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

IL-1β release is integral to the innate immune system. The release of mature IL-1β depends on 2 regulated events: the de novo induction of pro-IL-1β, generally via NF-κB-dependent transduction pathways; and the assembly and activation of the NLRP3 inflammasome. This latter step is reliant on active caspase-1, pannexin-1, and P2X₇ receptor activation. Pathogen-associated molecular patterns in gram-positive and gram-negative bacteria activate IL-1β release from immune cells via TLR2 and TLR4 receptors, respectively. We found that pro-IL-1β and mature IL-1β release from human monocytes is stimulated by the TLR2 agonists Pam₃CSK4 or FSL-1, as well as the TLR4 agonist LPS in the absence of additional ATP. TLR2 agonists required pannexin-1 and P2X₇ receptor activation to stimulate IL-1β release. In contrast, IL-1β release stimulated by the TLR4 agonist LPS is independent of both pannexin-1 and P2X₇ activation. In the absence of exogenous ATP, P2X₇ 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 findings suggest that in human monocytes, both TLR2 and TLR4 signaling induce pro-IL-1β expression, but the mechanism by which they activate caspase-1 diverges at the level of the pannexin-1/ATP/P2X₇ axis.-Parzych, K., Zetterqvist, A. V., Wright, W. R., Kirkby, N. S., Mitchell, J. A., Paul-Clark, M. J. Differential role of pannexin-1/ATP/P2X₇ axis in IL-1β release by human monocytes.