title: Activation of P2X(7) receptor by ATP plays an important role in regulating inflammatory responses during acute viral infection.
abstract: Acute viral infection causes damages to the host due to uncontrolled viral replication but even replication deficient viral vectors can induce systemic inflammatory responses. Indeed, overactive host innate immune responses to viral vectors have led to devastating consequences. Macrophages are important innate immune cells that recognize viruses and induce inflammatory responses at the early stage of infection. However, tissue resident macrophages are not easily activated by the mere presence of virus suggesting that their activation requires additional signals from other cells in the tissue in order to trigger inflammatory responses. Previously, we have shown that the cross-talk between epithelial cells and macrophages generates synergistic inflammatory responses during adenoviral vector infection. Here, we investigated whether ATP is involved in the activation of macrophages to induce inflammatory responses during an acute adenoviral infection. Using a macrophage-epithelial cell co-culture system we demonstrated that ATP signaling through P2X(7) receptor (P2X(7)R) is required for induction of inflammatory mediators. We also showed that ATP-P2X(7)R signaling regulates inflammasome activation as inhibition or deficiency of P2X(7)R as well as caspase-1 significantly reduced IL-1β secretion. Furthermore, we found that intranasal administration of replication deficient adenoviral vectors in mice caused a high mortality in wild-type mice with symptoms of acute respiratory distress syndrome but the mice deficient in P2X(7)R or caspase-1 showed increased survival. In addition, wild-type mice treated with apyrase or inhibitors of P2X(7)R or caspase-1 showed higher rates of survival. The improved survival in the P2X(7)R deficient mice correlated with diminished levels of IL-1β and IL-6 and reduced neutrophil infiltration in the early phase of infection. These results indicate that ATP, released during viral infection, is an important inflammatory regulator that activates the inflammasome pathway and regulates inflammatory responses.
authors.affiliation: Research Institute, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: David M
authors.initials: DM
authors.lastname: Hwang
authors.forename: Nades
authors.initials: N
authors.lastname: Palaniyar
authors.forename: Sergio
authors.initials: S
authors.lastname: Grinstein
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D000256:Adenoviridae / Q000276:immunology*; D000257:Adenoviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D000818:Animals; D020170:Caspase 1 / Q000276:immunology; D061945:Caspase Inhibitors; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000821:virology; D007113:Immunity, Innate; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000150:complications / Q000276:immunology* / Q000821:virology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D020170:Caspase 1