Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"Regional specification and complementation with non-neuroectodermal cells in human brain organoids.","authors":"Yoshiaki Tanaka,&nbsp;In-Hyun Park","doi":"10.1007/s00109-021-02051-9","DOIUrl":"https://doi.org/10.1007/s00109-021-02051-9","url":null,"abstract":"<p><p>Along with emergence of the organoids, their application in biomedical research has been currently one of the most fascinating themes. For the past few years, scientists have made significant contributions to deriving organoids representing the whole brain and specific brain regions. Coupled with somatic cell reprogramming and CRISPR/Cas9 editing, the organoid technologies were applied for disease modeling and drug screening. The methods to develop organoids further improved for rapid and efficient generation of cerebral organoids. Additionally, refining the methods to develop the regionally specified brain organoids enabled the investigation of development and interaction of the specific brain regions. Recent studies started resolving the issue in the lack of non-neuroectodermal cells in brain organoids, including vascular endothelial cells and microglia, which play fundamental roles in neurodevelopment and are involved in the pathophysiology of acute and chronic neural disorders. In this review, we highlight recent advances of neuronal organoid technologies, focusing on the region-specific brain organoids and complementation with endothelial cells and microglia, and discuss their potential applications to neuronal diseases.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"489-500"},"PeriodicalIF":4.7,"publicationDate":"2021-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-021-02051-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25427443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Molecular karyotyping and gene expression analysis in childhood cancer patients.","authors":"Danuta Galetzka,&nbsp;Tobias Müller,&nbsp;Marcus Dittrich,&nbsp;Miriam Endres,&nbsp;Nergiz Kartal,&nbsp;Olesja Sinizyn,&nbsp;Steffen Rapp,&nbsp;Tanja Zeller,&nbsp;Christian Müller,&nbsp;Thomas Hankeln,&nbsp;Peter Scholz-Kreisel,&nbsp;Heather Chorzempa,&nbsp;Johanna Mirsch,&nbsp;Alicia Poplawski,&nbsp;Heidi Rossmann,&nbsp;Claudia Spix,&nbsp;Thomas Haaf,&nbsp;Dirk Prawitt,&nbsp;Manuela Marron,&nbsp;Heinz Schmidberger","doi":"10.1007/s00109-020-01986-9","DOIUrl":"https://doi.org/10.1007/s00109-020-01986-9","url":null,"abstract":"<p><p>The correct Author names are presented in this paper.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1657"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01986-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38424325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gaining insight on mitigation of rubeosis iridis by UPARANT in a mouse model associated with proliferative retinopathy.","authors":"Filippo Locri,&nbsp;Noemi A Pesce,&nbsp;Monica Aronsson,&nbsp;Maurizio Cammalleri,&nbsp;Mario De Rosa,&nbsp;Vincenzo Pavone,&nbsp;Paola Bagnoli,&nbsp;Anders Kvanta,&nbsp;Massimo Dal Monte,&nbsp;Helder André","doi":"10.1007/s00109-020-01979-8","DOIUrl":"https://doi.org/10.1007/s00109-020-01979-8","url":null,"abstract":"<p><p>Proliferative retinopathies (PR) lead to an increase in neovascularization and inflammation factors, at times culminating in pathologic rubeosis iridis (RI). In mice, uveal puncture combined with injection of hypoxia-conditioned media mimics RI associated with proliferative retinopathies. Here, we investigated the effects of the urokinase plasminogen activator receptor (uPAR) antagonist-UPARANT-on the angiogenic and inflammatory processes that are dysregulated in this model. In addition, the effects of UPARANT were compared with those of anti-vascular endothelial growth factor (VEGF) therapies. Administration of UPARANT promptly decreased iris vasculature, while anti-VEGF effects were slower and less pronounced. Immunoblot and qPCR analysis suggested that UPARANT acts predominantly by reducing the upregulated inflammatory and extracellular matrix degradation responses. UPARANT appears to be more effective in comparison to anti-VEGF in the treatment of RI associated with PR in the murine model, by modulating multiple uPAR-associated signaling pathways. Furthermore, UPARANT effectiveness was maintained when systemically administered, which could open to novel improved therapies for proliferative ocular diseases, particularly those associated with PR. KEY MESSAGES: • Further evidence of UPARANT effectiveness in normalizing pathological iris neovascularization. • Both systemic and local administration of UPARANT reduce iris neovascularization in a model associated with proliferative retinopathies. • In the mouse models of rubeosis iridis associated with proliferative retinopathy, UPARANT displays stronger effects when compared with anti-vascular endothelial growth factor regimen.