Differential role of the pannexin-1/ATP/P2X7 axis in IL-1β release by human monocytes

Abstract

IL - 1 β release is integral to the innate immune system. The release of mature IL - 1 β depends on two regulated events; (i) the de novo induction of pro - IL - 1 β , generally via NF κ B - depend ent transduction pathways and (ii) the assembly and activation of the NLRP3 inflammasome . This latter step is reliant on active capase - 1, pannexin - 1 and P2X 7 receptor activation. Pathogen associated molecular patterns in Gram - positive and Gram - negative bacteria activate IL - 1 β release from immun e cells via TLR2 and TLR4 receptors respectively. Here , we show that pro - IL - 1 β and mature IL - 1 β release from human monocytes is stimulated by the TLR2 agonists , Pam 3 CSK4 or FSL - 1 , and the TLR4 agonist , LPS , in the absence of additional ATP . TLR2 agonists r equired pannexin - 1 and P2X 7 receptor activation to stimulate IL - 1 β release . By contrast, IL - 1 β release stimulated by the TLR4 agonist , LPS , is independent of both pannexin - 1 and P2X 7 activation. In the absence of exogenous ATP , P2X 7 activation requires endogenous ATP release, which occurs in some cells via pannexin - 1. In line with this , we found that LPS - stimulated human monocytes released relatively low levels of ATP , whereas cells stimulated with TLR2 agonists released high levels of ATP. These finding s suggest that , in human monocytes , TLR2 and TLR4 signalling both induce pro - IL - 1 β expression , but the mechanism by which they activate caspase - 1 diverges at the level of the pannexin - 1/ATP/P2X 7 axis.