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

Nadine Müller-Calleja
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
2   Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany
,
Antonia Köhler
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
,
Benjamin Siebald
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
,
Antje Canisius
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
,
Carolin Orning
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
,
Markus Radsak
3   IIIrd Department of Medicine, University Medical Center Mainz, Germany
,
Pamela Stein
3   IIIrd Department of Medicine, University Medical Center Mainz, Germany
,
René Mönnikes
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
,
Karl J. Lackner
1   Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Mainz, Germany
› Author Affiliations
Further Information

Publication History

Received: 23 July 2014

Accepted after major revision: 25 January 2014

Publication Date:
24 November 2017 (online)

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.

 
  • References

  • 1 Wilson WA, Gharavi AE, Koike T. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309-1311.
  • 2 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 04: 295-306.
  • 3 Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368: 1033-1044.
  • 4 Meroni PL, Borghi MO, Raschi E, Tedesco F. Pathogenesis of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol 2011; 07: 330-339.
  • 5 Willis R, Pierangeli SS. Anti-α2-glycoprotein I antibodies. Ann NY Acad Sci 2013; 1285: 44-58.
  • 6 Du VX, Kelchtermans H, de Groot PG. et al. From antibody to clinical phenotype, the black box of the antiphospholipid syndrome: Pathogenic mechanisms of the antiphospholipid syndrome. Thromb Res 2013; 132: 319-326.
  • 7 von Landenberg C, Lackner KJ, von Landenberg P. et al. Isolation and characterisation of two human monoclonal anti-phospholipid IgG from patients with autoimmune disease. J Autoimmun 1999; 13: 215-223.
  • 8 Buschmann C, Fischer C, Ochsenhirt V. et al. Generation and characterisation of three monoclonal IgM antiphospholipid antibodies recognizing different phospholipid antigens. Ann NY Acad Sci 2005; 1051: 240-254.
  • 9 Prinz N, Hauser F, Lorenz M. et al. Structural and functional characterisation of a human IgG monoclonal antiphospholipid antibody. Immunobiology 2011; 216: 145-151.
  • 10 Lackner KJ, von Landenberg C, Barlage S. et al. Analysis of prothrombotic effects of two human monoclonal IgG antiphospholipid antibodies of apparently similar specificity. Thromb Haemost 2000; 83: 583-588.
  • 11 Prinz N, Clemens N, Strand D. et al. Antiphospholipid antibodies induce translocation of TLR7 and TLR8 to the endosome in human monocytes and plasmacytoid dendritic cells. Blood 2011; 118: 2322-2332.
  • 12 Prinz N, Clemens N, Canisius A. et al. Endosomal NADPH-oxidase is critical for induction of the tissue factor gene in monocytes and endothelial cells. Lessons from the antiphospholipid syndrome. Thromb Haemost 2013; 109: 525-531.
  • 13 Hurst J, Prinz N, Lorenz M. et al. TLR7 and TLR8 ligands and antiphospholipid antibodies show synergistic effects on the induction of IL-1beta and caspase-1 in monocytes and dendritic cells. Immunobiology 2009; 214: 683-691.
  • 14 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821-832.
  • 15 Petrilli V, Dostert C, Muruve DA. et al. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol 2007; 19: 615-622.
  • 16 Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol 2013; 13: 397-411.
  • 17 Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Sem Immunol 2009; 21: 242-253.
  • 18 Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009; 27: 229-265.
  • 19 Hornung V, Latz E. Intracellular DNA recognition. Nat Rev Immunol 2010; 10: 123-130.
  • 20 Rathinam VA, Jiang Z, Waggoner SN. et al. The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 2010; 11: 395-402.
  • 21 Muruve DA, Petrilli V, Zaiss AK. et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 2008; 452: 103-107.
  • 22 Fernandes-Alnemri T, Yu JW, Datta P. et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 2009; 458: 509-513.
