Extracellular ATP and P2Y Receptor Activation Induce a Proinflammatory Host Response in the Human Urinary Tract

Abstract

Extracellular ATP is released from a variety of cells not only as a consequence of cell injury or cell death but also via nonlytic mechanisms (25). ATP has attracted increasing attention as a danger signal released during the initial phase of infection and inflammation in order to trigger innate immunity (18). In a healthy bladder, release of ATP from uroepithelial cells by stretch and distension mediates the sensation of bladder fullness by activation of P2X 3 receptors on suburothelial sensory nerves (5). Pathophysiological conditions cause enhanced bladder release of ATP as shown in patients diagnosed with interstitial cystitis (29,30,31). Although several studies have shown that pathology often results in augmented ATP release from the urothelium, there have not been any studies of ATP release from urothelium infected with bacteria. Patients with bacteriuria have increased urinary levels of ATP (21), but it is not known whether the bacteria, host, or both produce ATP during infection. In their function as extracellular mediators, nucleotides activate P2 nucleotide receptors that include the ionotrophic P2X receptors (P2X 1 to P2X 7 ) and G-proteincoupled P2Y receptors (P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 to P2Y 14 ) (33). In the urinary tract, extracellular ATP may communicate through P2X and P2Y receptors with different cells, such as uroepithelial cells, inflammatory cells, nerves, and myofibroblasts (5). Evidence that P2 receptors, in particular P2Y receptors, may regulate host immunity and modulate phagocytosis, chemotaxis, and cytokine production is now accumulating (14, 16). The P2Y receptor subtypes P2Y 1 , P2Y 2 , and P2Y 4 are expressed throughout the cat bladder urothelium (7), but P2Y receptor expression has not been examined in the human urothelium.Innate immunity is the first line of defense in the urinary tract and triggered by uropathogenic bacteria through activation of Toll-like receptors (TLRs) located on the uroepithelial cell surface (32). Lipopolysaccharide (LPS) is an established ligand for Toll-like receptor 4 (TLR4), but associated coeffector proteins, such as CD14 and MD2, are needed for LPS-induced stimulation of TLR4 (4, 27). TLR4 and CD14 expression by the human urinary tract epithelium remains controversial (3,23,24), and in vitro studies show that the TLR4 receptor can be activated in a LPS-independent manner by P-fimbriated uropathogenic Escherichia coli (UPEC) (12). Once activated, the uroepithelial cells play a central role in the host proinflammatory response through production of chemotactic substances, such as interleukin 6 (IL-6) and IL-8. Several lines of evidence demonstrate that IL-8 is essential for neutrophil transmigration across the infected urothelium and that neutrophils are important for clearance of bacterial infections in the urinary tract (32).

[Ca2+] Oscillations and IL-6 Release Induced by α-Hemolysin from Escherichia coli Require P2 Receptor Activation in Renal Epithelia

“…Surprisingly, the HlyA-induced KC release did not require P2Y 2 receptor activation in murine ISOM. This is not immediately consistent with the clear P2Y receptor dependence of the HlyA-induced IL-8 release in cultured human uroepithelia (40). It must, however, be stressed that KC only is a homolog of IL-8 and its release may not be regulated completely similar to the human IL-8.…”

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

“…In addition, ATP and adenosine participates in inflammatory signaling [43]. ATP has been described as a pro-inflammatory molecule acting as a chemotactic signal to immune phagocytes [44,45] while adenosine has an immunosuppressive role Fig. 4 a The images correspond to immunofluorescent staining of ecto-5′-NT/CD73 in different times of bladder cancer induction.…”

Innate Immune Response to Urinary Tract Infections Involving Escherichia coli

“…This binding and activation induces production of interleukin-8 (IL-8) by the uroepithelial cells. Binding of IL-8, plus binding of ATP to P2Y receptors on the neutrophils is required for chemotaxis of the neutrophils [32][33][34].…”