Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome

Nadine Müller-Calleja; Antonia Köhler; Benjamin Siebald; Antje Canisius; Carolin Orning; Markus Radsak; Pamela Stein; René Mönnikes; Karl J. Lackner

doi:10.1160/TH14-07-0628

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 113(05): 1071-1083
DOI: 10.1160/TH14-07-0628

Blood Cells, Inflammation and Infection

Schattauer GmbH

Cofactor-independent antiphospholipid antibodies activate the NLRP3-inflammasome via endosomal NADPH-oxidase: implications for the antiphospholipid syndrome

Authors

Nadine Müller-Calleja

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany

²Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
Antonia Köhler

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
Benjamin Siebald

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
Antje Canisius

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
Carolin Orning

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
Markus Radsak

³IIIrd Department of Medicine, University Medical Center Mainz, Germany
Pamela Stein

³IIIrd Department of Medicine, University Medical Center Mainz, Germany
René Mönnikes

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
Karl J. Lackner

¹Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany

Abstract

Summary

The 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.

Keywords

Antiphospholipid syndrome - autoimmunity - monocytes - endosomal ROS generation - thrombosis

Full Text

References

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