• autoinflammatory disease
• immune homeostasis
• inflammation

• Humans
• Biotechnology/methods
• CRISPR-Cas Systems/immunology
• Animals
• Gene Editing
• Bacteria/immunology
• Bacteria/enzymology
• Bacteria/genetics
• Endonucleases/metabolism
• Endonucleases/genetics
• Endonucleases/immunology
• Deoxyribonucleases/metabolism
• Deoxyribonucleases/immunology

• 2021-05641 Vetenskapsrådet
• HORIZON-MSCA-2022-COFUND-101126600-SmartBRAIN3
• Vetenskapsrådet

• Primary culture
• Thyrocytes
• Thyroid
• Thyroid function
• Thyroid hormones

• Humans
• Thyroid Gland/metabolism
• Thyroid Epithelial Cells/metabolism
• Cells, Cultured
• Thyroid Hormones/metabolism
• Triiodothyronine/pharmacology
• Thyroxine
• Thyrotropin/metabolism

• 81900712 National Natural Science Foundation of China

• senescence
• tumour-suppressor proteins

Atrophic (“dry”) form of age-related macular degeneration (AMD) is a leading cause of vision loss characterized by macular retinal pigment epithelium (RPE) and the ensuing photoreceptor degeneration. cGAS-STING signaling is a key cytosolic DNA sensor system in innate immunity and have recently been shown promotes RPE degeneration. However, expression regulation and therapeutic potential of cGAS and STING are not explored in retina under dry AMD pathogenic conditions. Our analysis shows upregulated STING RNA and increased chromatin accessibility around cGAS and STING promoters in macular retinas from dry AMD patients. cGAS-STING activation was detected in oxidative stress-induced mouse retina degeneration, accompanied with cytosolic leakage of damaged DNA in photoreceptors. Pharmaceutical or genetic approaches indicates STING promotes retina inflammation and degeneration upon oxidative damage. Drug screening reveals that BRD4 inhibitor JQ1 reduces cGAS-STING activation, inflammation and photoreceptor degeneration in the injured retina. BRD4 inhibition epigenetically suppresses STING transcription, and promotes autophagy-dependent cytosolic DNA clearance. Together, our results show that activation of cGAS-STING in retina may present pivotal innate immunity response in GA pathogenesis, whereas inhibition of cGAS-STING signaling by JQ1 could serve as a potential therapeutic strategy.

Schematic summary of the mechanism underlying BRD4 inhibition on cGAS-STING signaling during retina degeneration. Cytosolic DNA accumulation and activation of cGAS-STING pathway were detected in retina photoreceptors after oxidative injury. BRD4 inhibition alleviates retinal inflammation and degeneration by epigenetically silencing STING transcription and by promoting autophagy-dependent cytosolic DNA clearance.

Buruli ulcer is a chronic skin disease caused by a toxic lipid mycolactone produced by Mycobacterium ulcerans, which induces local skin tissue destruction and analgesia. However, the cytotoxicity pathway induced by mycolactone remains largely unknown. Here we investigated the mycolactone-induced cell death pathway by screening host factors using a genome-scale lenti-CRISPR mutagenesis assay in human premonocytic THP-1 cells. As a result, 884 genes were identified as candidates causing mycolactone-induced cell death, among which SEC61A1, the α-subunit of the Sec61 translocon complex, was the highest scoring. CRISPR/Cas9 genome editing of SEC61A1 in THP-1 cells suppressed mycolactone-induced endoplasmic reticulum stress, especially eIF2α phosphorylation, and caspase-dependent apoptosis. Although previous studies have reported that mycolactone targets SEC61A1 based on mutation screening and structural analysis in several cell lines, we have reconfirmed that SEC61A1 is a mycolactone target by genome-wide screening in THP-1 cells. These results shed light on the cytotoxicity of mycolactone and suggest that the inhibition of mycolactone activity or SEC61A1 downstream cascades will be a novel therapeutic modality to eliminate the harmful effects of mycolactone in addition to the 8-week antibiotic regimen of rifampicin and clarithromycin.

