Purinergic Signaling and the Immune Response in Sepsis: A Review

Abstract

Purpose Sepsis remains an unresolved clinical problem with high hospital mortality. Despite intensive research over decades, no treatments for sepsis have become available. Here we explore the role of adenosine triphosphate (ATP) in the pathophysiology of sepsis. ATP is not only a universal energy carrier but it also acts as an extracellular signaling molecule that regulates immune functions. ATP stimulates a large family of purinergic receptors found on the cell surface of virtually all mammalian cells. In severe sepsis and septic shock, ATP released in large amounts into the extracellular space acts as a “danger signal”. In this review, we focus on the roles of ATP as a key regulator of immune cell function and as a disruptive signal that contributes to immune dysfunction in sepsis. Methods We summarized the current understanding of the pathophysiology of sepsis with special emphasis on the emerging role of systemic ATP as a disruptive force that promotes morbidity and mortality in sepsis. Findings Over the last two decades, the discovery that regulated ATP release and purinergic signaling represent a novel regulatory mechanism in immune cell physiology has opened up new possibilities to treat sepsis. Immune cells respond to stimulation with the release of cellular ATP, which regulates cell functions in autocrine and paracrine fashions. In sepsis, large amounts of systemic ATP produced by tissue damage and inflammation disrupt these regulatory purinergic signaling mechanisms, leading to immune dysfunction that promotes pathophysiological processes involved in sepsis. Implications The knowledge of these ATP-dependent signaling processes is likely to reveal exciting new avenues to treat the unresolved clinical problem of sepsis.

Immunometabolic approaches to prevent, detect, and treat neonatal sepsis

“…Adenosine levels rise rapidly in response to systemic inflammation to reduce pro-inflammatory/Th1-polarizing immune responses. Both ATP and adenosine bind to purinergic receptors, so the overall inflammatory effect of ATP on the biological system depends on the balance between ATP and adenosine [26]. Interestingly, levels of adenosine are significantly higher in neonatal compared to adult plasma, contributing to Th2 polarization of Toll like Receptor (TLR)-mediated responses [27,28].…”

Immune recovery after fluid resuscitation in rats with severe hemorrhagic shock

“…Indeed previous studies have shown that HTS resuscitation can reduce the injury to lungs and intestinal mucosa after hemorrhagic shock (Fernandes et al, 2009;Gao et al, 2009;Lu et al, 2010). The proposed mechanism by which HTS can mediate these effects is by shrinking cells and mechanically altering membranes, resulting in the release of ATP and promotion of T-cell function (Loomis et al, 2003;Woehrle et al, 2010;Ledderose et al, 2016). Whether a similar mechanism is involved in the effect on Tregs in our rat hemorrhagic shock model requires further research.…”

Purinergic Regulation of Basic Physiological and Pathological Processes

“…Они перемещаются в иммунные синапсы, где высвобождают АТФ, который при помощи P2X1-и P2X4-рецепторов активирует аутокринные пуринергические сигнальные механизмы в синаптической щели [61]. Более того, именно эти рецепторы регулируют приток ионов кальция, так как способны функционировать в качестве кальциевых каналов [60,108]. Также было показано, что АТФ ускоряет активацию Т-клеток путем усиления TCRопосредованной (от англ.…”