Apoptosis in patients with primary antiphospholipid antibody syndrome

Tang, Kuo‐Tung; Hsieh, Tsu‐Yi; Chao, Ya‐Hsuan; Li, Ju‐Pi; Lan, Joung‐Liang; Lin, Chi-Chen; Chen, Der‐Yuan

doi:10.1111/1756-185x.13468

Cited by 7 publications

(5 citation statements)

References 45 publications

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“…Moreover, pyroptosis and apoptosis are two vital pathways that are implicated in APS pathogenesis. 17,53 A previous study confirmed that active STAT3 upregulates NLRP3 via directly enhancing histone H3 and H4 acetylation at the NLRP3 promoter in LPS-treated macrophages. 45 The upregulated NLRP3 triggered canonical pyroptosis and apoptosis, and also induced the release of proinflammatory cytokines in autoimmune diseases, implying its promising therapeutic potential.…”

Section: Discussionmentioning

confidence: 83%

“…STAT3 is a crucial transcriptional regulator of pyroptosis, apoptosis and related inflammation. Moreover, pyroptosis and apoptosis are two vital pathways that are implicated in APS pathogenesis 17,53 . A previous study confirmed that active STAT3 upregulates NLRP3 via directly enhancing histone H3 and H4 acetylation at the NLRP3 promoter in LPS‐treated macrophages 45 .…”

Section: Discussionmentioning

confidence: 87%

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ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

Tan,

Qiao,

Yang

et al. 2024

Clinical & Translational Med

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BackgroundAlterations of the trimethylation of histone 3 lysine 4 (H3K4me3) mark in monocytes are implicated in the development of autoimmune diseases. Therefore, the purpose of our study was to elucidate the role of H3K4me3‐mediated epigenetics in the pathogenesis of antiphospholipid syndrome (APS).MethodsH3K4me3 Cleavage Under Targets and Tagmentation and Assay for Transposase‐Accessible Chromatin were performed to determine the epigenetic profiles. Luciferase reporter assay, RNA immunoprecipitation, RNA pull‐down, co‐immunoprecipitation and chromatin immunoprecipitation were performed for mechanistic studies. Transmission electron microscopy and propidium iodide staining confirmed cell pyroptosis. Primary monocytes from patients with primary APS (PAPS) and healthy donors were utilised to test the levels of key molecules. A mouse model mimicked APS was constructed with beta2‐glycoprotein I (β2GPI) injection. Blood velocity was detected using murine Doppler ultrasound.ResultsH3K4me3 signal and open chromatin at the ARID5B promoter were increased in an in vitro model of APS. The epigenetic factor ARID5B directly activated LINC01128 transcription at its promoter. LINC01128 promoted the formation of the BTF3/STAT3 complex to enhance STAT3 phosphorylation. Activated STAT3 interacted with the NLRP3 promoter and subsequently stimulated pyroptosis and apoptosis. ARID5B or BTF3 depletion compensated for LINC01128‐induced pyroptosis and apoptosis by inhibiting STAT3 phosphorylation. In mice with APS, β2GPI exposure elevated the levels of key proteins of pyroptosis and apoptosis pathways in bone marrow‐derived monocytes, reduced the blood velocity of the ascending aorta, increased the thrombus size of the carotid artery, and promoted the release of interleukin (IL)‐18, IL‐1β and tissue factor. Patients with PAPS had the high‐expressed ARID5B and LINC01128, especially those with triple positivity for antiphospholipid antibodies. Moreover, there was a positive correlation between ARID5B and LINC01128 expression.ConclusionThis study indicated that ARID5B/LINC01128 was synergistically upregulated in APS, and they aggravated disease pathogenesis by enhancing the formation of the BTF3/STAT3 complex and boosting p‐STAT3‐mediated pyroptosis and apoptosis, thereby providing candidate therapeutic targets for APS.Highlights The H3K4me3 mark and chromatin accessibility at the ARID5B promoter are increased in vitro model mimicked APS. ARID5B‐mediated LINC01128 induces pyroptosis and apoptosis via p‐STAT3 by binding to BTF3. ARID5B is high‐ expressed in patients with primary APS and positively correlated with LINC01128 expression. OICR‐9429 treatment mitigates pyroptosis and related inflammation in vivo and in vitro models mimicked APS.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 87%

ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

Tan,

Qiao,

Yang

et al. 2024

Clinical & Translational Med

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“…Apoptosis is implicated in the pathogenesis of APS. Some controversy exists, since exposed anionic phospholipids during apoptosis may provide B2GPI binding sites, which then induce the generation of aPL [ 58 ]. Bondanza et al reported that autoimmunity, including anti-B2GPI IgG, would develop in mice only when apoptotic cells/B2GPI are injected along with syngeneic DCs [ 59 ].…”

Section: Resultsmentioning

confidence: 99%

Dendritic Cells and Antiphospholipid Syndrome: An Updated Systematic Review

Tang

Chen

et al. 2021

Life

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Antiphospholipid syndrome (APS) is an autoimmune disease characterized by autoreactive B and T cells against β2-glycoprotein I (B2GPI), with vascular thrombosis or obstetrical complications. Dendritic cells (DCs) are crucial in the generation of autoimmunity. Here, we conducted a comprehensive systematic review on the relationship between DC and APS. We performed a literature search of PubMed as of 26 March 2021. A total of 33 articles were extracted. DCs are pivotal in inducing inflammatory responses and orchestrating adaptive immunity. DCs contribute to the local inflammation regarding vascular thrombosis or obstetrical complications. Both B2GPI and antiphospholipid antibodies (aPL) can promote antigen presentation by DCs and the generation or maintenance of autoimmunity. In addition, plasmacytoid DC activation is enhanced by aPL, thereby augmenting the inflammatory response. In line with these findings, DC modulation appears promising as a future treatment for APS. In conclusion, our review indicated the crucial role of DCs in the pathogenesis of APS. Deeper understanding of the complex relationship would help in developing new treatment strategies.

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“…Although cleavage of vimentin by caspases is a requisite for apoptosis, 93 evidence regarding this dysregulation process of apoptosis in APS patients has not been proven. 95 …”

Section: Pathogenetic Mechanisms In Apsmentioning

confidence: 99%

“…Although cleavage of vimentin by caspases is a requisite for apoptosis, 93 evidence regarding this dysregulation process of apoptosis in APS patients has not been proven. 95 Finally, platelets are also activated by NETs, specifically by histones. These proteins activate platelets expressing phosphatidylserine, P-selectin, and FVa on their surface.…”

Section: Platelet Activation Mediated By Aplsmentioning

confidence: 99%

The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

Arreola-Díaz

Majluf‐Cruz

Sánchez-Torres

et al. 2022

Clin Appl Thromb Hemost

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The antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by a hypercoagulability associated to vascular thrombosis and/or obstetric morbidity, is caused by the presence of antiphospholipid antibodies such as lupus anticoagulant, anti-β-2-glycoprotein 1, and/or anticardiolipin antibodies. In the obstetrical APS, antiphospholipid antibodies induce the production of proinflammatory cytokines and tissue factor by placental tissues and recruited neutrophils. Moreover, antiphospholipid antibodies activate the complement system which, in turn, induces a positive feedback leading to recruitment of neutrophils as well as activation of the placenta. Activation of these cells triggers myometrial contractions and cervical ripening provoking the induction of labor. In thrombotic and obstetrical APS, antiphospholipid antibodies activate endothelial cells, platelets, and neutrophils and they may alter the multimeric pattern and concentration of von Willebrand factor, increase the concentration of thrombospondin 1, reduce the inactivation of factor XI by antithrombin, increase the activation of factor XII, and reduce the activity of tissue plasminogen activator with the subsequent production of plasmin. All these effects result in less permeable clots, denser, thinner, and with more branched fibrin fibers which are more difficult to lysate. As a consequence, thrombosis, the defining clinical criterion of APS, complicates the clinical course of the patient.

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Apoptosis in patients with primary antiphospholipid antibody syndrome

Cited by 7 publications

References 45 publications

ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

ARID5B‐mediated LINC01128 epigenetically activated pyroptosis and apoptosis by promoting the formation of the BTF3/STAT3 complex in β2GPI/anti‐β2GPI‐treated monocytes

Dendritic Cells and Antiphospholipid Syndrome: An Updated Systematic Review

The Pathophysiology of The Antiphospholipid Syndrome: A Perspective From The Blood Coagulation System

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