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The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine
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Journal Article
The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine
2015
Overview
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-SiO
2
) and titanium dioxide (nano-TiO
2
) 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-SiO
2
or nano-TiO
2
caused a significant increase in P2Y1, P2Y2, A2
A
and/or A2
B
receptor expression, whereas the P2X7 receptor was downregulated. Interestingly, IL-1
β
secretion in response to nanoparticles is increased by enhanced ATP and ADP hydrolysis, whereas it is decreased by adenosine degradation or selective A2
A
or A2
B
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-1
β
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/21
/ 64
/ 64/60
/ Adenosine Diphosphate - pharmacology
/ Adenosine Triphosphate - pharmacology
/ Adenylyl Cyclases - metabolism
/ Animals
/ Biomedical and Life Sciences
/ Carrier Proteins - metabolism
/ Humans
/ Inositol Phosphates - metabolism
/ Interleukin-1beta - secretion
/ Nerve Tissue Proteins - metabolism
/ NLR Family, Pyrin Domain-Containing 3 Protein
/ Original
/ Receptors, Purinergic P1 - metabolism
/ Receptors, Purinergic P2Y - metabolism
/ Signal Transduction - drug effects