Buruli ulcer is a chronic skin disease caused by the bacterium Mycobacterium ulcerans. The disease mainly affects children in West Africa, and the skin ulcers are induced by mycolactone, a toxin produced by the bacteria. The mycolactone diffuses through the skin, killing cells, creating irreversible ulceration, and weakening host immune defenses. However, the cytotoxic pathway induced by mycolactone remains largely unknown. We evaluated the mycolactone-induced cell death pathway by screening host factors using a genome-scale knockout assay in human premonocytic THP-1 cells. We identified 884 genes that are potentially involved in mycolactone-induced cell death, of which SEC61A1, the α-subunit of the Sec61 translocon complex, was the highest ranking. Knockout of SEC61A1 in THP-1 cells resulted in suppression of endoplasmic reticulum stress and caspase-dependent apoptosis induced by mycolactone. These results suggest that SEC61A1 is an essential mediator of mycolactone-induced cell death.

• Apoptosis
• Buruli Ulcer/microbiology
• Humans
• Macrolides/metabolism
• Mycobacterium ulcerans/metabolism
• THP-1 Cells

• Japan Society for the Promotion of Science
• Takeda Science Foundation
• GlaxoSmithKline foundation
• AMED

• ARF6
• cGAS
• extracellular DNA
• extracellular vesicles
• microvesicles

• Feature engineering
• SLE
• machine learning
• random forest modelling

• Antibodies, Antinuclear
• Cross-Sectional Studies
• Humans
• Hypothyroidism/complications
• Hypothyroidism/diagnosis
• Hypothyroidism/epidemiology
• Lupus Erythematosus, Systemic/complications
• Machine Learning

• Lt-4 therapy
• inflammasome
• obesity
• thyroid autoimmunity
• thyroid cancer
• weight regain

• Diabetes Mellitus, Type 2
• Graves Ophthalmopathy
• Humans
• Hypothyroidism/drug therapy
• Inflammasomes
• Inflammation/complications
• Obesity/complications
• Thyroid Diseases/complications
• Thyrotropin

Purpose:Prunella vulgaris (PV), a traditional Chinese medicine, has been used to treat patients with thyroid disease for centuries in China. The purpose of the present study was to investigate its bioactive ingredients and mechanisms against Hashimoto’s thyroiditis (HT) using network pharmacology and molecular docking technology to provide some basis for experimental research.

Methods: Ingredients of the PV formula were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Additionally, HT-related genes were retrieved from the UniProt and GeneCards databases. Cytoscape constructed networks for visualization. A protein–protein interaction (PPI) network analysis was constructed, and a PPI network was built using the Search Tool for the Retrieval of Interacting Genes (STRING) database. These key targets of PV were enriched and analyzed by molecular docking verification, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment.

Results: The compound–target network included 11 compounds and 66 target genes. Key targets contained Jun proto-oncogene (JUN), hsp90aa1.1 (AKI), mitogen-activated protein kinase 1 (MAPK1), and tumor protein p53 (TP53). The main pathways included the AGE-RAGE signaling pathway, the TNF signaling pathway, the PI3K–Akt signaling pathway, and the mitogen-activated protein kinase signaling pathway. The molecular docking results revealed that the main compound identified in the Prunella vulgaris was luteolin, followed by kaempferol, which had a strong affinity for HT.

Conclusion: Molecular docking studies indicated that luteolin and kaempferol were bioactive compounds of PV and might play an essential role in treating HT by regulating multiple signaling pathways.

• Hashimoto’s thyroiditis
• Prunella vulgaris
• anti-inflammatory response
• molecular docking
• network pharmacology

• AP-1
• NF-kB
• c-jun
• hormonal regulation
• major histocompatibility complex class I (MHC-1)
• p65
• thyroid

• Animals
• Antithyroid Agents/pharmacology
• Cell Line
• Electrophoretic Mobility Shift Assay
• Gene Expression Regulation/drug effects
• Genes, MHC Class I/drug effects
• Genes, MHC Class I/genetics
• Glucose/pharmacology
• Hormones/physiology
• Methimazole/analogs & derivatives
• Methimazole/pharmacology
• Rats
• Thiones/pharmacology
• Thymosin/pharmacology
• Thyroid Gland/cytology
• Thyroid Gland/drug effects
• Thyroid Gland/physiology
• Thyroiditis, Autoimmune/genetics
• Thyroiditis, Autoimmune/pathology
• Thyrotropin/pharmacology
• Transcription Factors/genetics

Many studies have shown that NLRC4 inflammasome polymorphisms are associated with a variety of autoimmune diseases, but the associations between NLRC4 polymorphisms and autoimmune thyroid diseases (AITDs) are unclear. Our research was aimed at identifying the correlations between NLRC4 polymorphisms and AITDs.

