keyword
https://read.qxmd.com/read/38490978/dual-inhibitors-of-dnmt-and-hdac-induce-viral-mimicry-to-induce-antitumour-immunity-in-breast-cancer
#21
JOURNAL ARTICLE
Wenjun Huang, Qingyun Zhu, Zhichao Shi, Yao Tu, Qinyuan Li, Wenwen Zheng, Zigao Yuan, Lulu Li, Xuyu Zu, Yue Hao, Bizhu Chu, Yuyang Jiang
The existing conventional treatments for breast cancer, including immune checkpoint blockade, exhibit limited effects in some cancers, particularly triple-negative breast cancer. Epigenetic alterations, specifically DNMT and HDAC alterations, are implicated in breast cancer pathogenesis. We demonstrated that DNMTs and HDACs are overexpressed and positively correlated in breast cancer. The combination of DNMT and HDAC inhibitors has shown synergistic antitumour effects, and our previously designed dual DNMT and HDAC inhibitor (termed DNMT/HDACi) 15a potently inhibits breast cancer cell proliferation, migration, and invasion and induces apoptosis in vitro and in vivo...
March 15, 2024: Cell Death Discovery
https://read.qxmd.com/read/38490196/type-i-interferon-responsive-microglia-shape-cortical-development-and-behavior
#22
JOURNAL ARTICLE
Caroline C Escoubas, Leah C Dorman, Phi T Nguyen, Christian Lagares-Linares, Haruna Nakajo, Sarah R Anderson, Jerika J Barron, Sarah D Wade, Beatriz Cuevas, Ilia D Vainchtein, Nicholas J Silva, Ricardo Guajardo, Yinghong Xiao, Peter V Lidsky, Ellen Y Wang, Brianna M Rivera, Sunrae E Taloma, Dong Kyu Kim, Elizaveta Kaminskaya, Hiromi Nakao-Inoue, Bjoern Schwer, Thomas D Arnold, Ari B Molofsky, Carlo Condello, Raul Andino, Tomasz J Nowakowski, Anna V Molofsky
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage...
March 8, 2024: Cell
https://read.qxmd.com/read/38489753/the-exonuclease-trex1-constitutes-an-innate-immune-checkpoint-limiting-cgas-sting-mediated-antitumor-immunity
#23
JOURNAL ARTICLE
Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan G Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon D Kayser, Robert J Johnston, Ira Mellman, Lélia Delamarre, Nathaniel R West, Sören Müller, Yan Qu, Klaus Heger
The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. Since tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity to limit their immunogenicity. Here we show, that in tumor cells TREX1 indeed restricts the spontaneous activation of the cGAS/STING pathway and the subsequent induction of a type I IFN response...
March 18, 2024: Cancer Immunology Research
https://read.qxmd.com/read/38487540/the-ifih1-a946t-risk-variant-promotes-diabetes-in-a-sex-dependent-manner
#24
JOURNAL ARTICLE
Amanda J Stock, Pierina Gonzalez Paredes, Luciana Previato de Almeida, Stanley D Kosanke, Srinivaas Chetlur, Hannah Budde, Paul Wakenight, Theresa A Zwingman, Aaron B I Rosen, Eric J Allenspach, Kathleen J Millen, Jane H Buckner, David J Rawlings, Jacquelyn A Gorman
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 ( IFIH1 ), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 ( IFIH1A946T ) and confers an increased risk for several autoimmune diseases, including T1D...
2024: Frontiers in Immunology
https://read.qxmd.com/read/38484578/ifitm1-and-ifitm2-inhibit-the-replication-of-senecavirus-a-by-positive-feedback-with-rig-i-signaling-pathway
#25
JOURNAL ARTICLE
Huizi Li, Ming Chen, Tingting Zheng, Xiaoling Lei, Cunhao Lin, Shuo Li, Jiacong Mo, Zhangyong Ning
The role of host factors in the replication of emerging senecavirus A (SVA) which induced porcine idiopathic vesicular disease (PIVD) distributed worldwide remains obscure. Here, interferon-induced transmembrane (IFITM) protein 1 and 2 inhibit SVA replication by positive feedback with RIG-I signaling pathway was reported. The expression levels of IFITM1 and IFITM2 increased significantly in SVA infected 3D4/21 cells. Infection experiments of cells with over and interference expression of IFITM1 and IFITM2 showed that these two proteins inhibit SVA replication by regulating the expression of interferon beta (IFN-β), IFN-stimulated gene 15 (ISG-15), interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha (TNF-α), IFN regulatory factor-3 (IRF3), and IRF7...
