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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 ATPdependent 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

Spinal cord injury (SCI) causes the release of danger signals by stressed and dying cells, a process that leads to neuroinflammation.Evidence suggests that inflammation plays a role in both the damage and repair of injured neural tissue. We show that microglia at sites of SCI rapidly express the alarmin interleukin (IL)-1␣, and that infiltrating neutrophils and macrophages subsequently produce IL-1␤. Infiltration of these cells is dramatically reduced in both IL-1␣Ϫ / Ϫ and IL-1␤ Ϫ / Ϫ mice, but only IL-1␣ Ϫ / Ϫ mice showed rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume. Similarly, intrathecal administration of the IL-1 receptor antagonist anakinra restored locomotor function post-SCI. Transcriptome analysis of SCI tissue at day 1 identified the survival factor Tox3 as being differentially regulated exclusively in IL-1␣ Ϫ / Ϫ mice compared with IL-1␤ Ϫ / Ϫ and wild-type mice. Accordingly, IL-1␣Ϫ / Ϫ mice have markedly increased Tox3 levels in their oligodendrocytes, beginning at postnatal day 10 (P10) and persisting through adulthood. At P10, the spinal cord of IL-1␣ Ϫ / Ϫ mice showed a transient increase in mature oligodendrocyte numbers, coinciding with increased IL-1␣ expression in wild-type animals. In adult mice, IL-1␣ deletion is accompanied by increased oligodendrocyte survival after SCI. TOX3 overexpression in human oligodendrocytes reduced cellular death under conditions mimicking SCI. These results suggest that IL-1␣-mediated Tox3 suppression during the early phase of CNS insult plays a crucial role in secondary degeneration.

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