Cutting Edge: Reactive Oxygen Species Inhibitors Block Priming, but Not Activation, of the NLRP3 Inflammasome

TLDR

The trigger for NLRP3 activation remains unclear, but ROS production has been proposed as a common upstream event. The study examined whether inhibiting ROS production or oxidative activity blocks NLRP3 activation. The authors tested ROS inhibitors that block ROS production or activity to assess their impact on NLRP3 priming and activation. ROS inhibition blocks the priming step required for NLRP3 activation but does not prevent activation once primed, indicating ROS acts upstream of induction but not activation.

Abstract

A common denominator among the multiple damage-inducing agents that ultimately lead to activation of NLRP3 has not yet been identified. Recently, production of reactive oxygen species (ROS) has been suggested to act as a common event upstream of the NLRP3 inflammasome machinery. Because de novo translation of NLRP3 is an essential step in the activation of NLRP3, we investigated the role of substances that inhibit either ROS production or its oxidative activity. Although we observe that NLRP3 inflammasome activation is unique among other known inflammasomes in its sensitivity to ROS inhibition, we have found that this phenomenon is attributable to the fact that NLRP3 strictly requires priming by a proinflammatory signal, a step that is blocked by ROS inhibitors. Although these data do not exclude a general role for ROS production in the process of NLRP3-triggered inflammation, they would put ROS upstream of NLRP3 induction, but not activation.