March 11, 2024: Veterinary Microbiology
https://read.qxmd.com/read/38483060/siah1-modulates-antiviral-immune-responses-by-targeting-deubiquitinase-usp19
#26
JOURNAL ARTICLE
Asela Weerawardhana, Thilina U B Herath, W A Gayan Chathuranga, Tae-Hwan Kim, Pathum Ekanayaka, Kiramage Chathuranga, Ho-Chul Kang, Jae U Jung, Jong-Soo Lee
Tight control of the type I interferon (IFN) signaling pathway is critical for maintaining host innate immune responses, and the ubiquitination and deubiquitination of signaling molecules are essential for signal transduction. Deubiquitinase ubiquitin-specific protein 19 (USP19) is known to be involved in deubiquitinating Beclin1, TRAF3, and TRIF for downregulation of the type I IFN signaling. Here, we show that SIAH1, a cellular E3 ubiquitin ligase that is involved in multicellular pathway, is a potent positive regulator of virus-mediated type I IFN signaling that maintains homeostasis within the antiviral immune response by targeting USP19...
March 2024: Journal of Medical Virology
https://read.qxmd.com/read/38483048/ump-cmp-kinase-2-inhibits-zikv-replication-through-activation-of-type-i-ifn-signaling-pathway
#27
JOURNAL ARTICLE
Ya Zhu, Qi Tan, Yaoqiang Shi, Qingyuan Li, Shilin Li, Wenxian Wen, He Xie, Bin Li, Xiaoqiong Duan, Limin Chen
Cytidine/uridine monophosphate kinase 2 (UMP-CMP kinase 2, CMPK2) has been reported as an antiviral interferon-stimulated gene (ISG). We previously observed that the expression of CMPK2 was significantly upregulated after Zika Virus (ZIKV) infection in A549 cells. However, the association and the underlying mechanisms between CMPK2 induction and ZIKV replication remain to be determined. We investigated the induction of CMPK2 during ZIKV infection and the effect of CMPK2 on ZIKV replication in A549, U251, Vero, IFNAR-deficient U5A and its parental 2fTGH cells, Huh7 and its RIG-I-deficient derivatives Huh7...
March 2024: Journal of Medical Virology
https://read.qxmd.com/read/38480836/universal-sting-mimic-boosts-antitumour-immunity-via-preferential-activation-of-tumour-control-signalling-pathways
#28
JOURNAL ARTICLE
Ying Wang, Sirui Li, Mengying Hu, Yuchen Yang, Ellie McCabe, Lillian Zhang, Andrew M Withrow, Jenny P-Y Ting, Rihe Liu
The efficacy of STING (stimulator of interferon genes) agonists is due to various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours, and a complex balance between tumour control and progression. Here we report a universal STING mimic (uniSTING) based on a polymeric architecture. UniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways...
March 13, 2024: Nature Nanotechnology
https://read.qxmd.com/read/38480499/apigenin-suppresses-innate-immune-responses-and-ameliorates-lipopolysaccharide-induced-inflammation-via-inhibition-of-sting-irf3-pathway
#29
JOURNAL ARTICLE
Xu-Wei Zhou, Juan Wang, Wen-Fu Tan
The stimulator of interferon genes (STING) signaling pathway is crucial for the pathogenesis of autoimmune and inflammatory disorders, including acute lung injury (ALI). Apigenin (4[Formula: see text],5,7-trihydroxyflavone) is a natural flavonoid widely found in fruits, vegetables, and Chinese medicinal herbs that exhibits a range of pharmacological effects, such as antibacterial and anti-inflammatory activities. However, the efficacy of apigenin in STING pathway-mediated diseases remains unclear. Accordingly, this study screened Chinese medicines to identify potent agents that reduced the synthesis of type I interferons (IFNs)...
March 14, 2024: American Journal of Chinese Medicine
https://read.qxmd.com/read/38479600/the-aryl-hydrocarbon-receptor-interacting-protein-in-cancer-and-immunity-beyond-a-chaperone-protein-for-the-dioxin-receptor
#30
REVIEW
Sarah A Kazzaz, John Tawil, Edward W Harhaj
The aryl hydrocarbon receptor (AhR) interacting protein (AIP) is a ubiquitously expressed, immunophilin-like protein best known for its role as a co-chaperone in the AhR-AIP-Hsp90 cytoplasmic complex. In addition to regulating AhR and the xenobiotic response, AIP has been linked to various aspects of cancer and immunity that will be the focus of this review article. Loss of function AIP mutations are associated with pituitary adenomas, suggesting that AIP acts as a tumor suppressor in the pituitary gland. However, the tumor suppressor mechanisms of AIP remain unclear, and AIP can exert oncogenic functions in other tissues...
