{"title":"IL-37 suppresses CNS autoimmunity by increasing the frequency of Treg cells and reducing CD4 + T cell-derived IL-10 production.","authors":"Reza Yazdani, Hamed Naziri, Gholamreza Azizi, Bogoljub Ciric, Mozhde Askari, Amir Moghadam Ahmadi, Jaya Aseervatham, Guang-Xian Zhang, Abdolmohamad Rostami","doi":"10.1186/s12974-024-03295-1","DOIUrl":"https://doi.org/10.1186/s12974-024-03295-1","url":null,"abstract":"<p><strong>Background: </strong>Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy.</p><p><strong>Aim: </strong>Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective.</p><p><strong>Findings: </strong>IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. IL-37 suppressed inflammation by decreasing infiltration of CD4 + T cells into the CNS and increasing the frequency of regulatory T cells, while IL-10 expression by CD4 + T cells decreased over time in the CNS.</p><p><strong>Conclusion: </strong>Our findings confirm the immunomodulatory role of IL-37 in CNS inflammation during ongoing disease, thus indicating the potential of IL-37 as an inhibitory reagent for MS therapy.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"301"},"PeriodicalIF":9.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676063","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}
Daniel P Nemeth, Xiaoyu Liu, Marianne C Monet, Haichen Niu, Gabriella Maxey, Matt S Schrier, Maria I Smirnova, Samantha J McGovern, Anu Herd, Damon J DiSabato, Trey Floyd, Rohit R Atluri, Alex C Nusstein, Braedan Oliver, Kristina G Witcher, Joshua St Juste Ellis, Jasmine Yip, Andrew D Crider, Daniel B McKim, Paula A Gajewski-Kurdziel, Jonathan P Godbout, Qi Zhang, Randy D Blakely, John F Sheridan, Ning Quan
{"title":"Localization of brain neuronal IL-1R1 reveals specific neural circuitries responsive to immune signaling.","authors":"Daniel P Nemeth, Xiaoyu Liu, Marianne C Monet, Haichen Niu, Gabriella Maxey, Matt S Schrier, Maria I Smirnova, Samantha J McGovern, Anu Herd, Damon J DiSabato, Trey Floyd, Rohit R Atluri, Alex C Nusstein, Braedan Oliver, Kristina G Witcher, Joshua St Juste Ellis, Jasmine Yip, Andrew D Crider, Daniel B McKim, Paula A Gajewski-Kurdziel, Jonathan P Godbout, Qi Zhang, Randy D Blakely, John F Sheridan, Ning Quan","doi":"10.1186/s12974-024-03287-1","DOIUrl":"https://doi.org/10.1186/s12974-024-03287-1","url":null,"abstract":"<p><p>Interleukin-1 (IL-1) is a pro-inflammatory cytokine that exerts a wide range of neurological and immunological effects throughout the central nervous system (CNS) and is associated with the etiology of affective and cognitive disorders. The cognate receptor for IL-1, Interleukin-1 Receptor Type 1 (IL-1R1), is primarily expressed on non-neuronal cells (e.g., endothelial cells, choroidal cells, ventricular ependymal cells, astrocytes, etc.) throughout the brain. However, the presence and distribution of neuronal IL-1R1 (nIL-1R1) has been controversial. Here, for the first time, a novel genetic mouse line that allows for the visualization of IL-1R1 mRNA and protein expression (Il1r1<sup>GR/GR</sup>) was used to map all brain nuclei and determine the neurotransmitter systems which express nIL-1R1 in adult male mice. The direct responsiveness of nIL-1R1-expressing neurons to both inflammatory and physiological levels of IL-1β in vivo was tested. Neuronal IL-1R1 expression across the brain was found in discrete glutamatergic and serotonergic neuronal populations in the somatosensory cortex, piriform cortex, dentate gyrus, and dorsal raphe nucleus. Glutamatergic nIL-1R1 comprises most of the nIL-1R1 expression and, using Vglut2-Cre-Il1r1<sup>r/r</sup> mice, which restrict IL-1R1 expression to only glutamatergic neurons, an atlas of glutamatergic nIL-1R1 expression across the brain was generated. Analysis of functional outputs of these nIL-1R1-expressing nuclei, in both Il1r1<sup>GR/GR</sup> and Vglut2-Cre-Il1r1<sup>r/r</sup> mice, reveals IL-1R1<sup>+</sup> nuclei primarily relate to sensory detection, processing, and relay pathways, mood regulation, and spatial/cognitive processing centers. Intracerebroventricular (i.c.v.) injections of IL-1 (20 ng) induces NFκB signaling in IL-1R1<sup>+</sup> non-neuronal cells but not in IL-1R1<sup>+</sup> neurons, and in Vglut2-Cre-Il1r1<sup>r/r</sup> mice IL-1 did not change gene expression in the dentate gyrus of the hippocampus (DG). GO pathway analysis of spatial RNA sequencing 1mo following restoration of nIL-1R1 in the DG neurons reveals IL-1R1 expression downregulates genes related to both synaptic function and mRNA binding while increasing select complement markers (C1ra, C1qb). Further, DG neurons exclusively express an alternatively spliced IL-1R Accessory protein isoform (IL-1RAcPb), a known synaptic adhesion molecule. Altogether, this study reveals a unique network of neurons that can respond directly to IL-1 via nIL-1R1 through non-autonomous transcriptional pathways; earmarking these circuits as potential neural substrates for immune signaling-triggered sensory, affective, and cognitive disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"303"},"PeriodicalIF":9.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676074","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}
Jian Mao, Yun Bao, Fan Liu, Qiyun Ye, Junxiang Peng, Jing Nie, Lijun Huang, Yonghong Liao, Yiheng Xing, Dongyang Wu, Ke Wang, Wenfeng Feng, Songtao Qi, Jun Pan, Binghui Qiu
{"title":"Microglia-derived ADAM9 promote GHRH neurons pyroptosis by Mad2L2-JNK-caspase-1 pathway in subarachnoid hemorrhage.","authors":"Jian Mao, Yun Bao, Fan Liu, Qiyun Ye, Junxiang Peng, Jing Nie, Lijun Huang, Yonghong Liao, Yiheng Xing, Dongyang Wu, Ke Wang, Wenfeng Feng, Songtao Qi, Jun Pan, Binghui Qiu","doi":"10.1186/s12974-024-03299-x","DOIUrl":"https://doi.org/10.1186/s12974-024-03299-x","url":null,"abstract":"<p><p>The incidence of growth hormone deficiency (GHD) after subarachnoid hemorrhage (SAH) is significantly higher than that of other neuroendocrine disorders, but the mechanism is still elusive. We used mass spectrometry to identify differentially expressed proteins in cerebrospinal fluid samples from a well-characterized cohort of patients. A total of 683 proteins were identified, including 39 upregulated proteins in the GHD group. ADAM9 was most highly associated with GHD. In vivo, ADAM9 colocalized with M1 microglia markers, GH and cognitive ability of mice decreased significantly, and microglia secreted ADAM9 significantly. ADAM9 regulates pyroptosis of GHRH neurons by the Mad2L2-JNK-caspase-1 pathway. Sorafenib inhibits ADAM9 secretion by microglia and improves GH levels and the cognitive ability of mice. This study found that the crosstalk between GHRH neurons and neuroglial cells in the hypothalamic arcuate nucleus, i.e., microglia, is an essential factor in the formation of GHD in SAH. We propose that neutralization of ADAM9 production by microglia might be a potential therapy for GHD after SAH.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"302"},"PeriodicalIF":9.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676085","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":"Fueling neurodegeneration: metabolic insights into microglia functions.","authors":"Mohammadamin Sadeghdoust, Aysika Das, Deepak Kumar Kaushik","doi":"10.1186/s12974-024-03296-0","DOIUrl":"10.1186/s12974-024-03296-0","url":null,"abstract":"<p><p>Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"300"},"PeriodicalIF":9.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647435","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}
Sarah Tarhini, Carla Crespo-Quiles, Emmanuelle Buhler, Louison Pineau, Emilie Pallesi-Pocachard, Solène Villain, Saswati Saha, Lucas Silvagnoli, Thomas Stamminger, Hervé Luche, Carlos Cardoso, Jean-Paul Pais de Barros, Nail Burnashev, Pierre Szepetowski, Sylvian Bauer
