Hanssen, Eric

Hewitson, Tim D.

Holt, Stephen G.

Pasch, Andreas

Smith, Edward R.

RERO DOC Digital Library

CHRONIC KIDNEY DISEASE.NUTRITION, INFLAMMATION ANDOXIDATIVE STRESSSP397 FETUIN-A ATTENUATES MINERAL NANOPARTICLEACTIVATION OF THE NLRP3 INFLAMMASOME IN THE HUMANMACROPHAGEEdward R Smith1, Tim D Hewitson1, Eric Hanssen2, Andreas Pasch3 and StephenG Holt11The Royal Melbourne Hospital, Nephrology, Melbourne, Australia, 2Bio21Molecular Science and Biotechnology Institute, Electron Microscopy Unit,Melbourne, Australia, 3University Hospital Bern, Clinical Chemistry, Bern,SwitzerlandIntroduction and Aims:Mineral nanoparticles may directly link inflammatory andcalcification processes that often co-exist in patients with CKD and in other age-relatedvascular diseases. Synthetic mineral nanoparticles are strong activators of apro-inflammatory response in the macrophage in vitro, inducing interleukin (IL)-1βsecretion via activation of the NOD-like receptor protein-3 (NLRP3) inflammasome.However, serum-derived mineral nanoparticles, colloidal complexes of insolublemineral and mineral-binding proteins, so-called calciprotein particles (CPP), appearcomparatively benign. This implies that mineral-binding proteins such as fetuin-A,abundant in extracellular fluid and major constituents of native CPP, may regulate theinflammatory potential of mineral nanoparticles and may thus be a key determinant ofcellular toxicity.Methods:We studied the ability of amorphous (CPP-I) and crystalline (CPP-II)serum-derived mineral nanoparticles to prime and activate the NLRP3 inflammasomein human macrophage derived from peripheral monocytes, and compared this to theeffect of synthetic hydroxyapatite nanocrystals and other known particulate/solubleinducers of the inflammasome platform.Results: Although CPP-I were rapidly internalised via class A scavengerreceptor-(SR-A)-mediated endocytosis, they failed to prime or activate theinflammasome even at high levels. In contrast, exposure of naïve cells to CPP-II,primed inflammatory cytokine synthesis through Toll-like receptor(TLR)-mediated/NF-κB-dependent signalling. Priming was potentiated byimmunochemical blockade of the SR-A. Endocytosis of CPP-II resulted inactivation of the NLRP3 inflammasome at very high levels through elevations inintracellular reactive oxygen species, calcium and cathepsin B release, secondary toendolysosomal destabilisation. Equivalent loads of synthetic hydroxyapatitenanocrystals induced greater release of IL-1β from macrophage, portending to aprotective role for mineral-binding proteins in this context. Importantly, fetuin-Awas found to inhibit cathepsin B activity and hence reveals one pathway throughwhich this mineral-binding protein might limit activation of intracellular dangersensors and unwanted inflammatory reactions in response to physiologic mineraldebris. Moreover, that CPP-II only activated the inflammasome at levels farexceeding than those detected in human serum suggests that such endogenousparticulates are unlikely to be potently pro-inflammatory.Conclusions: Fetuin-A limits mineral nanoparticle activation of the NLRP3inflammasome. Further work is needed to substantiate the involvement of nativeserum-derived mineral nanoparticles in the pathogenesis of inflammatory vasculardisease in vivo.© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.Nephrology Dialysis Transplantation 30 (Supplement 3): iii509–iii522, 2015doi:10.1093/ndt/gfv193.5

SP397FETUIN-A ATTENUATES MINERAL NANOPARTICLE ACTIVATION OF THE NLRP3 INFLAMMASOME IN THE HUMAN MACROPHAGE

http://doc.rero.ch/record/300887/files/gfv193.05.pdf

SP397FETUIN-A ATTENUATES MINERAL NANOPARTICLE ACTIVATION OF THE NLRP3 INFLAMMASOME IN THE HUMAN MACROPHAGE

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library