Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome
| العنوان: | Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome |
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| المؤلفون: | Antje Canisius, Markus P. Radsak, René Mönnikes, Karl J. Lackner, Benjamin Siebald, Nadine Müller-Calleja, Pamela Stein, Antonia Köhler, Carolin Orning |
| المصدر: | Thrombosis and Haemostasis. 113:1071-1083 |
| بيانات النشر: | Georg Thieme Verlag KG, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Inflammasomes, Interleukin-1beta, medicine.disease_cause, Monocytes, Autoimmunity, Pathogenesis, Mice, 0302 clinical medicine, Superoxides, immune system diseases, Lupus Erythematosus, Systemic, Membrane Glycoproteins, NADPH oxidase, Caspase 1, Antibodies, Monoclonal, Inflammasome, Hematology, Middle Aged, Antiphospholipid Syndrome, 030220 oncology & carcinogenesis, NADPH Oxidase 2, Monoclonal, Female, medicine.drug, Adult, Enzyme-Linked Immunosorbent Assay, Endosomes, Biology, 03 medical and health sciences, Antiphospholipid syndrome, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, neoplasms, Aged, Autoimmune disease, NADPH Oxidases, Thrombosis, TLR7, medicine.disease, Toll-Like Receptor 2, Mice, Inbred C57BL, Toll-Like Receptor 4, 030104 developmental biology, Immunoglobulin G, Immunology, Leukocytes, Mononuclear, biology.protein, Carrier Proteins, Reactive Oxygen Species, Spleen |
| الوصف: | SummaryThe antiphospholipid syndrome (APS) is an autoimmune disease characterised by thromboembolic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Here we show that three cofactor independent human monoclonal aPL can induce transcription of NLRP3 and caspase-1 resulting in inflammasome activation specific for NLRP3. This depends fully on activation of endosomal NADPH-oxidase-2 (NOX2) by aPL. Activation of NOX2 and subsequent inflammasome activation by aPL are independent from TLR2 or TLR4. While endosomal superoxide production induces caspase-1 and NLRP3 transcription, it does not affect prae-IL-1β transcription. Therefore, release of IL-1β occurs only after activation of additional pathways like TLR7/8 or TLR2. All effects exerted by the monoclonal aPL can be reproduced with IgG fractions of APS patients proving that the monoclonal aPL are representative for the APS. IgG fractions of healthy controls or patients suffering from systemic lupus erythematosus have no effect. In a mouse model of the APS we can show inflammasome activation in vivo. Furthermore, mononuclear cells isolated from patients with the APS show an increased expression of caspase-1 and NLRP3 which is accompanied by a three-fold increased serum concentration of IL-1β suggesting chronic inflammasome activation in APS patients. In summary, we provide further evidence that endosomal NOX2 can be activated by cofactor independent aPL. This leads to induction of the NLRP3 inflammasome. Our data indicate that cofactor independent aPL might contribute significantly to the pathogenesis of the APS. |
| تدمد: | 2567-689X 0340-6245 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5e3835cdce9caedc5d25846bcfc2b38bTest https://doi.org/10.1160/th14-07-0628Test |
| رقم الانضمام: | edsair.doi.dedup.....5e3835cdce9caedc5d25846bcfc2b38b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2567689X 03406245 |
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