Purinergic regulation of inflammasome activation after central nervous system injury

The body's response to immune challenges and tissue damage involves a complex inflammatory process. The innate immune system acts as the initial barrier that protects from infectious agents and also senses endog-enous danger molecules released after traumatic insults to mediate the response to injury. This latter role is particularly important in the central nervous system (CNS), where challenges like trauma, ischemia, or pathological neurodegeneration must be promptly contained. However , overactivation of the neuroinflammatory response can trigger deleterious effects and worsen the functional outcome of the injury, a process often observed after spinal cord injury (SCI) and stroke, as well as in neuropathic and inflammatory pain pathologies (Rice et al., 2007; Scholz and Woolf, 2007). Many pathological neuroinflammatory reactions are characterized by increased production of the proin-flammatory cytokine interleukin-1 (IL-1). Although the involvement of IL-1 in CNS injury pathologies is widely accepted, the mechanisms behind its formation and release are incompletely understood. The inflam-masome is emerging as the major determinant in the formation of mature IL-1, which undergoes proteo-lytic processing from its immature pro–IL-1 form by the protease caspase-1 (Gross et al., 2011). Inflamma-somes are multi-protein complexes formed of NOD-like receptor proteins (NLRPs) that act as scaffolds for the caspases necessary for cytokine processing. Of the several classes of inflammasomes that exist, both the NLRP1-and NLRP3-containing subfamilies assemble with caspase-1 to process IL-1. Because of its role in IL-1 maturation, activation of the inflammasome is critical to the induction of neuroinflammatory cascades. NLRP inflammasomes are activated by recognizing pathogen-associated molecular patterns or, in the case of endogenous signals released after injury, danger-associated molecular patterns. Among the many host-derived molecules that activate inflammasomes, ATP potently induces NLRP1-and NLRP3-mediated IL-1 processing. ATP is released or leaked from damaged cells after trauma, and the subsequent increase in extracellular levels of ATP is thought to play a major role in triggering the neuroinflamma-tory response in the CNS (Burnstock, 2008). However, the mechanism linking extracellular ATP to inflamma-some activation to IL-1 release in CNS pathologies is unresolved. A recent report by de Rivero Vaccari et al. (2012) addresses several unanswered questions, including the cellular source of IL-1 in SCI models as well as the identity of the ATP receptor involved. Specifically, their results indicate a neuronal contribution to IL-1 release in the SCI response and implicate the P2X4 pu-rinergic receptor in this system. Here, I discuss both of these results in light of previous work, …