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1629-1638"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01979-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38388698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical and pharmacological characterization of a full-length synthetic analog of the antitumor polypeptide crotamine.","authors":"Lucas de Carvalho Porta,&nbsp;Valmir Fadel,&nbsp;Joana D'Arc Campeiro,&nbsp;Eduardo Brandt Oliveira,&nbsp;Rosely Oliveira Godinho,&nbsp;Mirian Akemi Furuie Hayashi","doi":"10.1007/s00109-020-01975-y","DOIUrl":"https://doi.org/10.1007/s00109-020-01975-y","url":null,"abstract":"<p><p>Crotamine is a polypeptide isolated from the venom of a South American rattlesnake. Among the properties and biological activities of crotamine, the most extraordinary is its ability to enter cells with unique selective affinity and cytotoxic activity against actively proliferating cells, such as tumor cells. This peptide is also a cargo carrier, and anticipating commercial application of this native polypeptide as a potential theranostic compound against cancer, we performed here a side-by-side characterization of a chemically synthesized full-length crotamine compared with its native counterpart. The structural, biophysical, and pharmacological properties were evaluated. Comparative NMR studies showed structural conservation of synthetic crotamine. Moreover, similarly to native crotamine, the synthetic polypeptide was also capable of inhibiting tumor growth in vivo, increasing the survival of mice bearing subcutaneous tumor. We also confirmed the ability of synthetic crotamine to transfect and transport DNA into eukaryotic cells, in addition to the importance of proteoglycans on cell surface for its internalization. This work opens new opportunities for future evaluation of chimeric and/or point-mutated analogs of this snake polypeptide, aiming for improving crotamine properties and applications, as well as possibly diminishing its potential toxic effects. KEY MESSAGES: • Synthetic crotamine showed ex vivo and in vivo activities similar to native peptide. • Synthetic crotamine structure conservation was demonstrated by NMR analysis. • Synthetic crotamine is able to transfect and transport DNA into eukaryotic cells. • Synthetic crotamine shows tumor growth inhibition in vivo. • Synthetic crotamine increases survival of mice bearing tumor.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1561-1571"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01975-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38352238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligand-based discovery of small molecules suppressing cancer cell proliferation via autophagic flux inhibition.","authors":"Li Liu,&nbsp;Zhen Tian,&nbsp;Yalin Zhang,&nbsp;Peijun Liu,&nbsp;Zhiqian Xin,&nbsp;Yong Zhao,&nbsp;Yifan Li,&nbsp;Shan Miao,&nbsp;Junling Shi,&nbsp;Zhinan Chen,&nbsp;Jiyuan Liu,&nbsp;Hai Zhang","doi":"10.1007/s00109-020-01971-2","DOIUrl":"https://doi.org/10.1007/s00109-020-01971-2","url":null,"abstract":"<p><p>Autophagy is a conserved self-degradation system closely related to cancer progression. Small molecule inhibitors of autophagy have proven to be efficient tools in cancer therapy and are in high demand. Here we report the discovery of two compounds (LZ02/01) capable of suppressing cancer cell proliferation via inhibiting autophagy flux and promoting apoptosis. Potential autophagy inhibitors were selected based on the pharmacophore model derived from the structures of known autophagy inhibitors. LZ02/01-mediated autophagy flux disruption and apoptosis promotion in breast and hepatocellular carcinoma cells (MCF-7 and Hep3B) were examined using a combination of molecular methods in vitro and in vivo. The synergistic tumor-suppressing effects of LZ02 and chloroquine were validated by adopting a xenograft mice model of human breast cancer. Two potential inhibitors (LZ02/01) targeting an autophagy pathway were discovered from the Enamine database. In both MCF-7 and Hep3B cells, LZ02 and LZ01 had the effect of causing the co-occurrence of autophagic flux inhibition and apoptosis induction, robustly suppressing the growth, proliferation, and cell cycle progression. Further tests revealed that FoxO3a and its downstream target genes regulating autophagy, apoptosis, and cell cycle progression were activated and overexpressed, suggesting such effects of LZ02/01 on autophagy and apoptosis were associated with the activation and overexpression of FoxO3a. In addition, LZ02/01-mediated apoptosis is not independent; it was verified to be promoted by autophagic flux inhibition. Meanwhile, synergistic effects on tumor growth reduction were detected in the xenograft mice model of human breast