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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
The cardiac injury caused by MI also involves the cGAS/STING danger signal pathway. In this case, DNA released by necrotic myocardium is being sensed in macrophages by the cyclic GMP-AMP synthase (cGAS) PRR (60). This in turn leads to activation of the stimulator of interferon genes (STING) pathway and to elevated expression of interferon-stimulated genes, including those encoding inducible nitric oxide synthase (iNOS) and CXCL10 (74). Conversely, inhibition of the cGAS-STING axis protects from cardiac rupture (60) associated with a switch in macrophage pheno-type from pro-inflammatory toward a reparative one. This switch is accompanied by the increased formation of myofibroblasts and dense collagen deposition in the infarct areas. The myofibroblast formation could be also facilitated by fibronectin, whose expression is elevated in reparative macrophages (74) (Figure 5.2). Interestingly, ex vivo generation of M2b alternatively activated macrophages and injection to the infarcted zones ameliorated MI repair by reducing platelet-derived growth factor–dependent (PDGF) activation of cardiac fibroblasts (75) (Figure 5.2).
Current Application of CRISPR/Cas9 Gene-Editing Technique to Eradication of HIV/AIDS
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
It is often also observed that the HUSH complex can be degraded by Vpx and Vpr from HIV-1, HIV-2, and SIV to counteract HUSH-induced repression of provirus transcription [50]. The studies suggested that the HUSH complex could be a critical host factor in HIV infection. NONO has been identified as a capsid-binding factor for Cyclic GMP-AMP synthase (cGAS)-mediated immune activation in macrophages and dendritic cells after HIV-1/2 infection employing a two-hybrid yeast screening. NONO directly interacted with HIV-1/2 capsid proteins to extend DNA sensing mediated by cGAS, but had little effect on HIV infection, which suggest the important role of NONO in cGAS-mediated immune activation after infection with HIV [49]. Since these representative restriction factors can inhibit HIV infection via different mechanisms, the CRISPR/Cas9 technology may be utilized to simultaneously activate their expression in infected cells so as to focus on different phases of the viral life cycle.
Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
These pathways are important for the host responses to viral infections, and thorough understanding of their pathways can be useful in the development of vaccines and other antiviral strategies. Moreover, in addition to the RLR/MAVS and cGAS/STING pathways sensing host nucleic acids, these circuits are important for immunoregulation and, when overexpressed, to disease phenotypes. Regarding the former pathway, RIG-I deficiency has been associated with colitis, consistent with the downregulation of RIG-I in human inflammatory bowel disease and the role of RLRs in the induction of regulatory T cells. The abnormal accumulation of nucleic acids in certain autoimmune diseases can activate myeloid interferons in a pathologic manner, such as in systemic lupus erythematosus or in the intestinal mucosa undergoing ER stress. For example, during ER stress, activation of the RNAase activity of inositol requiring enzyme 1 (IRE1) generates RNA species potentially capable of activating RLRs.
Helicobacter pylori actively suppresses innate immune nucleic acid receptors
Published in Gut Microbes, 2022
Samuel D.R. Dooyema, Jennifer M. Noto, Lydia E. Wroblewski, M. Blanca Piazuelo, Uma Krishna, Giovanni Suarez, Judith Romero-Gallo, Alberto G. Delgado, Richard M. Peek
Microbial-specific nucleic acids are an important subclass of PAMPs, which are rapidly detected in the cytosol of host cells.33,34 Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor, which is activated in response to double-stranded DNA in a sequence-independent manner. Binding of DNA ligands to cGAS catalyzes the conversion of ATP and GTP into the dinucleotide 2’,3’-cyclic GMP-AMP (cGAMP). cGAMP can then directly activate stimulator of interferon genes (STING), a DNA sensor/adaptor localized to the endoplasmic reticulum (ER)33,34 and which is expressed in gastric epithelial cells.11 Sensing of cyclic dinucleotides induces a conformational change in STING that triggers trafficking of STING complexed with TANK-binding kinase 1 (TBK1) from the ER to endosomal/lysosomal compartments. Translocated TBK1 leads to phosphorylation and activation of the transcription factor interferon regulatory factor 3 (IRF3), which is then mobilized to the nucleus to induce expression of type 1 interferons (e.g., IFNα, IFNß).33,34 STING activation can also trigger other downstream pathways such as NF-κB35,36 as well as autophagy, which clears DNA or pathogens from the cytosol.37
IFN-γ activates the tumor cell-intrinsic STING pathway through the induction of DNA damage and cytosolic dsDNA formation
Published in OncoImmunology, 2022
Hui Xiong, Yu Xi, Zhiwei Yuan, Boyu Wang, Shaojie Hu, Can Fang, Yixin Cai, Xiangning Fu, Lequn Li
Cellular DNA is under constant threat from exogenous and endogenous damage. DNA damage can be detected as a danger-associated molecular pattern using cytosolic and endosomal sensors and adaptor molecules, leading to the production of type I interferon, proinflammatory cytokines, and chemokines.8 Cyclic GMP-AMP synthase (cGAS) is an important cytosolic nucleic acid sensor of double-stranded DNA.9,10 cGAS activation generates cyclic dinucleotide cyclic GMP-AMP (cGAMP), which in turn triggers the STING signaling pathway and induces IFN-β expression.11 In addition to cGAS, interferon-inducible factor-16 (IFI16) can recognize cytosolic double-stranded DNA, single-stranded DNA, and damaged nuclear DNA.12–14 Activation of the STING pathway in human macrophages and keratinocytes requires the cooperation of cGAS and IFI16.15,16
Low STING expression promotes endometrial stromal cell invasion and migration via the STING/IRF-3/IFN-β1 pathway in eutopic endometrium of women with endometriosis
Published in Gynecological Endocrinology, 2022
Zhen Xu, Heng Zhao, Caixin Yue, Lixia Zhang, Muzi Li, ,Yanbo Du, ,Na Zhang, Lei Yan
Endometriosis, also referred to as a ‘benign cancer’, is a chronic inflammatory disease characterized by endometriosis-related ectopic lesions formed by eutopic endometrium following stromal cell immune escape, invasion, and migration [1]. In addition, a correlation has been reported between endometriosis and autoimmune disease [2]. The immune-related factors underlying endometriosis pathogenesis induce immune dysfunction and imbalance the immune microenvironment of ectopic lesions [1,3–6]. Recent research studies have focused on the NF-κB pathway for identifying inflammatory mediators as it is engaged in cross-talk with other signaling pathways, thereby regulating various inflammatory phenotypes. Previously, we performed proteomic analysis of endometrial samples and found that NF-κB is an important contributor to inflammation-related signaling pathways [7]. NF-κB regulates the expression of several genes to promote numerous processes, including endometriotic lesion establishment, maintenance, and development. Moreover, the expression of stimulator of interferon genes (STING) is downregulated in the eutopic endometrium of endometriosis samples. Indeed, the NF-κB pathway had been well-characterized in several inflammatory diseases [8,9] including osteoarthritis, nonalcoholic steatohepatitis, tumors, and viral infections, wherein NF-κB signaling mediates STING and STING/TBK1/IRF3 pathway [9–11]. Notably, the cyclic GMP-AMP synthase (cGAS)-STING signaling pathway is functional in several processes of the innate immune system [12].