Cell-Free DNA in Rheumatoid Arthritis

Hashimoto, Teppei; Yoshida, Kohsuke; Hashiramoto, Akira

doi:10.3390/ijms22168941

Cited by 32 publications

(22 citation statements)

References 121 publications

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“…Based on these observations, dd-cfDNA may itself represent a danger signal that initiates an immune response in the form of dendritic cell (DC) activation. In a parallel vein, high levels of mitochondrial DNA (mtDNA) are found in the circulation of patients suffering from sepsis, trauma, and chronic organ-specific illnesses such as rheumatoid arthritis, gout, SLE, and hepatitis [ 56 , 57 , 58 , 59 ]. In transplantation, mtDNA is also released following allograft reperfusion and has also been shown to be a compelling danger signal that is recognized by the innate immune system, directly modifying the inflammatory response.…”

Section: The Nlrp3 Inflammasome and Dna Sensingmentioning

confidence: 99%

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Burke

Dale

Dholakia

2021

IJMS

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The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.

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Section: The Nlrp3 Inflammasome and Dna Sensingmentioning

confidence: 99%

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Burke

Dale

Dholakia

2021

IJMS

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“…cfDNA has been reported to be associated with RA, SLE, and other autoimmune diseases ( 12 , 13 ). Higher plasma cfDNA levels are related to an increased rate of deterioration, whereas lower cfDNA levels correspond to an improvement in clinical symptoms ( 14 ). cfDNA can be recognized by DNA sensors to activate cell signaling systems, generating a series of pro-inflammatory cytokines to activate the adaptive immune response ( 15 ).…”

Section: Introductionmentioning

confidence: 99%

Cell-Free DNA Promotes Inflammation in Patients With Oral Lichen Planus via the STING Pathway

Deng

Pan

et al. 2022

Front. Immunol.

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BackgroundDamaged and dead cells release cell-free DNA (cfDNA) that activates cyclic GMP–AMP (cGAMP) synthase (cGAS), which leads to the activation of stimulator of interferon genes (STING) via the second messenger cGAMP. STING promotes the production of inflammatory cytokines and type I interferons to induce an inflammatory response. Oral lichen planus (OLP), a chronic autoimmune disease involving oral mucosa characterized by the apoptosis of keratinocytes mediated by T-lymphocytes, is related to the activation of multiple inflammatory signaling pathways. Currently, the relationship between cfDNA and OLP has not been confirmed. We hypothesized that cfDNA may be a potential therapeutic target for OLP.MethodscfDNA was extracted from the saliva and plasma of OLP patients; its concentration was measured using the Quanti-iT-PicoGree kit and its relationship with OLP inflammation was assessed. cfDNA of OLP patients (cfDNA-OLP) was transfected into THP-1 macrophages and the expression of inflammatory factors was investigated by performing quantitative real time PCR (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA). STING expression was analyzed in the tissues of OLP patients and healthy controls using immunohistochemical staining and western blotting. siRNA was used to knockdown STING expression in THP-1 macrophages, and the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) secreted by cells following cfDNA-OLP transfection were detected using ELISA. Finally, the effect of the cationic polymer PAMAM-G3 was evaluated on the treatment of inflammation induced by cfDNA-OLP.ResultsThe concentration of cfDNA in the saliva and plasma of OLP patients was considerably higher than that of healthy controls, and it positively correlated with the levels of inflammatory cytokines and clinical characteristics. cfDNA-OLP induced an inflammatory response in THP-1 macrophages. STING expression was significantly higher in OLP tissues than in the gingival tissues of healthy controls. STING knockdown suppressed cfDNA-OLP-induced inflammation in THP-1 macrophages. PAMAM-G3 inhibited the inflammatory response caused by cfDNA-OLP.ConclusionThe cfDNA level is increased in OLP patients, and the STING pathway activated by cfDNA-OLP might play a critical role in OLP pathogenesis. Treatment with PAMAM-G3 reduced the inflammation induced by cfDNA-OLP, and therefore, may be a potential treatment strategy for OLP.

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“…25, № 2 системы и, в частности, при ревматоидном артрите (РА). Было показано, что уровень внДНК в плазме крови при РА существенно повышен и в некоторых случаях может быть связан с особенностями патологического процесса у индивидуальных больных [7,8,11].…”

Section: Introductionunclassified

“…О значимой положительной связи концентрации внДНК в плазме крови пациентов с РА со степенью активности патологического процесса, наблюдаемого у них в период исследования, говорят и статистически достоверные корреляции уровня внДНК с основными показателями, позволяющими оценивать активность заболевания в клинике: DAS-28 (ρ = 0,319; p < 0,05) и уровнем С-реактивного белка в сыворотке (ρ = 0,270; p < 0,05). Полученные результаты хорошо согласуются с данными, опубликованными другими авторами[7,8,11], о повышенииРисунок 1. Концентрация внДНК в плазме крови условно здоровых доноров и пациентов с ревматоидным артритом Примечание.…”

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Plasma extracellular DNA and neutrophilic leukocyte activity in patients with rheumatoid arthritis

Гаврилова

Демченко

Гойман

et al. 2022

Russian Journal of Immunology

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Neutrophilic leukocytes play a key role for the joint damage in development of rheumatoid arthritis (RA). The specific death mode of these cells (netosis) may be an important reason of increase of cell-free DNA (cfDNA) in peripheral blood of the RA patients. Of great interest would be studies of alleged relationships between the of blood cfDNA contents being able of playing the role of an auto-antigen participating in the initiation of autoimmune reactions, and indices of neutrophil activation in this immunopathological disorder. The aim of the present study was to determine the levels of cfDNA in blood plasma of patients with RA depending on the clinical course of the disease, and to evaluate possible relationships between this index and activation of neutrophilic leukocytes. The study was conducted on 28 conditionally healthy donors and 63 patients with RA from the Rheumatology Department at the Clinic of Immunopathology (Novosibirsk). The level of cfDNA was determined using PicoGreen fluorescent dye. Neutrophils from the peripheral blood of donors and patients with rheumatoid arthritis were isolated in a Ficoll-Urografin density gradient. Neutrophilic leukocytes accounted for more than 98% of the fraction of isolated cells, and their viability was 99%. A portion of freshly isolated neutrophils was stimulated by phorbol myristate acetate. Concentration of myeloperoxidase in blood plasma of donors and patients with RA was determined using the Human MPO ELISA kit. It has been shown that the increased concentration of extracellular DNA in blood plasma of RA patients correlates with an higher degree of disease activity, and this parameter may serve as a relatively independent indicator of the disease intensity. A correlation was found between the level of cfDNA and common biochemical markers used to assess the activity of disease, i.e., DAS-28 and C-reactive protein levels in serum (p 0.05). Decrease of cfDNA concentrations is detected during treatment of the RA patients. This is due to the expected prognosis, i.e., a decreased manifestation of the disease, which also means correct administration of therapy. A relationship was found between the level of cfDNA and blood myeloperoxidase concentration in RA patients. The data obtained during the study suggest a possible connection between increased concentration of extracellular DNA, and activation of neutrophilic leukocytes in rheumatoid arthritis, with increased netosis in the affected joints.

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Cell-Free DNA in Rheumatoid Arthritis

Cited by 32 publications

References 121 publications

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

The NLRP3 Inflammasome: Relevance in Solid Organ Transplantation

Cell-Free DNA Promotes Inflammation in Patients With Oral Lichen Planus via the STING Pathway

Plasma extracellular DNA and neutrophilic leukocyte activity in patients with rheumatoid arthritis

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