Hi-SNP high-throughput genotyping technology was used for detecting four single-nucleotide polymorphisms (SNPs) of NLRC4 in 1005 AITDs patients (including 629 Graves' disease and 376 Hashimoto's thyroiditis) and 781 healthy controls.

Compared with healthy controls, the allele frequencies and genotype distribution of rs385076 were statistically related to AITDs (P = 0.016 and P = 0.048, respectively) and Hashimoto's thyroiditis (P = 0.022 and P = 0.046, respectively). Before adjusting for age and gender, rs385076 and AITDs had a significant association in three models of allele model, dominant model, and homozygous model. After adjusting for age and gender, in the above three models, there is still a clear relationship between them. Before adjusting for age and gender, there were prominent discrepancy between rs385076 and Hashimoto's thyroiditis in the allele model (OR = 0.81, 95% CI 0.67-0.97; P = 0.021) and the dominant model (OR = 0.73, 95% CI 0.57-0.94; P = 0.014), after adjusting for age and gender, rs385076 and Hashimoto's thyroiditis were significantly related to allele model, dominant model, and homozygous model. However, rs455060, rs212704, and rs675712 were not related to AITDs in our study.

NLRC4 rs385076 was found to have a significant association with Hashimoto's thyroiditis for the first time. It laid a foundation for the disclosure of the pathogenesis of AITDs, and provided a possible treatment prospect for HT.

• active vitamin D
• genomic DNA
• inflammation
• keratinocyte
• psoriasis

DNA damage, caused by various oncogenic stresses, can induce cell death or cellular senescence as an important tumor suppressor mechanism. Senescent cells display the features of a senescence-associated secretory phenotype (SASP), secreting inflammatory proteins into surrounding tissues, and contributing to various age-related pathologies. In addition to this inflammatory protein secretion, the release of extracellular vesicles (EVs) is also upregulated in senescent cells. However, the molecular mechanism underlying this phenomenon remains unclear. Here, we show that DNA damage activates the ceramide synthetic pathway, via the downregulation of sphingomyelin synthase 2 (SMS2) and the upregulation of neutral sphingomyelinase 2 (nSMase2), leading to an increase in senescence-associated EV (SA-EV) biogenesis. The EV biogenesis pathway, together with the autophagy-mediated degradation pathway, functions to block apoptosis by removing cytoplasmic DNA fragments derived from chromosomal DNA or bacterial infections. Our data suggest that this SA-EV pathway may play a prominent role in cellular homeostasis, particularly in senescent cells. In summary, DNA damage provokes SA-EV release by activating the ceramide pathway to protect cells from excessive inflammatory responses.

• Bacillus Calmette–Guérin (BCG)
• DNA damage
• autophagy
• bacterial infection
• cellular senescence
• ceramide pathway
• exosome
• extracellular vesicle (EV)
• senescence-associated extracellular vesicle (SA-EV)
• senescence-associated secretory phenotype (SASP)

• Active Transport, Cell Nucleus
• Anthracyclines/pharmacology
• Antineoplastic Agents/pharmacology
• Cell Nucleus/metabolism
• Cell Proliferation
• Cytoplasm/metabolism
• Doxorubicin/pharmacology
• Fatty Acids, Unsaturated/metabolism
• Histones/metabolism
• Humans
• Jurkat Cells
• Laser Scanning Cytometry
• Mass Spectrometry
• Microscopy, Confocal
• Monocytes/cytology

• Prunella vulgaris
• autoimmune thyroid diseases
• dsDNA
• dsRNA
• innate immune response

• Animals
• Cells, Cultured
• Cytokines/genetics
• Cytokines/metabolism
• Hashimoto Disease/drug therapy
• Hashimoto Disease/metabolism
• Humans
• Immunity, Innate/drug effects
• Immunity, Innate/immunology
• Inflammation/drug therapy
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/pathology
• Plant Extracts/pharmacology
• Prunella/chemistry
• Rats
• Thyroid Epithelial Cells/drug effects
• Thyroid Epithelial Cells/immunology
• Thyroid Epithelial Cells/metabolism

The aim of this study was to determine if the inflammation of the sympathetic ganglia (SG) in thromboangiitis obliterans (TAO) is induced by an infectious pathogen inside or if it is a reactive sterile inflammation.

