title: P2X4 receptors influence inflammasome activation after spinal cord injury.
abstract: P2X(4) and P2X(7) are the predominant purinergic P2X receptor subtypes expressed on immune and neural cells. These receptor subtypes traffic between intracellular compartments and the plasma membrane and form protein interactions with each other to regulate ATP-dependent signaling. Our recent studies have shown that P2X(7) receptors in neurons and astrocytes activate NLRP1 inflammasomes, but whether P2X(4) receptors regulate inflammasome signaling is essentially unknown. Here, we demonstrate that P2X(4) receptors are expressed in neurons of the spinal cord. We provide direct evidence that spinal cord injury (SCI) induces an innate inflammatory response that leads to increased caspase-l cleavage and production of IL-1β but not IL-18. Consistent with these findings, P2X(4) knock-out mice showed impaired inflammasome signaling in the cord, resulting in decreased levels of IL-1β and reduced infiltration of neutrophils and monocyte-derived M1 macrophages, resulting in significant tissue sparing and improvement in functional outcomes. These results indicate that P2X(4) receptors influence inflammasome signaling involving caspase-1 activation and IL-1β processing in neurons after SCI. P2X(4) might thus represent a potential therapeutic target to limit inflammatory responses associated with SCI and neurodegenerative disorders.
authors.affiliation: The Miami Project to Cure Paralysis, Miami, Florida 33136, USA.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: de Rivero Vaccari
authors.forename: Dominic
authors.initials: D
authors.lastname: Bastien
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yurcisin
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pineau
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.forename: Yves
authors.initials: Y
authors.lastname: De Koninck
authors.forename: Robert W
authors.initials: RW
authors.lastname: Keane
authors.forename: Steve
authors.initials: S
authors.lastname: Lacroix
mesh_terms: D000818:Animals; D005260:Female; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D008262:Macrophage Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000473:pathology; D020556:Neutrophil Infiltration / Q000502:physiology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D058848:Receptors, Purinergic P2X4