Extracellular ATP drives systemic inflammation, tissue damage and mortality

Abstract

Systemic inflammatory response syndromes (SIRS) may be caused by both infectious and sterile insults, such as trauma, ischemia-reperfusion or burns. They are characterized by early excessive inflammatory cytokine production and the endogenous release of several toxic and damaging molecules. These are necessary to fight and resolve the cause of SIRS, but often end up progressively damaging cells and tissues, leading to life-threatening multiple organ dysfunction syndrome (MODS). As inflammasome-dependent cytokines such as interleukin-1b are critically involved in the development of MODS and death in SIRS, and ATP is an essential activator of inflammasomes in vitro, we decided to analyze the ability of ATP removal to prevent excessive tissue damage and mortality in a murine LPS-induced inflammation model. Our results indeed indicate an important pro-inflammatory role for extracellular ATP. However, the effect of ATP is not restricted to inflammasome activation at all. Removing extracellular ATP with systemic apyrase treatment not only prevented IL-1b accumulation but also the production of inflammasome-independent cytokines such as TNF and IL-10. In addition, ATP removal also prevented systemic evidence of cellular disintegration, mitochondrial damage, apoptosis, intestinal barrier disruption and even mortality. Although blocking ATP receptors with the broad-spectrum P2 purinergic receptor antagonist suramin imitated certain beneficial effects of apyrase treatment, it could not prevent morbidity or mortality at all. We conclude that removal of systemic extracellular ATP could be a valuable strategy to dampen systemic inflammatory damage and toxicity in SIRS.

Consensus guidelines for the detection of immunogenic cell death

“…141,[177][178][179] Moreover, extracellular ATP promotes the activation of the NLR family, pyrin domain containing 3 (NLRP3) inflammasome in APCs, hence stimulating the processing and release of interleukin (IL)-1b and IL-18. 119,[180][181][182][183][184][185][186][187][188][189] In line with this notion, the immunogenic potential of cells succumbing to ICD can be significantly reduced by pharmacological or genetic interventions that limit the availability of ATP in the pericellular space, such as the administration of recombinant apyrase (an ATP-degrading enzyme) or the transfection-enforced overexpression of ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, best known as CD39), which converts ATP into ADP and AMP. 190 Intriguingly, CD39 and 5 0 -nucleotidase, ecto (NT5E, best known as CD73), which transforms AMP into adenosine, are often overexpressed by malignant tissues.…”

Extracorporeal Photopheresis Promotes IL-1β Production

“…Because ATP does not act exclusively on the inflammasome but additionally has been reported to promote cellular damage via other pathways, one possible explanation could be that ATP removal via apyrase suppressed inhibitory or toxic by-products created by ECP (46).This activity may have improved cellular viability or the capacity to produce mature IL-1b.…”

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…Extracellular ATP was shown to drive systemic inflammation, tissue damage, and mortality not only by inflammasome-mediated cytokines, but also via inflammasome-independent mechanism in a model of systemic inflammatory response syndrome. 129 Energy depletion with loss of ATP potentially activates inflammasomes during stroke, but drop of tissue pH during ischemia may also contribute to inflammasome activation, as extra-and intracellular acidosis was recently demonstrated to activate NLRP3 inflammasome in vitro.…”