AD brain. While the initial activation of glial cells counteracts early brain Aβ deposition, the downregulation in the functional state of microglia occurs at more advanced disease stages. To address this issue, personalized neuroinflammatory modulation therapy is required. The emergence of reliable blood-based neuroinflammatory biomarkers, particularly glial fibrillary acidic protein, a marker of reactive astrocytes, may facilitate the classification of AD patients based on the ATI(N) biomarker framework. This expands upon the traditional classification of Aβ (\"A\"), tau (\"T\"), and neurodegeneration (\"N\"), by incorporating a novel inflammatory component (\"I\").</p><p><strong>Conclusions: </strong>The present review outlines the current knowledge on potential neuroinflammatory biomarkers and, importantly, emphasizes the role of longitudinal analyses, which are needed to accurately monitor the dynamics of cerebral inflammation. Such a precise information on time and place will be required before anti-inflammatory therapeutic interventions can be considered for clinical evaluation. We propose that an effective anti-neuroinflammatory therapy should specifically target microglia and astrocytes, while considering the individual ATI(N) status of patients.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855786","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}
Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation of substantial amounts of lactate to maintain the energy demand for neurons and other brain cells. Lactate has garnered increasing attention in recent years because of its emerging role in critical biological processes such as inflammation regulation and neuroprotection, particularly through its histone lactylation. Bromodomain-containing protein 4 (BRD4) plays a crucial role in maintaining neural development and promoting memory formation in the central nervous system. Nonetheless, the function and regulatory mechanism of BRD4 and histone lactylation in astrocytes following SAH remain elusive. Our findings indicate that BRD4, a crucial epigenetic regulator, plays a definitive role in histone lactylation. Both in vitro and in vivo, these results demonstrated that targeted silencing of BRD4 in astrocytes can significantly reduce H4K8la lactylation, thereby aggravating the A1 polarization of astrocytes and ultimately affecting the recovery of neural function and prognosis in mice after SAH. In summary, BRD4 plays a pivotal role in modulating astrocyte polarization following SAH via histone lactylation. Targeting this mechanism might offer an efficient therapeutic strategy for SAH.
{"title":"Lactylation of histone by BRD4 regulates astrocyte polarization after experimental subarachnoid hemorrhage.","authors":"Fan Zhang, Jian Zhou, Peng Lu, Xianhui Zhang, Lei Yang, Jinpeng Wu, Lihan Zhang, Lifang Zhang, Jinwei Pang, Huangfan Xie, Bingqing Xie, Yong Jiang, Jianhua Peng","doi":"10.1186/s12974-024-03185-6","DOIUrl":"10.1186/s12974-024-03185-6","url":null,"abstract":"<p><p>Under subarachnoid hemorrhage (SAH) conditions, astrocytes undergo a marked intensification of glycolytic activity, resulting in the generation of substantial amounts of lactate to maintain the energy demand for neurons and other brain cells. Lactate has garnered increasing attention in recent years because of its emerging role in critical biological processes such as inflammation regulation and neuroprotection, particularly through its histone lactylation. Bromodomain-containing protein 4 (BRD4) plays a crucial role in maintaining neural development and promoting memory formation in the central nervous system. Nonetheless, the function and regulatory mechanism of BRD4 and histone lactylation in astrocytes following SAH remain elusive. Our findings indicate that BRD4, a crucial epigenetic regulator, plays a definitive role in histone lactylation. Both in vitro and in vivo, these results demonstrated that targeted silencing of BRD4 in astrocytes can significantly reduce H4K8la lactylation, thereby aggravating the A1 polarization of astrocytes and ultimately affecting the recovery of neural function and prognosis in mice after SAH. In summary, BRD4 plays a pivotal role in modulating astrocyte polarization following SAH via histone lactylation. Targeting this mechanism might offer an efficient therapeutic strategy for SAH.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855785","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}
Pub Date : 2024-07-30DOI: 10.1186/s12974-024-03184-7
Sonia Do Carmo, Marie-Audrey I Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T Emmerson, Janice C Malcolm, Quentin Bonomo, Nicolas G Bazan, A Claudio Cuello
Background: Brain inflammation contributes significantly to the pathophysiology of Alzheimer's disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.
Methods: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer's-like amyloid and tau pathologies at early and advanced pathological stages.
Results: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.
Conclusions: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.