cancer simultaneously treated with LZ02 and chloroquine. Our findings suggest that LZ01 and LZ02 are potent in suppressing cancer cell proliferation and tumor growth through autophagic flux inhibition and apoptosis promotion. The synergistic anti-cancer effects of LZ02 with chloroquine may provide a rational basis for prospective cancer therapy. KEY MESSAGES: A ligand-based pharmacophore model of high quality is constructed to query hits and two novel scaffold lead compounds LZ01/02 were identified by high-throughput virtual screening. LZ01/02 works to inhibit autophagic flux by attenuating lysosome function. LZ01/02 induces apoptosis through autophagic flux inhibition and apoptosis is the main mechanism to inhibit MCF-7 and Hep3B cancer cell proliferation. The synergistic antitumor growth effects of LZ02 and chloroquine are verified in human xenograft model.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1573-1589"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01971-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38353031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas.","authors":"Efthalia Angelopoulou,&nbsp;Yam Nath Paudel,&nbsp;Christina Piperi","doi":"10.1007/s00109-020-01984-x","DOIUrl":"https://doi.org/10.1007/s00109-020-01984-x","url":null,"abstract":"<p><p>Despite extensive research, gliomas are associated with high morbidity and mortality, mainly attributed to the rapid growth rate, excessive invasiveness, and molecular heterogeneity, as well as regenerative potential of cancer stem cells. Therefore, elucidation of the underlying molecular mechanisms and the identification of potential molecular diagnostic and prognostic biomarkers are of paramount importance. HOX transcript antisense intergenic RNA (HOTAIR) is a well-studied long noncoding RNA, playing an emerging role in tumorigenesis of several human cancers. A growing amount of preclinical and clinical evidence highlights the pro-oncogenic role of HOTAIR in gliomas, mainly attributed to the enhancement of proliferation and migration, as well as inhibition of apoptosis. In vitro and in vivo studies demonstrate that HOTAIR modulates the activity of specific transcription factors, such as MXI1, E2F1, ATF5, and ASCL1, and regulates the expression of cell cycle-associated genes along with related signaling pathways, like the Wnt/β-catenin axis. Moreover, it can interact with specific miRNAs, including miR-326, miR-141, miR-148b-3p, miR-15b, and miR-126-5p. Of importance, HOTAIR has been demonstrated to enhance angiogenesis and affect the permeability of the blood-tumor barrier, thus modulating the efficacy of chemotherapeutic agents. Herein, we provide evidence on the functional role of HOTAIR in gliomas and discuss the benefits of its targeting as a novel approach toward glioma treatment.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1525-1546"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01984-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38424323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relevance of iNOS expression in tumor growth and maintenance of cancer stem cells in a bladder cancer model.","authors":"Denise Belgorosky,&nbsp;Julie Girouard,&nbsp;Yanina Veronica Langle,&nbsp;Jovane Hamelin-Morrissete,&nbsp;Lina Marino,&nbsp;Eduardo Imanol Agüero,&nbsp;Héctor Malagrino,&nbsp;Carlos Reyes-Moreno,&nbsp;Ana María Eiján","doi":"10.1007/s00109-020-01973-0","DOIUrl":"https://doi.org/10.1007/s00109-020-01973-0","url":null,"abstract":"<p><p>The expression of inducible nitric oxide (NO) synthase (iNOS) in human bladder cancer (BC) is a poor prognostic factor associated with invasion and tumor recurrence. Here, we evaluated the relevance of iNOS expression in BC progression and in cancer stem cell (CSC) maintenance in a murine BC model. Also, iNOS expression and CSC markers were analyzed in human BC samples. iNOS inhibitors (L-NAME or 1400W) or shRNA were used on murine BC model with different iNOS expressions and invasiveness grades: MB49 (iNOS+, non-muscle invasive (NMI)) and MB49-I (iNOS++, muscle invasive (MI)), in order to analyzed cell proliferation, tumor growth, angiogenesis, number of CSC, and pluripotential marker expression. iNOS, SOX2, Oct4, and Nanog expressions were also analyzed in human BC samples by qPCR and immunohistochemistry. iNOS inhibtion reduced parameters associated with tumor progression and reduced the number of CSC, wich resulted higher in MB49-I than in MB49, in concordance with the higher expression of SOX2, Oct4, and Nanog. The expression of SOX2 was notoriously diminished, when iNOS was inhibited only in the MI cell line. Similar results were observed in human samples, where MI tumors expressed higher levels of iNOS and pluripotential genes, in comparison to NMI tumors with a positive correlation between those and iNOS, suggesting that iNOS expression is associated with CSC. iNOS plays an important role in BC progression and CSC maintenance. Its inhibition could be a potential therapeutic target to eradicate CSC, responsible for tumor recurrences. KEY MESSAGES: • iNOS expression is involved in bladder tumor development, growth, and angiogenesis. • iNOS expression is involved in bladder cancer stem cell generation and maintenance, playing an important role regulating their self-renewal capacity, especially in muscle invasive murine bladder cancer cells. • iNOS expression is higher in human muscle invasive tumors, in association with a high expression of pluripotential genes, especially of SOX2.