{"title":"Cytomegalovirus infection of the fetal brain: intake of aspirin during pregnancy blunts neurodevelopmental pathogenesis in the offspring.","authors":"Sarah Tarhini, Carla Crespo-Quiles, Emmanuelle Buhler, Louison Pineau, Emilie Pallesi-Pocachard, Solène Villain, Saswati Saha, Lucas Silvagnoli, Thomas Stamminger, Hervé Luche, Carlos Cardoso, Jean-Paul Pais de Barros, Nail Burnashev, Pierre Szepetowski, Sylvian Bauer","doi":"10.1186/s12974-024-03276-4","DOIUrl":"10.1186/s12974-024-03276-4","url":null,"abstract":"<p><strong>Background: </strong>Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection.</p><p><strong>Methods: </strong>CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1.</p><p><strong>Results: </strong>Increased PGE2 levels and increased proportions of Cox-1<sup>+</sup> and Cox-2<sup>+</sup> microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1<sup>+</sup> fetal, but not neonatal, microglia, while leaving the proportions of Cox-2<sup>+</sup> microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups.</p><p><strong>Conclusion: </strong>Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"298"},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644456","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":"Reimagining the meninges from a neuroimmune perspective: a boundary, but not peripheral.","authors":"Xian Zhang, Liang Liu, Yan Chai, Jianning Zhang, Quanjun Deng, Xin Chen","doi":"10.1186/s12974-024-03286-2","DOIUrl":"10.1186/s12974-024-03286-2","url":null,"abstract":"<p><p>Recent advances in neuroscience have transformed our understanding of the meninges, the layers surrounding the central nervous system (CNS). Two key findings have advanced our understanding: researchers identified cranial bone marrow as a reservoir for meningeal immune cells, and rediscovered a brain lymphatic system. Once viewed merely as a protective barrier, the meninges are now recognized as a dynamic interface crucial for neuroimmune interactions. This shift in perspective highlights their unique role in maintaining CNS balance, shaping brain development, and regulating responses to injury and disease. This review synthesizes the latest insights into meningeal anatomy and function, with a focus on newly identified structures such as dural-associated lymphoid tissues (DALT) and arachnoid cuff exit (ACE) points. We also examine the diverse immune cell populations within the meninges and their interactions with the CNS, underscoring the emerging view of the meninges as active participants in brain immunity. Finally, we outline critical unanswered questions about meningeal immunity, proposing directions for future research. By addressing these knowledge gaps, we aim to deepen our understanding of the meninges' role in brain health and disease, potentially paving the way for novel therapeutic approaches.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"299"},"PeriodicalIF":9.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568633/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644458","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}
Nikita Golovachev, Lorraine Siebold, Richard L Sutton, Sima Ghavim, Neil G Harris, Brenda Bartnik-Olson
{"title":"Metabolic-driven analytics of traumatic brain injury and neuroprotection by ethyl pyruvate.","authors":"Nikita Golovachev, Lorraine Siebold, Richard L Sutton, Sima Ghavim, Neil G Harris, Brenda Bartnik-Olson","doi":"10.1186/s12974-024-03280-8","DOIUrl":"10.1186/s12974-024-03280-8","url":null,"abstract":"<p><strong>Background: </strong>Research on traumatic brain injury (TBI) highlights the significance of counteracting its metabolic impact via exogenous fuels to support metabolism and diminish cellular damage. While ethyl pyruvate (EP) treatment shows promise in normalizing cellular metabolism and providing neuroprotection, there is a gap in understanding the precise metabolic pathways involved. Metabolomic analysis of the acute post-injury metabolic effects, with and without EP treatment, aims to deepen our knowledge by identifying and comparing the metabolite profiles, thereby illuminating the injury's effects and EP's therapeutic potential.</p><p><strong>Methods: </strong>In the current study, an untargeted metabolomics approach was used to reveal brain metabolism changes in rats 24 h after a controlled cortical impact (CCI) injury, with or without EP treatment. Using principal component analysis (PCA), volcano plots, Random Forest and pathway analysis we differentiated the brain metabolomes of CCI and sham injured animals treated with saline (Veh) or EP, identifying key metabolites and pathways affected by injury. Additionally, the effect of EP on the non-injured brain was also explored.