EROS-mediated control of NOX2 and P2X7 biosynthesis

EROS (Essential for Reactive Oxygen Species) protein is indispensable for expression of the gp91phox-p22phox heterodimer of the phagocyte NADPH oxidase. EROS deficiency in humans causes the severe immunodeficiency, chronic granulomatous disease (CGD), but its mechanism of action remains unknown. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58kDa gp91phox directly, interacting with the OST glycosylation machinery and prevents gp91phox degradation. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions and P2X7 is almost absent in EROS deficiency. Accordingly, lack of EROS results in markedly abnormal P2X7 signalling, inflammasome activation and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, immunodeficiency and gene therapy.

Role of Purinergic Signaling in Acupuncture Therapeutics

Acupuncture is a therapeutic treatment that is well recognized in many countries. However, the initiation mechanisms of acupuncture are not well understood. Purinergic signaling has been considered a key signaling pathway in acupuncture in recent years. Acupuncture-induced ATP is mainly produced by mast cells and fibroblasts, and ATP is gradually hydrolyzed into adenosine. ATP and adenosine further participate in the process of acupuncture information transmission to the nervous and immune systems through specific purine receptors. Acupuncture initiates analgesia via the down-regulation of the expression of P2 receptors or up-regulation of the expression of adenosine A1 receptors on nerve fibers. ATP also promotes the proliferation of immune cells through P2 receptors and A3 receptors, causing inflammation. In contrast, adenosine activates A2 receptors, promotes the production and infiltration of immunosuppressive cells, and causes an anti-inflammatory response. In summary, we described the role of purinergic signaling as a general signaling pathway in the initiation of acupuncture and the influence of purinergic signaling on the neuroimmune network to lay the foundation for future systematic research on the mechanisms of acupuncture therapeutics.

ROLE OF PURINERGIC RECEPTORS IN IMMUNE RESPONSE

Purine receptors are located on immune and somatic cells of animal and human organisms. Summation of signals from purine and TOLL-like receptors takes place on the level of inflammasome formation and results in summation of the first and second signals of innate immunity. The first signal - from PAMPs (pathogen associated molecular patterns), the second - from DAMPs (danger associated molecular patterns). Adenosine triphosphate (ATP) is the most studied DAMP. ATP connects with purine receptors, which include P2 (P2X7 receptors are the best described), that results in opening of channels of these receptors and transit of ATP into the cell. In parallel exit of K+ from cells and entrance of Ca2+ and Na+ into the cells is observed, that is associated with activation of the immune competent cell. Damaged cells dying via necrosis or apoptosis are the source of extracellular ATP, as well as activated immunocytes. Signals from P2 and TOLL-like receptors are summarized in effectors of immune response, and activation of P2 receptors in lymphocytes makes a contribution into activation of cells, mediated by T-cell receptor. Negative side of purine receptor activation is a stimulating effect on proliferation and metastasis of malignant cells. The practical output of knowledge on functioning of purine receptors for clinical immunology is the application of agonists and antagonists of purine receptors, as well as explanation of effect of immune modulators from the position of launch of K+/Na+-pump, resulting in prolonged activation of immune competent cells.