ATP Activates a Reactive Oxygen Species-dependent Oxidative Stress Response and Secretion of Proinflammatory Cytokines in Macrophages

TLDR

Secretion of IL‑1β and IL‑18 requires two signals: microbial products trigger transcription and precursor accumulation, while ATP binding to purinergic receptors activates the Nalp3 inflammasome and caspase‑1 for cytokine cleavage and release. ROS inactivates PTEN by glutathionylation, thereby favoring PI3K signaling. ATP induces ROS that activates PI3K/Akt/ERK1/2, leading to oxidative‑stress gene transcription and caspase‑1 activation, which together promote IL‑1β and IL‑18 secretion and prime macrophages for subsequent oxidative or inflammatory challenges.

Abstract

Secretion of the proinflammatory cytokines, interleukin (IL)-1beta and IL-18, usually requires two signals. The first, due to microbial products such as lipopolysaccharide, initiates transcription of the cytokine genes and accumulation of the precursor proteins. Cleavage and secretion of the cytokines is mediated by caspase-1, in association with an inflammasome containing Nalp3, which can be activated by binding of extracellular ATP to purinergic receptors. We show that treatment of macrophages with ATP results in production of reactive oxygen species (ROS), which stimulate the phosphatidylinositol 3-kinase (PI3K) pathway and subsequent Akt and ERK1/2 activation. ROS exerts its effect through glutathionylation of PTEN (phosphatase and tensin homologue deleted from chromosome 10), whose inactivation would shift the equilibrium in favor of PI3K. ATP-dependent ROS production and PI3K activation also stimulate transcription of genes required for an oxidative stress response. In parallel, ATP-mediated ROS-dependent PI3K is required for activation of caspase-1 and secretion of IL-1beta and IL-18. Thus, an increase in ROS levels in ATP-treated macrophages results in activation of a single pathway that promotes both adaptation to subsequent exposure to oxidants or inflammation, and processing and secretion of proinflammatory cytokines.