For the purpose of this study, the gene expression of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), toll-like receptor 9 (TLR9), and the receptor for advanced glycation end-products (RAGE) were evaluated on the complementary DNA (cDNA) of the SG tissues of 24 TAO patients and two controls with hyperhidrosis by real-time polymerase chain reaction (PCR) and analysed by the Pfaffl method.

The gene expression of HMGB1 and TLR9 increased by about 25- and 2-fold changes in the SG of the TAO patients, respectively. However, there was no change in the gene expression of TLR4 or RAGE.

It appears that the inflammation in the SG of TAO patients is more likely a sterile inflammation, and its trigger may be mitochondrial DNA (mtDNA). Cadmium in cigarettes could be responsible for the induction of mtDNA release to the cell cytoplasm. In addition, the high expression of HMGB1 may play a role in the pathogenesis of TAO and may be responsible for both clinical manifestation of the disease and the imaging findings. Moreover, HMGB1 may be a target for treatment protocols for TAO. Further studies are highly recommended.

• Buerger's disease
• HMGB1
• Neurogenic inflammation
• RAGE
• Sympathectomy
• Sympathetic ganglia
• TLR4
• TLR9
• Thromboangiitis obliterans

• Iodine
• Iodotyrosine deiodinase 1 (Dehal1)
• Methimazole (MMI)
• Propylthiouracil (PTU)
• Thyroglobulin

• Animals
• Antithyroid Agents/pharmacology
• Cell Line
• Insulin/pharmacology
• Iodide Peroxidase/metabolism
• Methimazole/pharmacology
• Propylthiouracil/pharmacology
• Rats
• Thyroid Epithelial Cells/drug effects
• Thyroid Epithelial Cells/metabolism
• Thyrotropin/pharmacology

• Apoptosis
• Autoimmune thyroiditis
• Iodine
• Macrophages
• Phagocytosis

• Animals
• Apoptosis/genetics
• Apoptosis/physiology
• DNA Fragmentation
• Female
• Flow Cytometry
• In Situ Nick-End Labeling
• Iodine/toxicity
• Macrophages/immunology
• Macrophages/metabolism
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Phagocytosis/genetics
• Phagocytosis/physiology
• Thyroiditis, Autoimmune/chemically induced
• Thyroiditis, Autoimmune/immunology
• Thyroiditis, Autoimmune/metabolism

• chromosome aberrations
• cyclic GMP–AMP synthase
• micronuclei
• particle therapy
• radioimmunotherapy
• stimulator of interferon genes

• Chaperone
• Dendritic cell
• T regs
• Tumor immunity

• Animals
• Dendritic Cells/immunology
• Heat-Shock Proteins/immunology
• Heat-Shock Proteins/metabolism
• Humans
• Low Density Lipoprotein Receptor-Related Protein-1/metabolism
• Neoplasms/immunology
• Neoplasms/metabolism

• R21 AI132875 NIAID NIH HHS

Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA. This causes the aberrant activation of cGAS-STING cytoplasmic DNA sensors, provoking SASP through induction of interferon-β. Notably, the blockage of this pathway prevents SASP in senescent hepatic stellate cells, accompanied by a decline of obesity-associated hepatocellular carcinoma development in mice. These findings provide valuable new insights into the roles and mechanisms of SASP and possibilities for their control.

Activation of DNA damage response induces the acquisition of senescence-associated secretory phenotype (SASP) in senescent cells, but precise mechanisms remain unclear. Here, the authors show that the cytoplasmic accumulation of nuclear DNA activated cytoplasmic DNA sensors to provoke SASP.