March 11, 2024: Journal of Biological Chemistry
https://read.qxmd.com/read/38479055/humoral-immune-transcriptome-signature-in-myelomeningocele-patients
#31
JOURNAL ARTICLE
Rfm Felício, Almm Franco, D Corrêa-Moreira, F Martinez de Carvalho, Acr Guimarães, F R Vargas
INTRODUCTION: Myelomeningocele (MMC) results from incomplete closure of the neural tube, and has a complex multifactorial etiology, including an inflammatory microenvironment. OBJECTIVE: We evaluated the contribution of humoral immune response for development of inflammatory milieu. METHODS: Using public repository Gene Expression Omnibus (GEO), we retrieve dataset transcriptome from the amniotic fluid of ten fetuses with myelomeningocele and ten healthy control fetuses to found differential gene expression associated with disturbances and inflammatory signatures in MMC...
March 8, 2024: Journal of Reproductive Immunology
https://read.qxmd.com/read/38477596/identification-of-nonfunctional-alternatively-spliced-isoforms-of-sting-in-human-acute-myeloid-leukemia
#32
JOURNAL ARTICLE
Akash R Boda, Arthur J Liu, Susana Castro-Pando, Benjamin T Whitfield, Jeffrey J Molldrem, Gheath Al-Atrash, Maria Emilia Di Francesco, Philip Jones, Casey R Ager, Michael A Curran
Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I interferon (IFN) responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance...
March 13, 2024: Cancer Res Commun
https://read.qxmd.com/read/38474381/gene-signature-of-regulatory-t-cells-isolated-from-children-with-selective-iga-deficiency-and-common-variable-immunodeficiency
#33
JOURNAL ARTICLE
Magdalena Rutkowska-Zapała, Agnieszka Grabowska-Gurgul, Marzena Lenart, Anna Szaflarska, Anna Kluczewska, Monika Mach-Tomalska, Monika Baj-Krzyworzeka, Maciej Siedlar
Selective IgA deficiency (SIgAD) is the most common form and common variable immunodeficiency (CVID) is the most symptomatic form of predominant antibody deficiency. Despite differences in the clinical picture, a similar genetic background is suggested. A common feature of both disorders is the occurrence of autoimmune conditions. Regulatory T cells (Tregs ) are the major immune cell type that maintains autoimmune tolerance. As the different types of abnormalities of Treg cells have been associated with autoimmune disorders in primary immunodeficiency (PID) patients, in our study we aimed to analyze the gene expression profiles of Treg cells in CVID and SIgAD patients compared to age-matched healthy controls...
February 27, 2024: Cells
https://read.qxmd.com/read/38474014/targeting-atr-pathway-in-solid-tumors-evidence-of-improving-therapeutic-outcomes
#34
REVIEW
Dimitra Mavroeidi, Anastasia Georganta, Emmanouil Panagiotou, Konstantinos Syrigos, Vassilis L Souliotis
The DNA damage response (DDR) system is a complicated network of signaling pathways that detects and repairs DNA damage or induces apoptosis. Critical regulators of the DDR network include the DNA damage kinases ataxia telangiectasia mutated Rad3-related kinase (ATR) and ataxia-telangiectasia mutated (ATM). The ATR pathway coordinates processes such as replication stress response, stabilization of replication forks, cell cycle arrest, and DNA repair. ATR inhibition disrupts these functions, causing a reduction of DNA repair, accumulation of DNA damage, replication fork collapse, inappropriate mitotic entry, and mitotic catastrophe...
February 27, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38473743/type-i-ifn-in-glomerular-disease-scarring-beyond-the-sting
#35
REVIEW
Alexis Paulina Jimenez-Uribe, Steve Mangos, Eunsil Hahm
The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS), along with intracellular RIG-like receptors (RLRs) and toll-like receptors (TLRs), are potent inducers of type I interferon (IFN-I) expression. These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear...
February 21, 2024: International Journal of Molecular Sciences
https://read.qxmd.com/read/38472139/lamp3-induces-ectopic-tlr7-expression-in-salivary-gland-epithelial-cells-and-amplifies-type-i-ifn-production-in-sj%C3%A3-gren-s-disease
#36
JOURNAL ARTICLE
Hiroyuki Nakamura, Tsutomu Tanaka, Changyu Zheng, Sandra A Afione, Tatsuya Atsumi, Masayuki Noguchi, Fabiola Reis Oliveira, Ana Carolina F Motta, Fernando Chahud, Eduardo M Rocha, Blake M Warner, John A Chiorini
OBJECTIVE: Lysosome-associated membrane protein 3 (LAMP3) misexpression in salivary gland epithelial cells plays a causal role in the development of salivary gland dysfunction and autoimmunity associated with Sjögren's disease (SjD). This study aimed to clarify how epithelial LAMP3 misexpression is induced in SjD. METHODS: To explore upstream signaling pathways associated with LAMP3 expression, we conducted multiple RNA sequencing analyses of minor salivary glands from patients with SjD, submandibular glands from a mouse model of SjD, and salivary gland epithelial cell lines...
