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The Role of P2X7R in Priming the NLRP3 Inflammasome after Mechanical Strain

The NLRP3 inflammasome is a cytosolic multiprotein complex whose activation results in the maturation and release of cytokine IL‐1β. There are two steps in inflammasome involvement; first the relevant proteins must be primed and upregulated on a transcriptional and translational level. Second, the proteins must be activated to assemble and process the maturation of caspase 1 and IL‐1β. The P2X7 receptor (P2X7R) is known to activate the NLRP3 inflammasome. However, it is currently unclear whether the P2X7R also plays a role in priming the inflammasome components. Rat optic nerve head astrocytes were swollen by 30% hypotonic solution for 4 hours then RNA was extracted. For in vivo experiments, we elevated intraocular pressure (IOP) moderately to 50–60 mmHg for 4 hours, with RNA extracted 24 hrs later. qPCR analysis was used to measure the expression of inflammasome related genes. Rat optic nerve head astrocytes release ATP when swollen. Swelling these cells for 4 hours upregulated mRNA for NLRP3 and IL‐1β but not caspase 1. This upregulation was inhibited by 4 μM Bay11‐7082 (NFκB inhibitor), implicating NFκB. Inhibiting the P2X7R with 10 μM Brilliant blue G (BBG), 50 nM A839977, or 5 μM A740003 prevented the swelling‐induced upregulation of IL‐1β but not NLRP3. In vivo, the expression of IL‐1β, NLRP3 and caspase 1 were all increased at the mRNA level in optic nerve head astrocytes of eyes subjected to moderate elevation of IOP. Intraocular injection of BBG prevented the rise in IL‐1β but not NLRP3. In conclusion, mechanical strain upregulates NLRP3 and IL‐1β mRNA via NFκB; but only the upregulation of IL‐1β required P2X7R stimulation.