title: The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine.
abstract: The NLR pyrin domain containing 3 (NLRP3) inflammasome is a major component of the innate immune system, but its mechanism of activation by a wide range of molecules remains largely unknown. Widely used nano-sized inorganic metal oxides such as silica dioxide (nano-SiO2) and titanium dioxide (nano-TiO2) activate the NLRP3 inflammasome in macrophages similarly to silica or asbestos micro-sized particles. By investigating towards the molecular mechanisms of inflammasome activation in response to nanoparticles, we show here that active adenosine triphosphate (ATP) release and subsequent ATP, adenosine diphosphate (ADP) and adenosine receptor signalling are required for inflammasome activation. Nano-SiO2 or nano-TiO2 caused a significant increase in P2Y1, P2Y2, A2A and/or A2B receptor expression, whereas the P2X7 receptor was downregulated. Interestingly, IL-1β secretion in response to nanoparticles is increased by enhanced ATP and ADP hydrolysis, whereas it is decreased by adenosine degradation or selective A2A or A2B receptor inhibition. Downstream of these receptors, our results show that nanoparticles activate the NLRP3 inflammasome via activation of PLC-InsP3 and/or inhibition of adenylate cyclase (ADCY)-cAMP pathways. Finally, a high dose of adenosine triggers inflammasome activation and IL-1β secretion through adenosine cellular uptake by nucleotide transporters and by its subsequent transformation in ATP by adenosine kinase. In summary, we show for the first time that extracellular adenosine activates the NLRP3 inflammasome by two ways: by interacting with adenosine receptors at nanomolar/micromolar concentrations and through cellular uptake by equilibrative nucleoside transporters at millimolar concentrations. These findings provide new molecular insights on the mechanisms of NLRP3 inflammasome activation and new therapeutic strategies to control inflammation.
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: L
authors: L
authors: Baron
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: A
authors: A
authors: Gombault
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: M
authors: M
authors: Fanny
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: B
authors: B
authors: Villeret
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: F
authors: F
authors: Savigny
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: N
authors: N
authors: Guillou
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: C
authors: C
authors: Panek
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: M
authors: M
authors: Le Bert
authors: INSERM U991, University of Rennes, France.
authors: V
authors: V
authors: Lagente
authors: IGF, CNRS, UMR 5203 and INSERM U661, University of Montpellier, France.
authors: F
authors: F
authors: Rassendren
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: N
authors: N
authors: Riteau
authors: INEM, CNRS, UMR7355, University of Orleans, France.
authors: I
authors: I
authors: Couillin
mesh_terms: D000241:Adenosine / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D017630:Connexins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053758:Nanoparticles / Q000737:chemistry*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011014:Pneumonia / Q000473:pathology; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D058470:Receptors, Purinergic P2Y / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000494:pharmacology; D014025:Titanium / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D017630:Connexins; D058847:Inflammasomes; D007295:Inositol Phosphates; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009419:Nerve Tissue Proteins; D018047:Receptors, Purinergic P1; D058470:Receptors, Purinergic P2Y; C009495:titanium dioxide; C052128:inositol 3-phosphate; D000244:Adenosine Diphosphate; D012822:Silicon Dioxide; D000255:Adenosine Triphosphate; D014025:Titanium; D000242:Cyclic AMP; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D000241:Adenosine
references: J Clin Invest. 2006 Aug;116(8):2173-2182
references: 16841096
references: Science. 2006 Dec 15;314(5806):1792-5
references: 17170310
references: Prog Biophys Mol Biol. 2007 May-Jun;94(1-2):120-43
references: 17470375
references: J Immunol. 2007 Jun 15;178(12):8127-37
references: 17548651
references: J Clin Invest. 2007 Dec;117(12):3786-99
references: 17992263
references: Adv Drug Deliv Rev. 2008 Apr 29;60(7):830-40
references: 18280002
references: Nat Nanotechnol. 2009 Dec;4(12):876-83
references: 19893513
references: J Immunol. 2009 Dec 15;183(12):8195-202
references: 20007584
references: Am J Respir Cell Mol Biol. 2010 May;42(5):564-71
references: 19556606
references: Iran J Allergy Asthma Immunol. 2010 Mar;9(1):7-12
references: 20548128
references: J Clin Immunol. 2010 Sep;30(5):623-7
references: 20582456
references: Eur Respir J. 2011 Feb;37(2):299-309
references: 20530043
references: J Neurochem. 2011 Sep;118(5):826-40
references: 21294731
references: Chest. 2011 Oct;140(4):954-60
references: 21454402
references: Acta Pharmacol Sin. 2012 Mar;33(3):342-50
references: 22367283
references: Purinergic Signal. 2012 Sep;8(3):419-36
references: 22371149
references: Am J Respir Cell Mol Biol. 2012 Nov;47(5):604-13
references: 22744860
references: Nature. 2012 Dec 6;492(7427):123-7
references: 23143333
references: N Engl J Med. 2012 Dec 13;367(24):2322-33
references: 23234515
references: J Mol Med (Berl). 2013 Feb;91(2):173-81
references: 23340998
references: Biomaterials. 2013 May;34(14):3559-70
references: 23433773
references: Mol Aspects Med. 2013 Apr-Jun;34(2-3):529-47
references: 23506887
references: Nat Rev Drug Discov. 2013 Apr;12(4):265-86
references: 23535933
references: Trends Mol Med. 2013 Jun;19(6):355-67
references: 23601906
references: Blood. 2013 Sep 12;122(11):1935-45
references: 23908469
references: PLoS One. 2013;8(10):e76731
references: 24098558
references: Nat Commun. 2013;4:2909
references: 24352507
references: Adv Exp Med Biol. 2000;486:57-63
references: 11783528
references: Eur Respir J. 2000 Jun;15(6):1046-51
references: 10885423
references: Nat Immunol. 2014 Aug;15(8):738-48
references: 24952504
references: Eur Respir J. 2002 Dec;20(6):1393-8
references: 12503694
references: J Biol Chem. 2003 Jun 27;278(26):23331-42
references: 12684505
references: Pflugers Arch. 2004 Feb;447(5):735-43
references: 12838422
references: Mol Med. 1996 Mar;2(2):247-55
references: 8726467
references: J Clin Invest. 2005 Jan;115(1):35-43
references: 15630442
references: J Immunol. 2005 Aug 1;175(3):1937-46
references: 16034138