Autoimmune thyroid diseases (AITD) are a group of both B cell- and T cell-mediated organ-specific autoimmune diseases. Graves’ disease and Hashimoto thyroiditis are the two main clinical presentations of AITD. Both genetic and environmental factors have important roles in the development of AITD. Epigenetics have been considered to exert key roles in integrating those genetic and environmental factors, and epigenetic modifications caused by environmental factors may drive genetically susceptibility individuals to develop AITD. Recent studies on the epigenetics of AITD have provided some novel insights into the pathogenesis of AITD. The aim of this review is to provide an overview of recent advances in the epigenetic mechanisms of AITD, such as DNA methylation, histone modifications, and non-coding RNAs. This review highlights the key roles of epigenetics in the pathogenesis of AITD and potential clinical utility. However, the epigenetic roles in AITD are still not fully elucidated, and more researches are needed to provide further deeper insights into the roles of epigenetics in AITD and to uncover new therapeutic targets. Although there are many studies assessing the epigenetic modifications in AITD patients, the clinical utility of epigenetics in AITD remains poorly defined. More studies are needed to identify the underlying epigenetic modifications that can contribute to accurate diagnosis of AITD, adequate choice of treatment approach, and precise prediction of treatment outcomes.

• DNA methylation
• autoimmune thyroid diseases
• epigenetics
• histone modifications
• long non-coding RNAs
• microRNAs
• pathogenesis

The major histocompatibility complex (MHC) is the exclusive chaperone that presents intracellular antigens, either self or foreign to T cells. Interestingly, aberrant expression of MHC molecules has been reported in various autoimmune target tissues such as thyroid follicular cells in Grave’s disease. Herein, we review the discovery of an unexpected effect of cytosolic double-stranded DNA (dsDNA), despite its origins, to induce antigen processing and presenting genes, including MHC molecules, in non-immune cells. Moreover, we highlight several recent studies that suggest cell injury endows thyroid epithelial cells with a phenotype of mature antigen presenting cells by inducing multiple antigen processing and presenting genes via releasing genomic DNA fragments into the cytosol. We discuss the possibility that such cytosolic dsDNA, in naked form without binding to histone proteins, might be involved in the development of cell damage-triggered autoimmune responses. We also discuss the possible molecular mechanism by which cytosolic dsDNA can induce MHC molecules. It is reasonable to speculate that cytosolic dsDNA-induced MHC class I is partially due to an autocrine/paracrine effect of type I interferon (IFN). While the mechanism of cytosolic dsDNA-induced MHC class II expression appears, at least partially, distinct from that mediated by IFN-γ. Further in-depth are required to clarify this picture.

• Cytosolic double-stranded DNA
• Major histocompatibility complex molecules
• Autoimmune response
• Antigen presentation
• Tissue injury

• Graves’ disease
• experimental animal models
• genomic DNA
• major histocompatibility complex class II
• thyroid-stimulating hormone receptor

• Cytokines/metabolism
• Environment
• Genetic Predisposition to Disease
• Hashimoto Disease/etiology
• Hashimoto Disease/genetics
• Hashimoto Disease/immunology
• Humans
• Immunity, Humoral
• MicroRNAs/metabolism