March 12, 2024: Arthritis & Rheumatology
https://read.qxmd.com/read/38470955/the-activation-of-the-adaptor-protein-sting-depends-on-its-interactions-with-the-phospholipid-pi4p
#37
JOURNAL ARTICLE
Rutger D Luteijn, Sypke R van Terwisga, Jill E Ver Eecke, Liberty Onia, Shivam A Zaver, Joshua J Woodward, Richard W Wubbolts, David H Raulet, Frank J M van Kuppeveld
Activation of the endoplasmic reticulum (ER)-resident adaptor protein STING, a component of a cytosolic DNA-sensing pathway, induces the transcription of genes encoding type I interferons (IFNs) and other proinflammatory factors. Because STING is activated at the Golgi apparatus, control of the localization and activation of STING is important in stimulating antiviral and antitumor immune responses. Through a genome-wide CRISPR interference screen, we found that STING activation required the Golgi-resident protein ACBD3, which promotes the generation of phosphatidylinositol 4-phosphate (PI4P) at the trans-Golgi network, as well as other PI4P-associated proteins...
March 12, 2024: Science Signaling
https://read.qxmd.com/read/38467768/stat3-protects-hematopoietic-stem-cells-by-preventing-activation-of-a-deleterious-autocrine-type-i-interferon-response
#38
JOURNAL ARTICLE
Bhakti Patel, Yifan Zhou, Rachel L Babcock, Feiyang Ma, M Anna Zal, Dhiraj Kumar, Yusra B Medik, Laura M Kahn, Josué E Pineda, Elizabeth M Park, Sarah M Schneider, Ximing Tang, Maria Gabriela Raso, Collene R Jeter, Tomasz Zal, Karen Clise-Dwyer, Khandan Keyomarsi, Filippo G Giancotti, Simona Colla, Stephanie S Watowich
Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects...
March 11, 2024: Leukemia
https://read.qxmd.com/read/38466944/ifi16-positively-regulates-rig-i-mediated-type-i-interferon-production-in-a-sting-independent-manner
#39
JOURNAL ARTICLE
Xibao Shi, Menglu Wei, Yuwen Feng, Yuanhao Yang, Xiaozhuan Zhang, Hao Chen, Yuqi Xing, Keqi Wang, Wensheng Wang, Li Wang, Aiping Wang, Gaiping Zhang
Previous studies have shown that interferon gene-stimulating protein (STING) is essential for IFN-γ-inducible protein 16 (IFI16) as the DNA sensor and RNA sensor to induce transcription of type I interferon (IFN-I) and is essential for IFI16 to synergize with DNA sensor GMP-AMP (cGAMP) synthase (cGAS) in induction of IFN-I transcription. While other and our previous studies have shown that IFI16 enhanced retinoic acid-inducible gene I (RIG-I)-, which was an RNA sensor, and mitochondrial antiviral signaling (MAVS)-, which was the adaptor protein of RIG-I, induced production of IFN-I, so we wonder whether IFI16 regulates the signal pathway of RNA-RIG-I-MAVS-IFN-I in a STING-dependent manner...
March 11, 2024: DNA and Cell Biology
https://read.qxmd.com/read/38466560/type-i-interferon-signalling-and-ischemic-stroke-mechanisms-and-therapeutic-potentials
#40
REVIEW
Pan Cui, Bo Song, Zongping Xia, Yuming Xu
Type I interferon (IFN-I) signalling is intricately involved in the pathogenesis of multiple infectious diseases, autoimmune diseases, and neurological diseases. Acute ischemic stroke provokes overactivation of IFN-I signalling within the injured brain, particularly in microglia. Following cerebral ischemia, damage-associated molecular patterns (DAMPs) released from injured neural cells elicit marked proinflammatory episodes within minutes. Among these, self-nucleic acids, including nuclear DNA and mitochondrial DNA (mtDNA), have been recognized as a critical alarm signal to fan the flames of neuroinflammation, predominantly via inducing IFN-I signalling activation in microglia...
March 11, 2024: Translational Stroke Research
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