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

By C. Cruz, A. Rinna, H. Forman, A. Ventura, P. Persechini, D. Ojcius. Journal of Biological Chemistry, 2007

781 citations recorded by the source corpus.

Secretion of the proinflammatory cytokines, interleukin (IL)-1β 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-1β 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.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/b7b5fdc99c4cfea7bad1a4cb63137fb85a652fa1

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Citations in the corpus

The inflammasomes: guardians of the body. (2009, background): “Potassium efflux, the induction of frustrated phagocytosis, and ROS production are the most striking features associated with NALP3 activators (127).”
The Inflammasome: A Caspase-1 Activation Platform Regulating Immune Responses and Disease Pathogenesis (2009, background): “Indeed, involvement of reactive oxygen species, calcium-independent phospholipase A 2 and cathepsin B is proposed for activation of the NLRP3 inflammasom”
Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “Nearly all NLRP3 agonists induce and require ROS for activation (56, 57, 99, 100).”
Redox Regulation of NLRP3 Inflammasomes: ROS as Trigger or Effector? (2015, positive): “Some of the very early inflammasome studies reported the importance of NADPH oxidase-derived ROS in activating NLRP3 in response to ATP, asbestos, and silica (28, 33, 51).”
Mitochondria in the regulation of innate and adaptive immunity (2015, positive): “Pharmacologic and genetic inhibition of the enzyme acetyl-CoA carboxylase 1 (ACC1), the enzyme that catalyzes the first step of de novo fatty-acid synthesis, impaired Th17 cell differentiation, and promoted Tregs in vitro and in vivo, as well as attenuated EAE in mice (Berod et al., 2014).”
The adapter MAVS promotes NLRP3 mitochondrial localization and inflammasome activation (2013, positive): “The induced ROS is presumed to lead to the generation of a potential ligand of NLRP3 or to modify NLRP3 or associated proteins directly (Zhou et al., 2010).”
Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation (2013, background): “Interruption of ROS production with pharmacological inhibitors blocks activation of the Nlrp3 inflammasome, suggesting that the generation of ROS is a required upstream event for Nlrp3 activation (Cassel et al., 2008; Cruz et al., 2007; Dostert et al., 2008; Pétrilli et al., 2007; Zhou et al., 2011)”
Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration (2007, background): “Although the pathway connecting ROS to inflammasome activation remains unknown, a downstream role of MAPK (p38 or ERK) was suggested.(29,37) Additional work is also required for the elucidation of the link between low Kþ and ROS.”
Signaling Functions of Reactive Oxygen Species (2010, background): “There is an increasing number of proteins that appear to form a protein-glutathione mixed disulfide under physiological conditions, including PTP1B (71), cytosolic NADPþ-dependent isocitrate dehydrogenase (72), the yeast 20S proteasome (73), ryanodine receptor type 1 (74), signal transducer and acti”
Autophagy proteins regulate innate immune response by inhibiting NALP3 inflammasome-mediated mitochondrial DNA release (2010, positive): “The production of mitochondrial ROS was probably a consequence of ATP-driven activation of the P2X7 recepto”
Reactive oxygen species and mitochondria: A nexus of cellular homeostasis (2015, background): “Initial studies focused on NOX2 as the relevant ROS source: inhibition or knockdown of NOX2 were found to block IL-1β secretion in response to NLRP3 stimuli [105,109,131].”
The Nalp3 inflammasome is essential for the development of silicosis (2008, background): “The Nalp3 inflammasome activator ATP has been shown to be capable of inducing the production of ROS, which are important for caspase-1 activation (23).”
Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines (2018, background): “The NLRP3 is a major inflammasome sensor for intracellular stress molecules called DAMPs, which together with damaged aggregated proteins that are released from destabilized lysosomes and damaged mitochondria contribute to the cellular stress (ROS) and trigger NLRP3 activation (129).”