Polychlorinated biphenyls (PCBs) can severely interfere with multiple animals and human systems. To explore the molecular mechanisms underlying 2, 3′, 4, 4′, 5- pentachlorobiphenyl (PCB118)-induced thyroid dysfunction, Fischer rat thyroid cell line-5(FRTL-5) cells were treated with either different concentrations of PCB118 or dimethyl sulfoxide (DMSO). The effects of PCB118 on FRTL-5 cells viability and apoptosis were assessed by using a Cell Counting Kit-8 assay and apoptosis assays, respectively. Quantitative real-time polymerase chain reaction was used to quantify protein kinase B (Akt), Forkhead box protein O3a (FoxO3a), and sodium/iodide symporter (NIS) mRNA expression levels. Western blotting was used to detect Akt, phospho-Akt (p-Akt), FoxO3a, phospho-FoxO3a (p-FoxO3a), and NIS protein levels. Luciferase reporter gene technology was used to detect the transcriptional activities of FoxO3a and NIS promoters. The effects of the constitutively active Akt (CA-Akt) and dominant-negative Akt (DN-Akt) plasmids on p-Akt, p-FoxO3a, and NIS levels were examined in PCB118-treated FRTL-5 cells. The effects of FoxO3a siRNA on FoxO3a, p-FoxO3a, and NIS protein levels were examined in the PCB118-treated FRTL-5 cells. The effects of pcDNA3 (plsmid vectors designed for high-level stable and transient expression in mammalian host)-FoxO3a on NIS promoter activity were examined in the PCB118-treated FRTL-5 cells. Our results indicated that relatively higher PCB118 concentrations can inhibit cell viability in a concentration- and time-dependent manner. Akt, p-Akt, and p-FoxO3a protein or mRNA levels increased significantly in PCB118-treated groups and NIS protein and mRNA levels decreased considerably compared with the control groups. FoxO3a promoter activity increased significantly, whereas NIS promoter activity decreased. These effects on p-FoxO3a and NIS could be decreased by the DN-Akt plasmid, enhanced by the CA-Akt plasmid, and blocked by FoxO3a siRNA. The overexpressed FoxO3a could reduce NIS promoter activity. Our results suggested that PCB118 induces thyroid cell dysfunction through the Akt/FoxO3a/NIS signaling pathway.

• Animals
• Apoptosis/drug effects
• Cell Line
• Dimethyl Sulfoxide/pharmacology
• Down-Regulation/drug effects
• Forkhead Box Protein O3
• Forkhead Transcription Factors/antagonists & inhibitors
• Forkhead Transcription Factors/genetics
• Forkhead Transcription Factors/metabolism
• Phosphatidylinositol 3-Kinases/metabolism
• Phosphorylation
• Polychlorinated Biphenyls/toxicity
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• RNA, Messenger/metabolism
• RNA, Small Interfering/metabolism
• Rats
• Signal Transduction/drug effects
• Symporters/genetics
• Symporters/metabolism
• Thyroid Gland/cytology
• Thyroid Gland/drug effects
• Thyroid Gland/metabolism
• Up-Regulation/drug effects

• nuclear protein
• transcription factor
• nf-κb
• electrophoretic mobility shift assay

• Cell Line, Tumor
• Electrophoretic Mobility Shift Assay
• Humans
• NF-kappa B/chemistry
• NF-kappa B/isolation & purification

The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Excessive amounts of iodide have been linked to the development of autoimmune thyroiditis in humans and animals, while intrathyroidal depletion of iodine prevents disease in animal strains susceptible to severe thyroiditis. Although the mechanisms by which iodide induces thyroiditis are still unclear, several mechanisms have been proposed: (1) excess iodine induces the production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid; (2) processing excess iodine in thyroid epithelial cells may result in elevated levels of oxidative stress, leading to harmful lipid oxidation and thyroid tissue injuries; and (3) iodine incorporation in the protein chain of thyroglobulin may augment the antigenicity of this molecule. This review will summarize the current knowledge regarding excess iodide as an environmental toxicant and relate it to the development of autoimmune thyroid disease.

Histones are essential components of chromatin structure, and histone modification plays an important role in various cellular functions including transcription, gene silencing, and immunity. Histones also play distinct roles in extrachromosomal settings. Extrachromosomal histone H2B acts as a cytosolic sensor to detect double-stranded DNA (dsDNA) fragments derived from infectious agents or damaged cells to activate innate and acquired immune responses in various cell types. It also physically interacts with interferon (IFN)-β promoter stimulator 1 (IPS-1), an essential adaptor molecule that activates innate immunity, through COOH-terminal importin 9-related adaptor organizing histone H2B and IPS-1 (CIAO), resulting in a distinct signaling complex that induces dsDNA-induced type I IFN production. Such a molecular platform acts as a cellular sensor to recognize aberrant dsDNA in cases of viral infection and cell damage. This mechanism may also play roles in autoimmunity, transplantation rejection, gene-mediated vaccines, and other therapeutic applications.

