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Purinergic Signaling and the Immune Response in Sepsis: A Review - PubMed

Review

Purinergic Signaling and the Immune Response in Sepsis: A Review

Carola Ledderose et al. Clin Ther. 2016 May.

Abstract

Purpose: Sepsis remains an unresolved clinical problem with high in-hospital mortality. Despite intensive research over decades, no treatments for sepsis have become available. Here we explore the role of 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 function. 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 is released in large amounts into the extracellular space where it 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 past 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 in the treatment of 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 the pathophysiologic processes involved in sepsis.

Implications: The knowledge of these ATP-dependent signaling processes is likely to reveal exciting new avenues in the treatment of the unresolved clinical problem of sepsis.

Keywords: ATP; adenosine; purinergic signaling; sepsis.

Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

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Figures

Figure 1
Figure 1. Elements of the autocrine purinergic signaling mechanisms in immune cells.

Stimulation of specific surface receptors of immune cells that recognize pathogens, antigens, cytokines, or chemokines triggers mitochondrial ATP formation and ATP release through pannexin-1 (panx1) channels. ATP in the extracellular space can stimulate P2X or P2Y receptors. Ectonucleotidases such as CD39 or CD73 catalyze the stepwise hydrolysis of ATP to ADP (the ligand of certain P2Y receptors), AMP, and adenosine, which is the ligand of P1 (adenosine) receptors. Adenosine is removed by nucleoside transporters (NT) that facilitate the cellular uptake of adenosine or by adenosine deaminase (ADA) that converts adenosine to inosine.

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