  • 23 Kerur N, Veettil MV, Sharma-Walia N. et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 2011; 09: 363-375.
  • 24 Gross O, Thomas CJ, Guarda G. et al. The inflammasome: an integrated view. Immunol Rev 2011; 243: 136-151.
  • 25 Kostura MJ, Tocci MJ, Limjuco G. et al. Identification of a monocyte specific pre-interleukin 1 beta convertase activity. Proc Natl Acad Sci USA 1989; 86: 5227-5231.
  • 26 Rice AP, Kostura M, Mathews MB. Identification of a 90-kDa polypeptide which associates with adenovirus VA RNAI and is phosphorylated by the doublestranded RNA-dependent protein kinase. J Biol Chem 1989; 264: 20632-20637.
  • 27 Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002; 10: 417-426.
  • 28 Shaw PJ, McDermott MF, Kanneganti TD. Inflammasomes and autoimmunity. Trends Mol Med 2011; 17: 57-64.
  • 29 Ben-Sasson SZ, Hu-Li J, Quiel J. et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA 2009; 106: 7119-7124.
  • 30 Maliszewski CR, Sato TA, Vanden Bos T. et al. Cytokine receptors and B cell functions. I. Recombinant soluble receptors specifically inhibit IL-1- and IL- 4-induced B cell activities in vitro. J Immunol 1990; 144: 3028-3033.
  • 31 Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol 2010; 10: 89-102.
  • 32 Chung Y, Chang SH, Martinez GJ. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signalling. Immunity 2009; 30: 576-587.
  • 33 Kryczek I, Wei S, Vatan L. et al. Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J Immunol 2007; 179: 1423-1426.
  • 34 Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A. et al. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 2007; 08: 942-949.
  • 35 Waite JC, Skokos D. Th17 response and inflammatory autoimmune diseases. Int J Inflam 2012; 2012: 819467.
  • 36 Martinon F. Signalling by ROS drives inflammasome activation. Eur J Immunol 2010; 40: 616-619.
  • 37 Netea MG, van de Veerdonk FL, Kullberg BJ. et al. The role of NLRs and TLRs in the activation of the inflammasome. Expert Opin Biol Ther 2008; 08: 1867-1872.
  • 38 Doring Y, Hurst J, Lorenz M. et al. Human antiphospholipid antibodies induce TNFalpha in monocytes via Toll-like receptor 8. Immunobiology 2010; 215: 230-241.
  • 39 Jourdan T, Godlewski G, Cinar R. et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat Med 2013; 19: 1132-1140.
  • 40 Pollock JD, Williams DA, Gifford MA. et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 1995; 09: 202-209.
  • 41 Hoshino K, Takeuchi O, Kawai T. et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 1999; 162: 3749-3752.
  • 42 Takeuchi O, Hoshino K, Kawai T. et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999; 11: 443-451.
  • 43 Hemmi H, Kaisho T, Takeuchi O. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signalling pathway. Nat Immunol 2002; 03: 196-200.
  • 44 Hemmi H, Takeuchi O, Kawai T. et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408: 740-745.
  • 45 Jackson SH, Gallin JI, Holland SM. The p47phox mouse knock-out model of chronic granulomatous disease. J Exp Med 1995; 182: 751-758.
  • 46 Miller FJ, Jr. Filali M, Huss GJ. et al. Cytokine activation of nuclear factor kappa B in vascular smooth muscle cells requires signalling endosomes containing Nox1 and ClC-3. Circ Res 2007; 101: 663-671.
  • 47 Bauernfeind FG, Horvath G, Stutz A. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 2009; 183: 787-791.
  • 48 Bakimer R, Fishman P, Blank M. et al. Induction of primary antiphospholipid syndrome in mice by immunisation with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89: 1558-1563.
  • 49 Mulla MJ, Salmon JE, Chamley LW. et al. A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1α production by human first trimester trophoblast. PLoS One 2013; 08: e65237.
  • 50 Juliana C, Fernandes-Alnemri T, Kang S. et al. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 2012; 287: 36617-36622.
  • 51 Hu Y, Mao K, Zeng Y. et al. Tripartite-motif protein 30 negatively regulates NLRP3 inflammasome activation by modulating reactive oxygen species production. J Immunol 2010; 185: 7699-7705.