• DNA damage
• DNA sensor
• epigenetic modifications
• extrachromosomal histone
• virus infection

• Animals
• Autoimmune Diseases/immunology
• Autoimmune Diseases/metabolism
• Autoimmunity/immunology
• Cell Line
• Humans
• Immunity, Innate/immunology
• Interferon-beta/metabolism
• Mice
• RNA, Messenger/metabolism
• Rats
• Thyroid Diseases/immunology
• Thyroid Diseases/metabolism
• Thyroid Gland/cytology
• Thyroid Gland/drug effects
• Thyroid Gland/immunology
• Thyroid Gland/metabolism
• Toll-Like Receptors/metabolism

All mammalian cells are equipped with large numbers of sensors for protection from various sorts of invaders, who, in turn, are equipped with molecules containing pathogen-associated molecular patterns (PAMPs). Once these sensors recognize non-self antigens containing PAMPs, various physiological responses including inflammation are induced to eliminate the pathogens. However, the host sometimes suffers from chronic infection or continuous injuries, resulting in production of self-molecules containing damage-associated molecular patterns (DAMPs). DAMPs are also responsible for the elimination of pathogens, but promiscuous recognition of DAMPs through sensors against PAMPs has been reported. Accumulation of DAMPs leads to massive inflammation and continuous production of DAMPs; that is, a vicious circle leading to the development of autoimmune disease. From a vaccinological point of view, the accurate recognition of both PAMPs and DAMPs is important for vaccine immunogenicity, because vaccine adjuvants are composed of several PAMPs and/or DAMPs, which are also associated with severe adverse events after vaccination. Here, we review as the roles of PAMPs and DAMPs upon infection with pathogens or inflammation, and the sensors responsible for recognizing them, as well as their relationship with the development of autoimmune disease or the immunogenicity of vaccines.

• DAMPs (damage-associated molecular patterns)
• DNA sensors
• PAMPs (pathogen-associated molecular patterns)
• innate immunity
• metabolites
• nucleic acids
• uric acid
• vaccine adjuvant

• Animals
• Cells, Cultured
• Dual Oxidases
• Flavoproteins/biosynthesis
• Hydrogen Peroxide/metabolism
• Membrane Proteins/biosynthesis
• NADPH Oxidases/biosynthesis
• RNA, Messenger/metabolism
• Rats
• Thyroglobulin/pharmacology
• Thyroid Gland/physiology

• Animals
• Graves Disease/metabolism
• Iodides/metabolism
• Methimazole/pharmacology
• Propylthiouracil/pharmacology
• RNA, Messenger/metabolism
• Rats
• Real-Time Polymerase Chain Reaction
• Symporters/biosynthesis
• Symporters/genetics
• Thyroid Gland/drug effects
• Thyroid Gland/metabolism
• Thyrotropin/pharmacology

• Animals
• DNA/blood
• DNA Damage
• DNA, Mitochondrial/blood
• Humans
• Neoplasms/blood
• Neoplasms/genetics
• Nucleosomes/metabolism
• RNA/blood

Circulating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear.

To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24–39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iT^TM high sensitivity DNA assay was used to measure cf-DNA directly from serum.

The results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (p<5×10⁻⁸). All of these significant SNPs were localised to chromosome 2q37, near the UDP-glucuronosyltransferase 1 (UGT1) family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1) gene region.

The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations.

• Adult
• Cohort Studies
• DNA/blood
• Female
• Finland
• Genetic Association Studies
• Genotype
• Glucuronosyltransferase/genetics
• Glucuronosyltransferase/physiology
• Humans
• Male
• Polymorphism, Single Nucleotide

• Animals
• Cell Line
• Cell Proliferation/drug effects
• Culture Media, Serum-Free/pharmacology
• DNA Replication/drug effects
• Enzyme Activation
• Extracellular Signal-Regulated MAP Kinases/biosynthesis
• Flavonoids/pharmacology
• Gene Expression/drug effects
• Insulin/pharmacology
• MAP Kinase Kinase Kinases/biosynthesis
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-fos/metabolism
• Proto-Oncogene Proteins c-jun/metabolism
• Proto-Oncogene Proteins c-myc/metabolism
• Proto-Oncogene Proteins c-raf/biosynthesis
• Rats
• Thyroglobulin/pharmacology
• Thyroid Gland/cytology
• Thyroid Gland/drug effects
• Thyroid Gland/enzymology
• Thyrotropin/pharmacology