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1615-1627"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01973-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38499168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting X chromosome-linked inhibitor of apoptosis protein in mucoepidermoid carcinoma of the head and neck: A novel therapeutic strategy using nitidine chloride.","authors":"Hye-Jeong Kwon,&nbsp;Kyungsil Yoon,&nbsp;Ji-Youn Jung,&nbsp;Mi Heon Ryu,&nbsp;Sung-Hyun Kim,&nbsp;Eun-Seon Yoo,&nbsp;So-Young Choi,&nbsp;In-Hyoung Yang,&nbsp;Seong Doo Hong,&nbsp;Ji-Ae Shin,&nbsp;Sung-Dae Cho","doi":"10.1007/s00109-020-01977-w","DOIUrl":"https://doi.org/10.1007/s00109-020-01977-w","url":null,"abstract":"<p><p>Nitidine chloride (NC) was recently reported to exhibit a wide range of pharmacological properties for several diseases, including cancer. Here we report for the first time that NC is a potential therapeutic agent for mucoepidermoid carcinoma (MEC) occurring in the head and neck because it suppresses X chromosome-linked inhibitor of apoptosis protein (XIAP) in human MEC in vitro and in vivo. The antitumor effects of NC were evaluated by trypan blue exclusion assay, western blotting, live/dead assay, 4',6-diamidino-2-phenylindole (DAPI) staining, human apoptosis antibody array, immunofluorescence staining, immunohistochemistry, small interfering RNA assay, transient transfection of XIAP overexpression vector, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and histopathological examination of organs. NC inhibited cell viability and induced caspase-dependent apoptosis in vitro. A human apoptosis antibody array assay showed that XIAP is suppressed by NC treatment. XIAP was overexpressed in oral squamous cell carcinoma (OSCC) tissues that arose from the head and neck, and high XIAP expression was correlated with poor prognosis in OSCC patients. XIAP depletion significantly increased apoptosis, and ectopic XIAP overexpression attenuated the apoptosis induced by NC treatment. NC suppressed tumor growth in vivo at a dosage of 5 mg/kg/day. The number of TUNEL-positive cells increased and the protein expression of XIAP was consistently downregulated in NC-treated tumor tissues. In addition, NC caused no histopathological changes in the liver or kidney. These findings provide new insights into the mechanism of action underlying the anticancer effects of NC and demonstrate that NC is a promising therapeutic agent for the treatment of human MEC of the head and neck. KEY MESSAGES: • Nitidine chloride induces caspase-dependent apoptosis in MEC of the head and neck. • High XIAP expression correlates with poor prognosis of OSCC patients. • Nitidine chloride suppresses tumor growth in vivo without any systemic toxicities. • Targeting XIAP is a novel chemotherapeutic strategy for MEC of the head and neck.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1591-1602"},"PeriodicalIF":4.7,"publicationDate":"2020-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01977-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38356187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis.","authors":"Kristina S Lechner,&nbsp;Markus F Neurath,&nbsp;Benno Weigmann","doi":"10.1007/s00109-020-01958-z","DOIUrl":"https://doi.org/10.1007/s00109-020-01958-z","url":null,"abstract":"<p><p>ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1385-1395"},"PeriodicalIF":4.7,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01958-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38275105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the VISTA of microglia: immune checkpoints in CNS inflammation.","authors":"Malte Borggrewe,&nbsp;Susanne M Kooistra,&nbsp;Randolph J Noelle,&nbsp;Bart J L Eggen,&nbsp;Jon D Laman","doi":"10.1007/s00109-020-01968-x","DOIUrl":"https://doi.org/10.1007/s00109-020-01968-x","url":null,"abstract":"<p><p>Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":" ","pages":"1415-1430"},"PeriodicalIF":4.7,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00109-020-01968-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38318383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}