背景:脑部炎症在阿尔茨海默病的病理生理学中起着重要作用,表现为神经胶质细胞活化、细胞因子/趋化因子分泌增加,以及脂质介质从有利于稳态转变为有利于炎症。然而,在 Aβ 斑块沉积和 tau 过度磷酸化之前的早期阶段,生物活性脂质介质的产生是否会受到影响尚不清楚。淀粉样蛋白和tau病理学的演变对膜磷脂和生物活性脂质介质的组成和丰度的不同影响也仍未解决:在这项研究中,我们通过液相色谱-串联质谱法检测了阿尔茨海默氏症类淀粉样蛋白和tau病理早期和晚期转基因大鼠皮质中DHA和AA衍生的生物活性脂质介质以及膜磷脂的水平:结果:我们的研究结果表明,在促炎症过程和促溶解过程之间存在着复杂的平衡,其中tau病理学的影响比淀粉样病理学更为明显。在 tau 蛋白错误折叠和聚集之前的阶段,促溶解脂质介质(RVD6 和 NPD1)、含 DHA 的磷脂和 IFN-γ 水平均有所增加。然而,在显示 NFT 样包涵体、神经元死亡、神经胶质细胞活化和认知障碍的晚期 tau 病理学中,细胞因子和 PGD2、PGE2 和 PGF2α 生成增加,而 IFN-γ 水平下降。这种病理变化还导致含 AA 的磷脂明显增加。相比之下,斑块淀粉样病变前的细胞因子和含 AA 磷脂水平已经很高,RVD6 和 NPD1 水平也有所升高。最后,Aβ斑块沉积伴随着前列腺素的适度增加、含AA磷脂的增加和含DHA磷脂的减少:我们的研究结果表明,炎症介质和脂质介质在淀粉样蛋白和 tau 病理学的演变过程中呈现出动态轨迹,并支持它们对膜特性以及信号转导所起的不同作用。
{"title":"Differential effect of an evolving amyloid and tau pathology on brain phospholipids and bioactive lipid mediators in rat models of Alzheimer-like pathology.","authors":"Sonia Do Carmo, Marie-Audrey I Kautzmann, Surjyadipta Bhattacharjee, Bokkyoo Jun, Carolyn Steinberg, Joshua T Emmerson, Janice C Malcolm, Quentin Bonomo, Nicolas G Bazan, A Claudio Cuello","doi":"10.1186/s12974-024-03184-7","DOIUrl":"10.1186/s12974-024-03184-7","url":null,"abstract":"<p><strong>Background: </strong>Brain inflammation contributes significantly to the pathophysiology of Alzheimer's disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.</p><p><strong>Methods: </strong>In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer's-like amyloid and tau pathologies at early and advanced pathological stages.</p><p><strong>Results: </strong>Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.</p><p><strong>Conclusions: </strong>Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855784","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}
Pub Date : 2024-07-29DOI: 10.1186/s12974-024-03177-6
Helena C Oft, Dennis W Simon, Dandan Sun
Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social, and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinical research of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together, this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as well as the limitations and future considerations for TBI "omics" work.
{"title":"New insights into metabolism dysregulation after TBI.","authors":"Helena C Oft, Dennis W Simon, Dandan Sun","doi":"10.1186/s12974-024-03177-6","DOIUrl":"10.1186/s12974-024-03177-6","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) remains a leading cause of death and disability that places a great physical, social, and financial burden on individuals and the health system. In this review, we summarize new research into the metabolic changes described in clinical TBI trials, some of which have already shown promise for informing injury classification and staging. We focus our discussion on derangements in glucose metabolism, cell respiration/mitochondrial function and changes to ketone and lipid metabolism/oxidation to emphasize potentially novel biomarkers for clinical outcome prediction and intervention and offer new insights into possible underlying mechanisms from preclinical research of TBI pathology. Finally, we discuss nutrition supplementation studies that aim to harness the gut/microbiome-brain connection and manipulate systemic/cellular metabolism to improve post-TBI recovery. Taken together, this narrative review summarizes published TBI-associated changes in glucose and lipid metabolism, highlighting potential metabolite biomarkers for clinical use, the cellular processes linking these markers to TBI pathology as well as the limitations and future considerations for TBI \"omics\" work.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11288120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141792662","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}
Pub Date : 2024-07-28DOI: 10.1186/s12974-024-03156-x
James Dooley, Jasmine G. Hughes, Edward J. Needham, Katerina A. Palios, Adrian Liston
Therapeutics for traumatic brains injuries constitute a global unmet medical need. Despite the advances in neurocritical care, which have dramatically improved the survival rate for the ~ 70 million patients annually, few treatments have been developed to counter the long-term neuroinflammatory processes and accompanying cognitive impairments, frequent among patients. This review looks at gene delivery as a potential therapeutic development avenue for traumatic brain injury. We discuss the capacity of gene delivery to function in traumatic brain injury, by producing beneficial biologics within the brain. Gene delivery modalities, promising vectors and key delivery routes are discussed, along with the pathways that biological cargos could target to improve long-term outcomes for patients. Coupling blood-brain barrier crossing with sustained local production, gene delivery has the potential to convert proteins with useful biological properties, but poor pharmacodynamics, into effective therapeutics. Finally, we review the limitations and health economics of traumatic brain injury, and whether future gene delivery approaches will be viable for patients and health care systems.
{"title":"The potential of gene delivery for the treatment of traumatic brain injury","authors":"James Dooley, Jasmine G. Hughes, Edward J. Needham, Katerina A. Palios, Adrian Liston","doi":"10.1186/s12974-024-03156-x","DOIUrl":"https://doi.org/10.1186/s12974-024-03156-x","url":null,"abstract":"Therapeutics for traumatic brains injuries constitute a global unmet medical need. Despite the advances in neurocritical care, which have dramatically improved the survival rate for the ~ 70 million patients annually, few treatments have been developed to counter the long-term neuroinflammatory processes and accompanying cognitive impairments, frequent among patients. This review looks at gene delivery as a potential therapeutic development avenue for traumatic brain injury. We discuss the capacity of gene delivery to function in traumatic brain injury, by producing beneficial biologics within the brain. Gene delivery modalities, promising vectors and key delivery routes are discussed, along with the pathways that biological cargos could target to improve long-term outcomes for patients. Coupling blood-brain barrier crossing with sustained local production, gene delivery has the potential to convert proteins with useful biological properties, but poor pharmacodynamics, into effective therapeutics. Finally, we review the limitations and health economics of traumatic brain injury, and whether future gene delivery approaches will be viable for patients and health care systems.","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141783843","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}