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.

Macrophages participate in local and systemic inflammation induced by amorphous silica nanoparticles through intratracheal instillation

“…NLRP3 and IL-1β are the key molecules in the innate immune system to protect against foreign particles and promote the inflammatory response. [25][26][27] The NLRP3 inflammasome is a multiprotein platform that contains mainly the Nod-like receptor protein NLRP3, apoptosis-associated speck-like protein containing C-terminal caspase recruitment, and caspase-1. Once the NLRP3 inflammasome is active, the precursor IL-1β (31 kD) is cleaved to the mature type (17 kD).…”

Molybdenum disulfide/graphene oxide nanocomposites show favorable lung targeting and enhanced drug loading/tumor-killing efficacy with improved biocompatibility

“…Moreover, macrophages are a vital type of immune cells in recognizing and interacting with nanomaterials, which may further lead to phagocytosis and clearance of extraneous nanomaterials. 74,75 As shown in the TEM images (Figure 8), MoS 2 /GO manifested reduced capability to adsorb onto plasma membrane, associated with compromised phagocytosis, compared with GO. This finding thus implied less loss of drug delivered by MoS 2 /GO due to the clearance of macrophages, giving rise to enhanced capacity of MoS 2 /GO@DOX nanocomposites to kill tumor cells through this mechanism.…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…50 Nanoparticle-induced ATP release activates the NLRP3 inflammasome through interaction with adenosine receptors as well as cellular uptake by nucleoside transporters. 51 However, ATP-induced NLRP3 inflammasome activation is differentially regulated between dendritic cells and macrophages. In dendritic cells, stimulation with TLR ligands in the absence of ATP stimulation was sufficient to produce mature IL-1b.…”