Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Amadio, Roberto; Piperno, Giulia Maria; Benvenuti, Federica

doi:10.3389/fimmu.2021.657344

Cited by 22 publications

(12 citation statements)

References 130 publications

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“…In the same manner, bacterial infection may evoke microtubule rearrangement-mediated nucleolar fusion at later times, possibly maximizing the effectiveness of inflammatory pre-mRNA decay in preventing hyperinflammation and maintaining immune homeostasis. Because the LPS- or CpG-DNA-evoked TLR signaling pathway is likely to influence microtubule organization 75 – 77 , it may provide a starting point for nucleolar fusion. In addition, macrophages are well known to be phagocytic cells with cytoskeletal dynamics that, compared with those of fibroblasts, are especially suited for active circular ruffling and delivery of extracellular components 78 .…”

Section: Discussionmentioning

confidence: 99%

The nucleolus is the site for inflammatory RNA decay during infection

et al. 2022

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Inflammatory cytokines are key signaling molecules that can promote an immune response, thus their RNA turnover must be tightly controlled during infection. Most studies investigate the RNA decay pathways in the cytosol or nucleoplasm but never focused on the nucleolus. Although this organelle has well-studied roles in ribosome biogenesis and cellular stress sensing, the mechanism of RNA decay within the nucleolus is not completely understood. Here, we report that the nucleolus is an essential site of inflammatory pre-mRNA instability during infection. RNA-sequencing analysis reveals that not only do inflammatory genes have higher intronic read densities compared with non-inflammatory genes, but their pre-mRNAs are highly enriched in nucleoli during infection. Notably, nucleolin (NCL) acts as a guide factor for recruiting cytosine or uracil (C/U)-rich sequence-containing inflammatory pre-mRNAs and the Rrp6-exosome complex to the nucleolus through a physical interaction, thereby enabling targeted RNA delivery to Rrp6-exosomes and subsequent degradation. Consequently, Ncl depletion causes aberrant hyperinflammation, resulting in a severe lethality in response to LPS. Importantly, the dynamics of NCL post-translational modifications determine its functional activity in phases of LPS. This process represents a nucleolus-dependent pathway for maintaining inflammatory gene expression integrity and immunological homeostasis during infection.

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Section: Discussionmentioning

confidence: 99%

The nucleolus is the site for inflammatory RNA decay during infection

et al. 2022

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“…Gene delivery systems should consider the toxicity associated with DNA delivery, which includes the sensing of cytosolic DNA by host cells [152,153]. Cellular DNA sensors detect cytosolic genetic material, usually due to viral infections or self-DNA leaking from different cellular compartments [154][155][156][157]. The detection of cytosolic nucleic acids triggers the host immune response and is pivotal for mammalian organisms to control malignant transformation and to mediate cellintrinsic onco-suppression [158].…”

Section: Dna-based Payloadmentioning

confidence: 99%

Current strategies employed in the manipulation of gene expression for clinical purposes

et al. 2022

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Abnormal gene expression level or expression of genes containing deleterious mutations are two of the main determinants which lead to genetic disease. To obtain a therapeutic effect and thus to cure genetic diseases, it is crucial to regulate the host’s gene expression and restore it to physiological conditions. With this purpose, several molecular tools have been developed and are currently tested in clinical trials. Genome editing nucleases are a class of molecular tools routinely used in laboratories to rewire host’s gene expression. Genome editing nucleases include different categories of enzymes: meganucleses (MNs), zinc finger nucleases (ZFNs), clustered regularly interspaced short palindromic repeats (CRISPR)- CRISPR associated protein (Cas) and transcription activator-like effector nuclease (TALENs). Transposable elements are also a category of molecular tools which includes different members, for example Sleeping Beauty (SB), PiggyBac (PB), Tol2 and TcBuster. Transposons have been used for genetic studies and can serve as gene delivery tools. Molecular tools to rewire host’s gene expression also include episomes, which are divided into different categories depending on their molecular structure. Finally, RNA interference is commonly used to regulate gene expression through the administration of small interfering RNA (siRNA), short hairpin RNA (shRNA) and bi-functional shRNA molecules. In this review, we will describe the different molecular tools that can be used to regulate gene expression and discuss their potential for clinical applications. These molecular tools are delivered into the host's cells in the form of DNA, RNA or protein using vectors that can be grouped into physical or biochemical categories. In this review we will also illustrate the different types of payloads that can be used, and we will discuss recent developments in viral and non-viral vector technology.

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“…Of note, TLR9 and cGAS-STING pathway sense intracellular DNA oligonucleotides within different cellular compartments. [54][55][56] cGAS-STING pathways senses DNA within the cytoplasm, while TLR9 senses DNA within endosomes. The divergent effects of TLR9 antagonism versus cGAS-inhibition could be due to limitation in experimental conditions with the cationic peptide LL37 32 preferentially facilitating uptake of oxmtDNA by endosomes rather than into the cytosolic compartment.…”

Section: Myositismentioning

confidence: 99%

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

Wilkinson¹,

Moulding

McDonnell

et al. 2022

Ann Rheum Dis

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ObjectivesTo define the host mechanisms contributing to the pathological interferon (IFN) type 1 signature in Juvenile dermatomyositis (JDM).MethodsRNA-sequencing was performed on CD4+, CD8+, CD14+and CD19+cells sorted from pretreatment and on-treatment JDM (pretreatment n=10, on-treatment n=11) and age/sex-matched child healthy-control (CHC n=4) peripheral blood mononuclear cell (PBMC). Mitochondrial morphology and superoxide were assessed by fluorescence microscopy, cellular metabolism by13C glucose uptake assays, and oxidised mitochondrial DNA (oxmtDNA) content by dot-blot. Healthy-control PBMC and JDM pretreatment PBMC were cultured with IFN-α, oxmtDNA, cGAS-inhibitor, TLR-9 antagonist and/orn-acetyl cysteine (NAC). IFN-stimulated gene (ISGs) expression was measured by qPCR. Total numbers of patient and controls for functional experiments, JDM n=82, total CHC n=35.ResultsDysregulated mitochondrial-associated gene expression correlated with increased ISG expression in JDM CD14+ monocytes. Altered mitochondrial-associated gene expression was paralleled by altered mitochondrial biology, including ‘megamitochondria’, cellular metabolism and a decrease in gene expression of superoxide dismutase (SOD)1. This was associated with enhanced production of oxidised mitochondrial (oxmt)DNA. OxmtDNA induced ISG expression in healthy PBMC, which was blocked by targeting oxidative stress and intracellular nucleic acid sensing pathways. Complementary experiments showed that, under in vitro experimental conditions, targeting these pathways via the antioxidant drug NAC, TLR9 antagonist and to a lesser extent cGAS-inhibitor, suppressed ISG expression in pretreatment JDM PBMC.ConclusionsThese results describe a novel pathway where altered mitochondrial biology in JDM CD14+ monocytes lead to oxmtDNA production and stimulates ISG expression. Targeting this pathway has therapeutical potential in JDM and other IFN type 1-driven autoimmune diseases.

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Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

Cited by 22 publications

References 130 publications

The nucleolus is the site for inflammatory RNA decay during infection

The nucleolus is the site for inflammatory RNA decay during infection

Current strategies employed in the manipulation of gene expression for clinical purposes

Role of CD14+ monocyte-derived oxidised mitochondrial DNA in the inflammatory interferon type 1 signature in juvenile dermatomyositis

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