P2X7 receptor activation leads to NLRP3-independent IL-1β release by human macrophages

BackgroundThe purinergic receptor P2X7 plays a crucial role in infection, inflammation, and cell death. It is thought that P2X7 receptor stimulation triggers processing and release of the pro-inflammatory cytokine interleukin (IL)-1 beta by activation of the NLRP3 inflammasome; however, the underlying mechanisms remain poorly understood.MethodsModulation of IL-1 beta secretion was studied in THP-1 macrophages. Adenosine 5'-triphosphate (ATP), BzATP, nigericin and pharmacological inhibitors of P2X receptors, inflammatory caspases and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome were used to characterize signaling.ResultsIn primed macrophages, IL-1 beta release was increased after P2X7 receptor activation by ATP and 2,3-O-(4-benzoylbenzoyl)-ATP (BzATP). Pharmacological inhibition or genetic knockout of NLRP3 does not completely inhibit IL-1 beta release in TLR2/1-primed macrophages. Increase in extracellular K+ as well as inhibition of caspase-1 or serine proteases maintained IL-1 beta release in macrophages stimulated with P2X7 receptor agonists at 50%.ConclusionsOur findings suggest a previously unrecognized mechanism of P2X7 receptor mediated IL-1 beta release and highlight the existence of an NLRP3-independent pathway in human macrophages.4h-1gv1RJyWYx97JbdiPpXVideo AbstractConclusionsOur findings suggest a previously unrecognized mechanism of P2X7 receptor mediated IL-1 beta release and highlight the existence of an NLRP3-independent pathway in human macrophages.4h-1gv1RJyWYx97JbdiPpXVideo Abstract