Extracellular ATP drives systemic inflammation, tissue damage and mortality

A Cauwels,P Brouckaert,S Shiva,E Rogge,B Vandendriessche

doi:10.1038/cddis.2014.70

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-1β 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-1β 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.

Highlights

The inflammatory response following either infection or sterile tissue injury involves several types of pattern recognition receptors (PRR), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and C-type Lectin receptors (CLRs)
We found that removal of extracellular ATP by apyrase treatment prevented systemic IL-1b accumulation and precluded the induction of inflammasome-independent cytokines, such as TNF and IL-10, of mitochondrial damage, cellular disintegration, apoptotic death, intestinal injury and barrier breakdown, and subsequent mortality, in a murine model of LPS-induced shock
In contrast to other published studies, we chose to antagonize extracellular ATP signaling by removing extracellular ATP via apyrase treatment rather than using P2X7deficient mice or the currently available P2 receptor antagonists, because recent evidence excludes a crucial role for P2X7 in LPS-induced IL-1b production in vivo[17] and even suggests an important protective role for other P2X receptors.[19]

Summary

Introduction

The inflammatory response following either infection or sterile tissue injury involves several types of pattern recognition receptors (PRR), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and C-type Lectin receptors (CLRs). Sepsis was originally believed to be caused by the presence of bacteria in the blood, the clinical signs are frequently presented by patients without a detectable source of infection.[7] In addition, similar and overlapping signaling networks seem to be involved in propelling our body’s exaggerated and mortal response against both infectious and sterile inflammation.[8] various microbial components are recognized by PRRs, and many endogenous danger-associated molecular patterns (DAMPs), which are usually intracellular molecules that have reached the extracellular space, either actively or passively following cellular damage or death Our data suggest a key role for extracellular ATP in triggering various aspects of systemic inflammation and cellular and tissue damage during endotoxemia, which may be successfully and completely antagonized by ATP removal but not by broad-spectrum blocking of its P2 receptors

Methods

Results

Conclusion