</p><p><strong>Results: </strong>PCA showed a clear separation of the four study groups (sham-Veh, CCI-Veh, sham-EP, CCI-EP) based on injury. Following CCI injury (CCI-Veh), 109 metabolites belonging to the amino acid, carbohydrate, lipid, nucleotide, and xenobiotic families exhibited a twofold change at 24 h compared to the sham-Veh group, with 93 of these significantly increasing and 16 significantly decreasing (p < 0.05). CCI animals were treated with EP (CCI-EP) showed only 5 metabolites in the carbohydrate, amino acids, peptides, nucleotides, lipids, and xenobiotics super families that exhibited a twofold change, compared to the CCI-Veh group (p < 0.05). In the non-injured brain, EP treatment (sham-EP) resulted in a twofold change in 6 metabolites within the amino acid, peptide, nucleotide, and lipid super families compared to saline treated sham animals (sham-Veh, p < 0.05).</p><p><strong>Conclusions: </strong>This study delineates the unique metabolic signatures resulting from a CCI injury and those related to EP treatment in both the injured and non-injured brain, underscoring the metabolic adaptations to brain injury and the effects of EP. Our analysis uncovers significant shifts in metabolites associated with inflammation, energy metabolism, and neuroprotection after injury, and demonstrates how EP intervention after injury alters metabolites associated with mitigating inflammation and oxidative damage.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"294"},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622249","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}
Jiaxuan Jiang, Pengzi Zhang, Yue Yuan, Xiang Xu, Tianyu Wu, Zhou Zhang, Jin Wang, Yan Bi
{"title":"Prolactin deficiency drives diabetes-associated cognitive dysfunction by inducing microglia-mediated synaptic loss.","authors":"Jiaxuan Jiang, Pengzi Zhang, Yue Yuan, Xiang Xu, Tianyu Wu, Zhou Zhang, Jin Wang, Yan Bi","doi":"10.1186/s12974-024-03289-z","DOIUrl":"10.1186/s12974-024-03289-z","url":null,"abstract":"<p><strong>Background: </strong>Diabetes-associated cognitive dysfunction, characterized by hippocampal synaptic loss as an early pathological feature, seriously threatens patients' quality of life. Synapses are dynamic structures, and hormones play important roles in modulating the formation and elimination of synapses. The pituitary, the master gland of the body, releases several hormones with multiple roles in hippocampal synaptic regulation. In this study, we aimed to explore the relationship between pituitary hormones and cognitive decline in diabetes.</p><p><strong>Methods: </strong>A total of 744 patients with type 2 diabetes (T2DM) (445 men and 299 postmenopausal women) who underwent serum pituitary hormone level assessments, comprehensive cognitive evaluations and MRI scans were enrolled. Dynamic diet interventions were applied in both chow diet-fed mice and high-fat diet (HFD)-fed diabetic mice. The cognitive performance and hippocampal pathology of prolactin (PRL)-knockout mice, neuronal prolactin receptor (PRLR)-specific knockout mice and microglial PRLR-specific knockout mice were assessed. Microglial PRLR-specific knockout mice were fed an HFD to model diabetes. Diabetic mice received an intracerebroventricular infusion of recombinant PRL protein or vehicle.</p><p><strong>Results: </strong>This clinical study revealed that decreased PRL levels were associated with cognitive impairment and hippocampal damage in T2DM patients. In diabetic mice, PRL levels diminished before hippocampal synaptic loss and cognitive decline occurred. PRL loss could directly cause cognitive dysfunction and decreased hippocampal synaptic density. Knockout of PRLR in microglia, rather than neurons, induced hippocampal synaptic loss and cognitive impairment. Furthermore, blockade of PRL/PRLR signaling in microglia exacerbated abnormal microglial phagocytosis of synapses, further aggravating hippocampal synaptic loss and cognitive impairment in diabetic mice. Moreover, PRL infusion reduced microglia-mediated synaptic loss, thereby alleviating cognitive impairment in diabetic mice.