Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

Nishimoto, Sei‐ichi; Fukuda, Daiju; Sata, Masataka

doi:10.1186/s41232-020-00118-7

Cited by 34 publications

(28 citation statements)

References 108 publications

(111 reference statements)

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“…Chronic low-grade inflammation seems to be of importance for the development of metabolic complications of obesity, especially insulin resistance (5)(6)(7). The causes are unknown but could include damage-associated molecular patterns (DAMPs) such as extracellular DNA (ecDNA) recognized by Toll-like receptor 9 or other pattern recognition receptors (8).…”

Section: Introductionmentioning

confidence: 99%

Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents

Celec

Janovičová

Gurecká

et al. 2021

Physiological Genomics

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Obesity is associated with chronic low-grade inflammation that eventually leads to metabolic complications. Extracellular DNA (ecDNA) is a damage-associated molecular pattern. Extracellular mitochondrial DNA can activate innate immunity. We hypothesized that ecDNA, especially of mitochondrial origin could be associated with components of the metabolic syndrome in young healthy probands. In a cross-sectional study healthy adolescents (n=1249) provided blood samples. Anthropometric data, blood pressure and blood counts were assessed. In addition, biochemical analysis of sera or plasma was conducted including the quantification of advanced oxidation protein products (AOPP) as a marker of oxidative stress induced by neutrophil or monocyte activation. Plasma ecDNA was isolated and measured using fluorometry. Nuclear and mitochondrial DNA were quantified using real time PCR. Males had higher total plasma ecDNA (15 (11-21) vs 11 (8-17) ng/ml; median (IQR)), nuclear (1760 (956-3273) vs 1153 (600-2292) GE/ml) and mitochondrial DNA (37181 (14836-90896) vs 30089 (12587-72286) GE/ml). EcDNA correlated positively with the continuous metabolic syndrome score (r= 0.158 for males and r= 0.134 for females). Stronger correlations were found between ecDNA of mitochondrial origin and AOPP (r= 0.202 and 0.186 for males and females respectively). Multivariate regression analysis revealed associations of nuclear DNA with leukocyte and erythrocyte counts. The results of this study on healthy adolescents show that circulating ecDNA is associated with the risk of metabolic syndrome, not with obesity per se. The association between mitochondrial ecDNA and AOPP requires further attention as it supports a potential role of mitochondria-induced sterile inflammation in the pathogenesis of the metabolic syndrome.

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Section: Introductionmentioning

confidence: 99%

Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents

Celec

Janovičová

Gurecká

et al. 2021

Physiological Genomics

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“…In a similar way to atherogenic vascular diseases, metabolic abnormalities, such as insulin resistance and hepatic steatosis, share sterile chronic inflammation in metabolic organs as a fundamental aspect of their pathology. The release of various endogenous ligands (including saturated fatty acids, heat-shock protein, and self-derived DNA) has been demonstrated 24,[57][58][59] and therefore, the role of PRRs has been extensively studied.…”

Section: The Role Of Tlr9 In Metabolic Diseasesmentioning

confidence: 99%

“…We previously reported the causal role of TLR9 in adipose tissue inflammation and subsequent insulin resistance in obese mice 24,58) . To investigate the role of TLR9, we genetically deleted TLR9 in C57BL/6 mice, because we found an elevation of TLR9 expression in adipose tissue in obese C57BL/6 mice fed a HFD.…”

Section: The Role Of Tlr9 In Metabolic Diseasesmentioning

confidence: 99%

Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases

Fukuda

Phương

Sata

2022

JAT

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Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)-one of the most studied DNA sensors-recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.The innate immune system uses pattern recognition receptors (PRRs) to recognize nonselfmicrobial products (pathogen-associated molecular patterns (PAMPs)). Following the ligation of PAMPs, PRRs activate various downstream signaling pathways to

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“…The circulating endogenous host-derived ssDNA and dsDNA also increase in obese people, patients with visceral obesity, and high-fat diet (HFD) fed mice ( 229 , 230 ). The circulating ssDNA levels in obese people well-correlate with the homeostasis model assessment of insulin resistance (HOMA-IR) that serves as an index for insulin resistance.…”

Section: Tlr9 Recognizing Self-dnamentioning

confidence: 99%

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

Kumar

2021

Front. Immunol.

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The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

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Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

Cited by 34 publications

References 108 publications

Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents

Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents

Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA

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