</p><p><strong>Conclusion: </strong>PRL is associated with cognitive dysfunction and hippocampal damage in T2DM patients. In diabetes, a decrease in PRL level drives hippocampal synaptic loss and cognitive impairment by increasing microglia-mediated synapse engulfment. Restoration of PRL levels ameliorates cognitive dysfunction and hippocampal synaptic loss in diabetic mice.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"295"},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622251","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}
Stefaniya K Boneva, Julian Wolf, Malte Jung, Gabriele Prinz, Toco Y P Chui, Jacqueline Jauch, Anne Drougard, J Andrew Pospisilik, Anja Schlecht, Felicitas Bucher, Richard B Rosen, Hansjürgen Agostini, Günther Schlunck, Clemens A K Lange
{"title":"The multifaceted role of vitreous hyalocytes: Orchestrating inflammation, angiomodulation and erythrophagocytosis in proliferative diabetic retinopathy.","authors":"Stefaniya K Boneva, Julian Wolf, Malte Jung, Gabriele Prinz, Toco Y P Chui, Jacqueline Jauch, Anne Drougard, J Andrew Pospisilik, Anja Schlecht, Felicitas Bucher, Richard B Rosen, Hansjürgen Agostini, Günther Schlunck, Clemens A K Lange","doi":"10.1186/s12974-024-03291-5","DOIUrl":"10.1186/s12974-024-03291-5","url":null,"abstract":"<p><strong>Background: </strong>Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis.</p><p><strong>Results: </strong>A total of 55 patients were included in this study encompassing RNA-Sequencing analysis of hyalocytes isolated from the vitreous of PDR and control patients, multiplex immunoassay and ELISA analyses of vitreous samples from PDR and control patients, as well as isolation and immunohistochemical staining of cultured porcine hyalocytes. Transcriptional analysis revealed an enhanced inflammatory response of hyalocytes contributing to the cytokine pool within the vitreous of PDR patients by expressing interleukin-6, among others. Further, increased angiopoietin-2 expression indicated that hyalocytes from PDR patients undergo a proangiogenic shift and may thus mediate the formation of retinal neovascularizations, the hallmark of PDR. Finally, RNA-Sequencing revealed an upregulation of factors known from hemoglobin catabolism in hyalocytes from PDR patients. By immunohistochemistry, cultured porcine hyalocytes exposed to red blood cells were shown to engulf and phagocytose these, which reveals hyalocytes' potential to dispose of erythrocytes. Thus, our data suggest a potential role for vitreous macrophages in erythrophagocytosis and, thereby, clearance of vitreous hemorrhage, a severe complication of PDR.</p><p><strong>Conclusion: </strong>Our results strongly indicate a critical role for vitreous hyalocytes in key pathophysiological processes of proliferative diabetic retinopathy: inflammation, angiomodulation and erythrophagocytosis. Immunomodulation of hyalocytes may thus prove an essential novel therapeutic approach in diabetic vitreoretinal disease.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"297"},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622254","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}
Xinnan Zhao, Xiaohan Yang, Cong Du, Huimin Hao, Shuang Liu, Gang Liu, Guangyin Zhang, Kai Fan, Jianmei Ma
{"title":"Up-regulated succinylation modifications induce a senescence phenotype in microglia by altering mitochondrial energy metabolism.","authors":"Xinnan Zhao, Xiaohan Yang, Cong Du, Huimin Hao, Shuang Liu, Gang Liu, Guangyin Zhang, Kai Fan, Jianmei Ma","doi":"10.1186/s12974-024-03284-4","DOIUrl":"10.1186/s12974-024-03284-4","url":null,"abstract":"<p><p>The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.</p>","PeriodicalId":16577,"journal":{"name":"Journal of Neuroinflammation","volume":"21 1","pages":"296"},"PeriodicalIF":9.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622272","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}